Renal Insufficiency
Conditions
Brief summary
The purpose of this open-label, 2-period, fixed-sequence study is to characterize the plasma pharmacokinetic profiles of midazolam, dabigatran, pitavastatin, atorvastatin, and rosuvastatin following a single oral dose administration of a microdose cocktail in healthy participants, in participants with mild, moderate, severe (not on dialysis) renal impairment, and in participants with end-stage renal disease (ESRD; on dialysis).
Interventions
Midazolam hydrochloride 10 μg (1 mL of 10 μg/mL oral solution), administered orally as part of a microdose cocktail
DRUGDabigatran and pitavastatin oral solution
375/10 μg dabigatran etexilate and pitavastatin (1 mL of 375/10 μg/mL oral solution), administered orally as part of a microdose cocktail
DRUGAtorvastatin and rosuvastatin oral solution
100/50 μg atorvastatin and rosuvastatin (2 mL of 50/25 μg/mL oral solution), administered orally as part of a microdose cocktail
DRUGRifampin
Rifampin 600 mg single dose (two 300 mg capsules) administered orally
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 78 Years
Healthy volunteers
Yes
Inclusion criteria
All participants (with mild, moderate or severe renal impairment, end stage renal disease, or healthy): * a female must be non-pregnant, non-breast feeding and if she is of reproductive potential: must agree to use (and/or have their partner use) two acceptable methods of birth control beginning at screening, throughout the study and until 2 weeks after the last dosing of study drug * a female of non-childbearing potential: must have undergone a sterilization procedure at least 6 months prior to the first dose or be postmenopausal with amenorrhea for at least 1 year prior to the first dose * a non-vasectomized male participant must agree to use a condom with spermicide or abstain from sexual intercourse from the first dose until 90 days after the last dose of study drug * a male participant must agree not to donate sperm from dosing until 90 days after the last dose of study drug * has a body mass index (BMI) ≤ 40.0 kg/m\^2 * is a non-smoker or moderate smoker (≤ 20 cigarettes/day or the equivalent) Participants with mild, moderate or severe renal impairment or end stage renal disease: * has a clinical diagnosis of renal impairment and meets the protocol-specified renal impairment function qualifications at the prestudy visit (screening) Healthy participants: * has baseline creatinine clearance ≥ 90 mL/min based on Cockcroft-Gault equation * is judged to be in good health based on medical history, physical examination, vital signs, pulse oximetry, and laboratory safety tests
Exclusion criteria
All participants (with mild, moderate or severe renal impairment, end stage renal disease, or healthy): * is mentally or legally incapacitated or has significant emotional problems at the time of the screening visit or expected during the conduct of the study. * history or presence of clinically significant medical or psychiatric condition or disease * history of stroke, chronic seizures, or major neurological disorders * history of malignant neoplastic disease * history or presence of alcoholism or drug abuse within the past 6 months * female participant who is pregnant or lactating Participants with mild, moderate or severe renal impairment: * has had a renal transplant or has had nephrectomy * has uncontrolled type 2 diabetes mellitus (T2DM), a history of Type 1 diabetes, or ketoacidosis * history of significant endocrine, gastrointestinal, cardiovascular, hematological, immunological, respiratory, or genitourinary diseases Participants with end stage renal disease (ESRD): * had a failed renal allograft within the last 2 years prior to the first dose, or a successful renal allograft * has uncontrolled T2DM, a history of Type 1 diabetes, or ketoacidosis * history of significant endocrine, gastrointestinal, cardiovascular, hematological, immunological, respiratory, or genitourinary diseases Healthy participants: * history of hypoglycemia, glucose intolerance, T2DM, or ketoacidosis * history of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, or genitourinary abnormalities or diseases.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1 | 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose | Vz/F is the distribution of study drug between the plasma and the rest of the body after the dose. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail in healthy participants, participants with renal impairment, and 24 hours prior to hemodialysis in participants with end-stage renal disease requiring hemodialysis. Vz/F was to be calculated for the parent plasma analytes only, midazolam, dabigatran, pitavastatin, atorvastatin, and rosuvastatin. |
| Effect of Rifampin on AUC0-inf Post-dose Period 2 | Microdose cocktail: 0 hour (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose; rifampin: 0 hour (pre-dose) and 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose | To evaluate the effect of a single oral dose of rifampin on the AUC0-inf of midazolam, dabigatran, pitavastatin, pitavastatin lactone, atorvastatin, ortho-hydroxyatorvastatin, and rosuvatatin. AUC0-inf is the area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail and rifampin in healthy participants and participants with renal impairment. As pre-specified in the protocol, this outcome measure does not include data from the end-stage renal disease participants as they did not receive rifampin during Period 2. |
| Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | 0 hour (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post-dose | AUC0-24 is the area under the plasma concentration-time curve from time 0 to 24 hours post-dose. This is a measure of the average amount of study drug in the blood plasma over a period of 24 hours after the dose. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail in healthy participants, participants with renal impairment, and 24 hours prior to hemodialysis in participants with end-stage renal disease requiring hemodialysis. |
| Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | 0 hour (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose | AUC0-last is the area under the plasma concentration-time curve from time zero to time of last measurable concentration. This is a measure of the amount of study drug in the blood plasma from pre-dose until the last measurable concentration of study drug could be determined. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail in healthy participants, participants with renal impairment, and 24 hours prior to hemodialysis in participants with end-stage renal disease requiring hemodialysis. |
| Maximum Plasma Concentration (Cmax) Post-dose Period 1 | 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose | Cmax is the peak plasma concentration of study drug after administration. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail in healthy participants, participants with renal impairment, and 24 hours prior to hemodialysis in participants with end-stage renal disease requiring hemodialysis. |
| Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | 24 hours post-dose | C24hr is a measure of the plasma study drug concentration 24 hours post-dose. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail in healthy participants, participants with renal impairment, and 24 hours prior to hemodialysis in participants with end-stage renal disease requiring hemodialysis. |
| Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose | Tmax is the amount of time to reach maximum (peak) plasma drug concentration following drug administration. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail in healthy participants, participants with renal impairment, and 24 hours prior to hemodialysis in participants with end-stage renal disease requiring hemodialysis. |
| Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose | T1/2 is the elimination half-life of study drug. T1/2 is the time it takes for half of the study drug in the blood plasma to dissipate. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail in healthy participants, participants with renal impairment, and 24 hours prior to hemodialysis in participants with end-stage renal disease requiring hemodialysis. |
| Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1 | 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose | CL/F is the rate at which study drug was removed from the body. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail in healthy participants, participants with renal impairment, and 24 hours prior to hemodialysis in participants with end-stage renal disease requiring hemodialysis. CL/F was to be calculated for the parent plasma analytes only, midazolam, dabigatran, pitavastatin, atorvastatin, and rosuvastatin. |
| Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | 0 hour (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose | AUC0-inf is the area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail in healthy participants, participants with renal impairment, and 24 hours prior to hemodialysis in participants with end-stage renal disease (ESRD) requiring hemodialysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Rifampin on AUC0-last Post-dose Period 2 | Microdose cocktail: 0 hour (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose; rifampin: 0 hour (pre-dose) and 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose | To evaluate the effect of a single oral dose of rifampin on the AUC0-last of midazolam, dabigatran, pitavastatin, pitavastatin lactone, atorvastatin, ortho-hydroxyatorvastatin, and rosuvatatin. AUC0-last is the area under the plasma concentration-time curve from time zero to time of last measurable concentration. It is a measure of the amount of study drug in the blood plasma from pre-dose until the last measurable concentration of study drug could be determined. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail and rifampin in healthy participants and participants with renal impairment. As pre-specified in the protocol, this outcome measure does not include end-stage renal disease participants as they did not receive rifampin during Period 2. |
| Effect of Rifampin on Cmax Post-dose Period 2 | Microdose cocktail: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose; rifampin: 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose | To evaluate the effect of a single oral dose of rifampin on the Cmax of midazolam, dabigatran, pitavastatin, pitavastatin lactone, atorvastatin, ortho-hydroxyatorvastatin, and rosuvatatin. Cmax is the peak plasma concentration of study drug after administration. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail and rifampin in healthy participants and participants with renal impairment. As pre-specified in the protocol, this outcome measure does not include end-stage renal disease participants as they did not receive rifampin during Period 2. |
| Effect of Rifampin on C24 Post-dose Period 2 | 24 hours post-dose | To evaluate the effect of a single oral dose of rifampin on the C24 of midazolam, dabigatran, pitavastatin, pitavastatin lactone, atorvastatin, ortho-hydroxyatorvastatin, and rosuvatatin. C24 is a measure of the plasma study drug concentration 24 hours post-dose. C24 is reported as median (minimum and maximum) in severe renal impairment arm due to zero values. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail and rifampin in healthy participants and participants with renal impairment. As pre-specified in the protocol, this outcome measure does not include end-stage renal disease participants as they did not receive rifampin during Period 2. |
| Effect of Rifampin on Tmax Post-dose Period 2 | Microdose cocktail: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose; rifampin: 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose | To evaluate the effect of a single oral dose of rifampin on the Tmax of midazolam, dabigatran, pitavastatin, pitavastatin lactone, atorvastatin, ortho-hydroxyatorvastatin, and rosuvatatin. Tmax is the amount of time to reach maximum (peak) plasma drug concentration following drug administration. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail and rifampin in healthy participants and participants with renal impairment. As pre-specified in the protocol, this outcome measure does not include end-stage renal disease participants as they did not receive rifampin during Period 2. |
| Effect of Rifampin on t1/2 Post-dose Period 2 | Microdose cocktail: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose; rifampin: 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose | To evaluate the effect of a single oral dose of rifampin on the t1/2 of midazolam, dabigatran, pitavastatin, pitavastatin lactone, atorvastatin, ortho-hydroxyatorvastatin, and rosuvatatin. T1/2 is the elimination half-life of study drug. T1/2 is the time it takes for half of the study drug in the blood plasma to dissipate. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail and rifampin in healthy participants and participants with renal impairment. As pre-specified in the protocol, this outcome measure does not include end-stage renal disease participants as they did not receive rifampin during Period 2. |
| Effect of Rifampin on CL/F Post-dose Period 2 | Microdose cocktail: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose; rifampin: 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose | To evaluate the effect of a single oral dose of rifampin on the CL/F of midazolam, dabigatran, pitavastatin, atorvastatin, and rosuvatatin. CL/F is the rate at which study drug was removed from the body. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail and rifampin in healthy participants and participants with renal impairment. As pre-specified in the protocol, this outcome measure does not include end-stage renal disease participants as they did not receive rifampin during Period 2. |
| Effect of Rifampin on Vz/F Post-dose Period 2 | Microdose cocktail: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose; rifampin: 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose | To evaluate the effect of a single oral dose of rifampin on the Vz/F of midazolam, dabigatran, pitavastatin, pitavastatin lactone, atorvastatin, ortho-hydroxyatorvastatin, and rosuvatatin. Vz/F is the distribution of study drug between the plasma and the rest of the body after the dose. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail and rifampin in healthy participants and participants with renal impairment. As pre-specified in the protocol, this outcome measure does not include end-stage renal disease participants as they did not receive rifampin during Period 2. |
| Effect of Rifampin on AUC0-24 Post-dose Period 2 | Microdose cocktail: 0 hour (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post-dose; rifampin: 0 hour (pre-dose) and 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose | To evaluate the effect of a single oral dose of rifampin on the AUC0-24 of midazolam, dabigatran, pitavastatin, pitavastatin lactone, atorvastatin, ortho-hydroxyatorvastatin, and rosuvatatin. AUC0-24 is the area under the plasma concentration-time curve from time 0 to 24 hours post-dose. This is a measure of the average amount of study drug in the blood plasma over a period of 24 hours after the dose. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail and rifampin in healthy participants and participants with renal impairment. As pre-specified in the protocol, this outcome measure does not include end-stage renal disease participants as they did not receive rifampin during Period 2. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| End-Stage Renal Disease Participants requiring hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). A washout period of at least 14 days will separate dosings | 6 |
| Severe Impairment Participants with \<30 mL/min/1.73m\^2 estimated glomerular filtration rate (eGFR) not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings. | 7 |
| Moderate Impairment Participants with 30 to \<60 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings. | 6 |
| Mild Impairment Participants with 60 to \<90 mL/min/1.73m\^2 eGFR not on hemodialysis. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings. | 7 |
| Healthy Control Participants with ≥90 mL/min creatinine clearance. Period 1/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution). Period 2/Day 1: participants receive a single oral dose of the microdose cocktail (midazolam oral solution, dabigatran etexilate and pitavastatin oral solution, atorvastatin and rosuvastatin oral solution) and rifampin. A washout period of at least 14 days will separate dosings. | 6 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| 14-day Wash-out | Adverse Event | 0 | 1 | 0 | 0 | 0 |
| 14-day Wash-out | Non-Compliance With Study Drug | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | End-Stage Renal Disease | Severe Impairment | Moderate Impairment | Mild Impairment | Healthy Control | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 56.7 Years STANDARD_DEVIATION 8.04 | 64.9 Years STANDARD_DEVIATION 7.1 | 67.0 Years STANDARD_DEVIATION 11.19 | 65.4 Years STANDARD_DEVIATION 8.9 | 57.8 Years STANDARD_DEVIATION 7.88 | 62.5 Years STANDARD_DEVIATION 9.15 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 5 Participants | 4 Participants | 5 Participants | 6 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 2 Participants | 2 Participants | 2 Participants | 0 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 00 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 7 Participants | 6 Participants | 3 Participants | 6 Participants | 22 Participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 4 Participants | 3 Participants | 3 Participants | 11 Participants |
| Sex: Female, Male Male | 6 Participants | 6 Participants | 2 Participants | 4 Participants | 3 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 7 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 7 | 0 / 6 | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 1 / 6 | 2 / 7 | 1 / 6 | 2 / 6 | 1 / 6 | 3 / 7 | 2 / 6 | 0 / 6 | 0 / 6 |
| serious Total, serious adverse events | 0 / 6 | 1 / 7 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 7 | 0 / 6 | 0 / 6 | 0 / 6 |
Outcome results
Primary
Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1
CL/F is the rate at which study drug was removed from the body. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail in healthy participants, participants with renal impairment, and 24 hours prior to hemodialysis in participants with end-stage renal disease requiring hemodialysis. CL/F was to be calculated for the parent plasma analytes only, midazolam, dabigatran, pitavastatin, atorvastatin, and rosuvastatin.
Time frame: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose
Population: All participants who were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of CL/F for the following reasons: non-compliance with the protocol or high pre-dose concentrations.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| End-Stage Renal Disease | Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1 | Pitavastatin | 14.8 liters/hour | Geometric Coefficient of Variation 60 |
| End-Stage Renal Disease | Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1 | Midazolam | 90.8 liters/hour | Geometric Coefficient of Variation 46.5 |
| End-Stage Renal Disease | Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1 | Rosuvastatin | 240 liters/hour | Geometric Coefficient of Variation 121 |
| End-Stage Renal Disease | Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1 | Atorvastatin | 304 liters/hour | Geometric Coefficient of Variation 64.7 |
| End-Stage Renal Disease | Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1 | Dabigatran | 52.5 liters/hour | Geometric Coefficient of Variation 74.1 |
| Severe Impairment | Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1 | Pitavastatin | 15.4 liters/hour | Geometric Coefficient of Variation 58.6 |
| Severe Impairment | Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1 | Rosuvastatin | 137 liters/hour | Geometric Coefficient of Variation 49 |
| Severe Impairment | Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1 | Midazolam | 38.5 liters/hour | Geometric Coefficient of Variation 62.7 |
| Severe Impairment | Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1 | Dabigatran | 35.7 liters/hour | Geometric Coefficient of Variation 32.3 |
| Severe Impairment | Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1 | Atorvastatin | 210 liters/hour | Geometric Coefficient of Variation 82.9 |
| Moderate Impairment | Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1 | Midazolam | 27.5 liters/hour | Geometric Coefficient of Variation 46.3 |
| Moderate Impairment | Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1 | Pitavastatin | 9.84 liters/hour | Geometric Coefficient of Variation 29.7 |
| Moderate Impairment | Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1 | Dabigatran | 61.8 liters/hour | Geometric Coefficient of Variation 70.3 |
| Moderate Impairment | Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1 | Rosuvastatin | 87.0 liters/hour | Geometric Coefficient of Variation 32.3 |
| Moderate Impairment | Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1 | Atorvastatin | 196 liters/hour | Geometric Coefficient of Variation 54 |
| Mild Impairment | Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1 | Rosuvastatin | 191 liters/hour | Geometric Coefficient of Variation 82.5 |
| Mild Impairment | Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1 | Midazolam | 56.9 liters/hour | Geometric Coefficient of Variation 32.3 |
| Mild Impairment | Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1 | Pitavastatin | 14.5 liters/hour | Geometric Coefficient of Variation 41.1 |
| Mild Impairment | Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1 | Dabigatran | 175 liters/hour | Geometric Coefficient of Variation 47.3 |
| Mild Impairment | Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1 | Atorvastatin | 304 liters/hour | Geometric Coefficient of Variation 28.7 |
| Healthy Control | Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1 | Rosuvastatin | 171 liters/hour | Geometric Coefficient of Variation 47.8 |
| Healthy Control | Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1 | Dabigatran | 178 liters/hour | Geometric Coefficient of Variation 61.5 |
| Healthy Control | Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1 | Pitavastatin | 19.2 liters/hour | Geometric Coefficient of Variation 52.7 |
| Healthy Control | Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1 | Midazolam | 36.6 liters/hour | Geometric Coefficient of Variation 50.6 |
| Healthy Control | Apparent Clearance After Extravascular Administration (CL/F) Post-dose Period 1 | Atorvastatin | 343 liters/hour | Geometric Coefficient of Variation 56.9 |
Primary
Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1
T1/2 is the elimination half-life of study drug. T1/2 is the time it takes for half of the study drug in the blood plasma to dissipate. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail in healthy participants, participants with renal impairment, and 24 hours prior to hemodialysis in participants with end-stage renal disease requiring hemodialysis.
Time frame: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose
Population: All participants who were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of t1/2 for the following reasons: non-compliance with the protocol or high pre-dose concentrations.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| End-Stage Renal Disease | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 12.4 hours | Geometric Coefficient of Variation 25.8 |
| End-Stage Renal Disease | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Midazolam | 4.41 hours | Geometric Coefficient of Variation 59.6 |
| End-Stage Renal Disease | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Atorvastatin | 8.03 hours | Geometric Coefficient of Variation 28.5 |
| End-Stage Renal Disease | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Dabigatran | 41.4 hours | Geometric Coefficient of Variation 47.9 |
| End-Stage Renal Disease | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Rosuvastatin | 14.0 hours | Geometric Coefficient of Variation 107.3 |
| End-Stage Renal Disease | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Pitavastatin | 11.8 hours | Geometric Coefficient of Variation 61.4 |
| End-Stage Renal Disease | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 11.0 hours | Geometric Coefficient of Variation 55.3 |
| Severe Impairment | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 18.1 hours | Geometric Coefficient of Variation 31 |
| Severe Impairment | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Pitavastatin | 20.4 hours | Geometric Coefficient of Variation 63.6 |
| Severe Impairment | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Rosuvastatin | 18.8 hours | Geometric Coefficient of Variation 78.3 |
| Severe Impairment | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 21.9 hours | Geometric Coefficient of Variation 65.9 |
| Severe Impairment | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Atorvastatin | 17.5 hours | Geometric Coefficient of Variation 57 |
| Severe Impairment | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Dabigatran | 24.0 hours | Geometric Coefficient of Variation 22 |
| Severe Impairment | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Midazolam | 7.79 hours | Geometric Coefficient of Variation 54.1 |
| Moderate Impairment | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Pitavastatin | 22.4 hours | Geometric Coefficient of Variation 15.8 |
| Moderate Impairment | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 24.6 hours | Geometric Coefficient of Variation 18.3 |
| Moderate Impairment | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Rosuvastatin | 24.9 hours | Geometric Coefficient of Variation 19.4 |
| Moderate Impairment | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Dabigatran | 11.9 hours | Geometric Coefficient of Variation 30.3 |
| Moderate Impairment | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 22.0 hours | Geometric Coefficient of Variation 13.2 |
| Moderate Impairment | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Atorvastatin | 18.6 hours | Geometric Coefficient of Variation 41.8 |
| Moderate Impairment | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Midazolam | 10.3 hours | Geometric Coefficient of Variation 33 |
| Mild Impairment | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Dabigatran | 8.40 hours | Geometric Coefficient of Variation 10.7 |
| Mild Impairment | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 20.5 hours | Geometric Coefficient of Variation 31.4 |
| Mild Impairment | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Rosuvastatin | 15.5 hours | Geometric Coefficient of Variation 100.2 |
| Mild Impairment | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Midazolam | 6.76 hours | Geometric Coefficient of Variation 30.6 |
| Mild Impairment | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Atorvastatin | 16.7 hours | Geometric Coefficient of Variation 14.8 |
| Mild Impairment | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 22.8 hours | Geometric Coefficient of Variation 35.7 |
| Mild Impairment | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Pitavastatin | 19.3 hours | Geometric Coefficient of Variation 23.5 |
| Healthy Control | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Dabigatran | 6.75 hours | Geometric Coefficient of Variation 19.8 |
| Healthy Control | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Atorvastatin | 14.9 hours | Geometric Coefficient of Variation 10.3 |
| Healthy Control | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Midazolam | 7.99 hours | Geometric Coefficient of Variation 25 |
| Healthy Control | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 18.5 hours | Geometric Coefficient of Variation 15.9 |
| Healthy Control | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Rosuvastatin | 16.2 hours | Geometric Coefficient of Variation 78.6 |
| Healthy Control | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 21.2 hours | Geometric Coefficient of Variation 29.5 |
| Healthy Control | Apparent Plasma Terminal Half-life (t1/2) Post-dose Period 1 | Pitavastatin | 17.8 hours | Geometric Coefficient of Variation 26.7 |
Primary
Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1
Vz/F is the distribution of study drug between the plasma and the rest of the body after the dose. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail in healthy participants, participants with renal impairment, and 24 hours prior to hemodialysis in participants with end-stage renal disease requiring hemodialysis. Vz/F was to be calculated for the parent plasma analytes only, midazolam, dabigatran, pitavastatin, atorvastatin, and rosuvastatin.
Time frame: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose
Population: All participants who were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of Vz/F for the following reasons: non-compliance with the protocol or high pre-dose concentrations.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| End-Stage Renal Disease | Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1 | Atorvastatin | 3520 liters | Geometric Coefficient of Variation 40.3 |
| End-Stage Renal Disease | Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1 | Midazolam | 579 liters | Geometric Coefficient of Variation 45 |
| End-Stage Renal Disease | Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1 | Rosuvastatin | 4870 liters | Geometric Coefficient of Variation 63.2 |
| End-Stage Renal Disease | Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1 | Dabigatran | 3140 liters | Geometric Coefficient of Variation 38.4 |
| End-Stage Renal Disease | Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1 | Pitavastatin | 252 liters | Geometric Coefficient of Variation 19.5 |
| Severe Impairment | Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1 | Atorvastatin | 5310 liters | Geometric Coefficient of Variation 47.7 |
| Severe Impairment | Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1 | Pitavastatin | 454 liters | Geometric Coefficient of Variation 51.9 |
| Severe Impairment | Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1 | Dabigatran | 1230 liters | Geometric Coefficient of Variation 36.4 |
| Severe Impairment | Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1 | Rosuvastatin | 3720 liters | Geometric Coefficient of Variation 51.3 |
| Severe Impairment | Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1 | Midazolam | 433 liters | Geometric Coefficient of Variation 16.9 |
| Moderate Impairment | Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1 | Pitavastatin | 317 liters | Geometric Coefficient of Variation 15.4 |
| Moderate Impairment | Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1 | Midazolam | 409 liters | Geometric Coefficient of Variation 38 |
| Moderate Impairment | Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1 | Dabigatran | 1060 liters | Geometric Coefficient of Variation 54.1 |
| Moderate Impairment | Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1 | Atorvastatin | 5240 liters | Geometric Coefficient of Variation 57.5 |
| Moderate Impairment | Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1 | Rosuvastatin | 3120 liters | Geometric Coefficient of Variation 35.9 |
| Mild Impairment | Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1 | Rosuvastatin | 4270 liters | Geometric Coefficient of Variation 117.9 |
| Mild Impairment | Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1 | Midazolam | 555 liters | Geometric Coefficient of Variation 58 |
| Mild Impairment | Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1 | Atorvastatin | 7300 liters | Geometric Coefficient of Variation 32.5 |
| Mild Impairment | Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1 | Pitavastatin | 405 liters | Geometric Coefficient of Variation 46.8 |
| Mild Impairment | Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1 | Dabigatran | 2120 liters | Geometric Coefficient of Variation 57.9 |
| Healthy Control | Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1 | Pitavastatin | 495 liters | Geometric Coefficient of Variation 46.6 |
| Healthy Control | Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1 | Atorvastatin | 7380 liters | Geometric Coefficient of Variation 58.6 |
| Healthy Control | Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1 | Midazolam | 422 liters | Geometric Coefficient of Variation 37.5 |
| Healthy Control | Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1 | Rosuvastatin | 4010 liters | Geometric Coefficient of Variation 34.4 |
| Healthy Control | Apparent Volume of Distribution During the Terminal Phase (Vz/F) Post-dose Period 1 | Dabigatran | 1730 liters | Geometric Coefficient of Variation 46.4 |
Primary
Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1
AUC0-24 is the area under the plasma concentration-time curve from time 0 to 24 hours post-dose. This is a measure of the average amount of study drug in the blood plasma over a period of 24 hours after the dose. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail in healthy participants, participants with renal impairment, and 24 hours prior to hemodialysis in participants with end-stage renal disease requiring hemodialysis.
Time frame: 0 hour (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post-dose
Population: All participants who were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of AUC0-24 for the following reasons: non-compliance with the protocol or high pre-dose concentrations.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| End-Stage Renal Disease | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Midazolam | 106 pg*hr/mL |
| End-Stage Renal Disease | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Rosuvastatin | 162 pg*hr/mL |
| End-Stage Renal Disease | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 115 pg*hr/mL |
| End-Stage Renal Disease | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Pitavastatin | 593 pg*hr/mL |
| End-Stage Renal Disease | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Dabigatran | 2100 pg*hr/mL |
| End-Stage Renal Disease | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 858 pg*hr/mL |
| End-Stage Renal Disease | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Atorvastatin | 287 pg*hr/mL |
| Severe Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Atorvastatin | 300 pg*hr/mL |
| Severe Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 1100 pg*hr/mL |
| Severe Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Dabigatran | 4470 pg*hr/mL |
| Severe Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Midazolam | 235 pg*hr/mL |
| Severe Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 112 pg*hr/mL |
| Severe Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Pitavastatin | 525 pg*hr/mL |
| Severe Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Rosuvastatin | 223 pg*hr/mL |
| Moderate Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 1280 pg*hr/mL |
| Moderate Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Midazolam | 317 pg*hr/mL |
| Moderate Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Dabigatran | 3440 pg*hr/mL |
| Moderate Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Pitavastatin | 764 pg*hr/mL |
| Moderate Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Atorvastatin | 329 pg*hr/mL |
| Moderate Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 143 pg*hr/mL |
| Moderate Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Rosuvastatin | 343 pg*hr/mL |
| Mild Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Pitavastatin | 543 pg*hr/mL |
| Mild Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Atorvastatin | 219 pg*hr/mL |
| Mild Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Dabigatran | 1380 pg*hr/mL |
| Mild Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Rosuvastatin | 191 pg*hr/mL |
| Mild Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 139 pg*hr/mL |
| Mild Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Midazolam | 168 pg*hr/mL |
| Mild Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 1040 pg*hr/mL |
| Healthy Control | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Pitavastatin | 415 pg*hr/mL |
| Healthy Control | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Rosuvastatin | 153 pg*hr/mL |
| Healthy Control | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 108 pg*hr/mL |
| Healthy Control | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Atorvastatin | 198 pg*hr/mL |
| Healthy Control | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Dabigatran | 1440 pg*hr/mL |
| Healthy Control | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Midazolam | 252 pg*hr/mL |
| Healthy Control | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 1010 pg*hr/mL |
Comparison: Comparison of midazolam95% CI: [0.4, 1.11]
Comparison: Comparison of midazolam95% CI: [0.76, 2.09]
Comparison: Comparison of midazolam95% CI: [0.57, 1.52]
Comparison: Comparison of midazolam95% CI: [0.25, 0.7]
Comparison: Comparison of dabigatran95% CI: [0.53, 1.73]
Comparison: Comparison of dabigatran95% CI: [1.32, 4.32]
Comparison: Comparison of dabigatran95% CI: [1.75, 5.48]
Comparison: Comparison of dabigatran95% CI: [0.8, 2.64]
Comparison: Comparison of pitavastatin95% CI: [0.78, 2.2]
Comparison: Comparison of pitavastatin95% CI: [1.09, 3.09]
Comparison: Comparison of pitavastatin95% CI: [0.77, 2.09]
Comparison: Comparison of pitavastatin95% CI: [0.85, 2.4]
Comparison: Comparison of pitavastatin lactone95% CI: [0.68, 1.56]
Comparison: Comparison of pitavastatin lactone95% CI: [0.83, 1.92]
Comparison: Comparison of pitavastatin lactone95% CI: [0.73, 1.63]
Comparison: Comparison of pitavastatin lactone95% CI: [0.56, 1.29]
Comparison: Comparison of atorvastatin95% CI: [0.55, 2.23]
Comparison: Comparison of atorvastatin95% CI: [0.89, 3.11]
Comparison: Comparison of atorvastatin95% CI: [0.83, 2.77]
Comparison: Comparison of atorvastatin95% CI: [0.78, 2.71]
Comparison: Comparison of ortho-hydroxyatorvastatin95% CI: [0.7, 2.34]
Comparison: Comparison of ortho-hydroxyatorvastatin95% CI: [0.78, 2.28]
Comparison: Comparison of ortho-hydroxyatorvastatin95% CI: [0.62, 1.74]
Comparison: Comparison of ortho-hydroxyatorvastatin95% CI: [0.62, 1.82]
Comparison: Comparison of rosuvastatin95% CI: [0.58, 2.67]
Comparison: Comparison of rosuvastatin95% CI: [1.09, 4.63]
Comparison: Comparison of rosuvastatin95% CI: [0.72, 2.93]
Comparison: Comparison of rosuvastatin95% CI: [0.51, 2.19]
Primary
Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1
AUC0-inf is the area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail in healthy participants, participants with renal impairment, and 24 hours prior to hemodialysis in participants with end-stage renal disease (ESRD) requiring hemodialysis.
Time frame: 0 hour (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose
Population: All participants who were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of AUC0-inf for the following reasons: non-compliance with the protocol or high pre-dose concentrations.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| End-Stage Renal Disease | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Midazolam | 110 pg*hr/mL |
| End-Stage Renal Disease | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Rosuvastatin | 208 pg*hr/mL |
| End-Stage Renal Disease | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 163 pg*hr/mL |
| End-Stage Renal Disease | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Pitavastatin | 676 pg*hr/mL |
| End-Stage Renal Disease | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Dabigatran | 5370 pg*hr/mL |
| End-Stage Renal Disease | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 1100 pg*hr/mL |
| End-Stage Renal Disease | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Atorvastatin | 329 pg*hr/mL |
| Severe Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Atorvastatin | 476 pg*hr/mL |
| Severe Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 1680 pg*hr/mL |
| Severe Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Dabigatran | 7900 pg*hr/mL |
| Severe Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Midazolam | 260 pg*hr/mL |
| Severe Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 226 pg*hr/mL |
| Severe Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Pitavastatin | 648 pg*hr/mL |
| Severe Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Rosuvastatin | 365 pg*hr/mL |
| Moderate Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 2240 pg*hr/mL |
| Moderate Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Midazolam | 364 pg*hr/mL |
| Moderate Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Dabigatran | 4550 pg*hr/mL |
| Moderate Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Pitavastatin | 1020 pg*hr/mL |
| Moderate Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Atorvastatin | 511 pg*hr/mL |
| Moderate Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 273 pg*hr/mL |
| Moderate Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Rosuvastatin | 575 pg*hr/mL |
| Mild Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Pitavastatin | 688 pg*hr/mL |
| Mild Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Atorvastatin | 329 pg*hr/mL |
| Mild Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Dabigatran | 1610 pg*hr/mL |
| Mild Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Rosuvastatin | 262 pg*hr/mL |
| Mild Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 286 pg*hr/mL |
| Mild Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Midazolam | 176 pg*hr/mL |
| Mild Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 1610 pg*hr/mL |
| Healthy Control | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Pitavastatin | 520 pg*hr/mL |
| Healthy Control | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Rosuvastatin | 292 pg*hr/mL |
| Healthy Control | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 208 pg*hr/mL |
| Healthy Control | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Atorvastatin | 292 pg*hr/mL |
| Healthy Control | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Dabigatran | 1580 pg*hr/mL |
| Healthy Control | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Midazolam | 273 pg*hr/mL |
| Healthy Control | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 1540 pg*hr/mL |
Comparison: Comparison of midazolam95% CI: [0.37, 1.11]
Comparison: Comparison of midazolam95% CI: [0.77, 2.31]
Comparison: Comparison of midazolam95% CI: [0.56, 1.62]
Comparison: Comparison of midazolam95% CI: [0.23, 0.7]
Comparison: Comparison of dabigatran95% CI: [0.53, 1.93]
Comparison: Comparison of dabigatran95% CI: [1.51, 5.47]
Comparison: Comparison of dabigatran95% CI: [2.62, 9.48]
Comparison: Comparison of dabigatran95% CI: [1.78, 6.44]
95% CI: [0.76, 2.31]
Comparison: Comparison of pitavastatin95% CI: [1.12, 3.42]
Comparison: Comparison of pitavastatin95% CI: [0.73, 2.13]
Comparison: Comparison of pitavastatin95% CI: [0.74, 2.27]
Comparison: Comparison of pitavastatin lactone95% CI: [0.64, 1.72]
Comparison: Comparison of pitavastatin lactone95% CI: [0.88, 2.38]
95% CI: [0.68, 1.76]
95% CI: [0.43, 1.17]
95% CI: [0.53, 2.41]
95% CI: [0.89, 3.46]
Comparison: Comparison of atorvastatin95% CI: [0.85, 3.14]
95% CI: [0.57, 2.22]
95% CI: [0.76, 2.49]
95% CI: [0.75, 2.29]
95% CI: [0.65, 1.81]
95% CI: [0.46, 1.33]
95% CI: [0.33, 2.45]
95% CI: [0.75, 5.14]
95% CI: [0.49, 3.16]
95% CI: [0.27, 1.86]
Primary
Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1
AUC0-last is the area under the plasma concentration-time curve from time zero to time of last measurable concentration. This is a measure of the amount of study drug in the blood plasma from pre-dose until the last measurable concentration of study drug could be determined. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail in healthy participants, participants with renal impairment, and 24 hours prior to hemodialysis in participants with end-stage renal disease requiring hemodialysis.
Time frame: 0 hour (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose
Population: All participants who were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of AUC0-last for the following reasons: non-compliance with the protocol or high pre-dose concentrations.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| End-Stage Renal Disease | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Midazolam | 105 pg*hr/mL |
| End-Stage Renal Disease | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Rosuvastatin | 171 pg*hr/mL |
| End-Stage Renal Disease | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 126 pg*hr/mL |
| End-Stage Renal Disease | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Pitavastatin | 649 pg*hr/mL |
| End-Stage Renal Disease | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Dabigatran | 3740 pg*hr/mL |
| End-Stage Renal Disease | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 1060 pg*hr/mL |
| End-Stage Renal Disease | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Atorvastatin | 298 pg*hr/mL |
| Severe Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Atorvastatin | 419 pg*hr/mL |
| Severe Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 1570 pg*hr/mL |
| Severe Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Dabigatran | 7450 pg*hr/mL |
| Severe Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Midazolam | 248 pg*hr/mL |
| Severe Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 176 pg*hr/mL |
| Severe Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Pitavastatin | 602 pg*hr/mL |
| Severe Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Rosuvastatin | 269 pg*hr/mL |
| Moderate Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 2020 pg*hr/mL |
| Moderate Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Midazolam | 344 pg*hr/mL |
| Moderate Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Dabigatran | 4230 pg*hr/mL |
| Moderate Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Pitavastatin | 950 pg*hr/mL |
| Moderate Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Atorvastatin | 459 pg*hr/mL |
| Moderate Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 256 pg*hr/mL |
| Moderate Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Rosuvastatin | 479 pg*hr/mL |
| Mild Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Pitavastatin | 643 pg*hr/mL |
| Mild Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Atorvastatin | 295 pg*hr/mL |
| Mild Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Dabigatran | 1440 pg*hr/mL |
| Mild Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Rosuvastatin | 231 pg*hr/mL |
| Mild Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 221 pg*hr/mL |
| Mild Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Midazolam | 167 pg*hr/mL |
| Mild Impairment | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 1490 pg*hr/mL |
| Healthy Control | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Pitavastatin | 483 pg*hr/mL |
| Healthy Control | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Rosuvastatin | 181 pg*hr/mL |
| Healthy Control | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 152 pg*hr/mL |
| Healthy Control | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Atorvastatin | 255 pg*hr/mL |
| Healthy Control | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Dabigatran | 1410 pg*hr/mL |
| Healthy Control | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Midazolam | 264 pg*hr/mL |
| Healthy Control | Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 1450 pg*hr/mL |
Comparison: Comparison of midazolam95% CI: [0.36, 1.11]
Comparison: Comparison of midazolam95% CI: [0.75, 2.28]
Comparison: Comparison of midazolam95% CI: [0.55, 1.61]
Comparison: Comparison of midazolam95% CI: [0.23, 0.69]
Comparison: Comparison of dabigatran95% CI: [0.53, 1.95]
Comparison: Comparison of dabigatran95% CI: [1.57, 5.74]
Comparison: Comparison of dabigatran95% CI: [2.83, 9.87]
Comparison: Comparison of dabigatran95% CI: [1.39, 5.07]
Comparison: Comparison of pitavastatin95% CI: [0.76, 2.34]
Comparison: Comparison of pitavastatin lactone95% CI: [0.64, 1.65]
Comparison: Comparison of pitavastatin lactone95% CI: [0.87, 2.24]
Comparison: Comparison of pitavastatin95% CI: [1.12, 3.46]
Comparison: Comparison of pitavastatin95% CI: [0.72, 2.15]
Comparison: Comparison of pitavastatin95% CI: [0.76, 2.36]
Comparison: Comparison of pitavastatin lactone95% CI: [0.68, 1.71]
Comparison: Comparison of pitavastatin lactone95% CI: [0.45, 1.17]
Comparison: Comparison of atorvastatin95% CI: [0.53, 2.52]
Comparison: Comparison of atorvastatin95% CI: [0.9, 3.62]
Comparison: Comparison of atorvastatin95% CI: [0.84, 3.23]
Comparison: Comparison of atorvastatin95% CI: [0.58, 2.35]
Comparison: Comparison of ortho-hydroxyatorvastatin95% CI: [0.71, 2.97]
Comparison: Comparison of ortho-hydroxyatorvastatin95% CI: [0.89, 3.19]
Comparison: Comparison of ortho-hydroxyatorvastatin95% CI: [0.63, 2.14]
Comparison: Comparison of ortho-hydroxyatorvastatin95% CI: [0.44, 1.57]
Comparison: Comparison of rosuvastatin95% CI: [0.56, 2.91]
Comparison: Comparison of rosuvastatin95% CI: [1.21, 5.81]
Comparison: Comparison of rosuvastatin95% CI: [0.7, 3.18]
Comparison: Comparison of rosuvastatin95% CI: [0.43, 2.08]
Primary
Effect of Rifampin on AUC0-inf Post-dose Period 2
To evaluate the effect of a single oral dose of rifampin on the AUC0-inf of midazolam, dabigatran, pitavastatin, pitavastatin lactone, atorvastatin, ortho-hydroxyatorvastatin, and rosuvatatin. AUC0-inf is the area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail and rifampin in healthy participants and participants with renal impairment. As pre-specified in the protocol, this outcome measure does not include data from the end-stage renal disease participants as they did not receive rifampin during Period 2.
Time frame: Microdose cocktail: 0 hour (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose; rifampin: 0 hour (pre-dose) and 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose
Population: All participants who received rifampin, were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of AUC0-inf for the following reasons: non-compliance with the protocol or high pre-dose concentrations. Per protocol, end-stage renal disease participants did not receive rifampin.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Severe Impairment | Effect of Rifampin on AUC0-inf Post-dose Period 2 | Midazolam | 244 pg*hr/mL |
| Severe Impairment | Effect of Rifampin on AUC0-inf Post-dose Period 2 | Pitavastatin | 2850 pg*hr/mL |
| Severe Impairment | Effect of Rifampin on AUC0-inf Post-dose Period 2 | Rosuvastatin | 1240 pg*hr/mL |
| Severe Impairment | Effect of Rifampin on AUC0-inf Post-dose Period 2 | Pitavastatin lactone (metabolite) | 1560 pg*hr/mL |
| Severe Impairment | Effect of Rifampin on AUC0-inf Post-dose Period 2 | Ortho-hydroxyatorvastatin (metabolite) | 1620 pg*hr/mL |
| Severe Impairment | Effect of Rifampin on AUC0-inf Post-dose Period 2 | Dabigatran | 10700 pg*hr/mL |
| Severe Impairment | Effect of Rifampin on AUC0-inf Post-dose Period 2 | Atorvastatin | 2240 pg*hr/mL |
| Moderate Impairment | Effect of Rifampin on AUC0-inf Post-dose Period 2 | Ortho-hydroxyatorvastatin (metabolite) | 1870 pg*hr/mL |
| Moderate Impairment | Effect of Rifampin on AUC0-inf Post-dose Period 2 | Dabigatran | 7240 pg*hr/mL |
| Moderate Impairment | Effect of Rifampin on AUC0-inf Post-dose Period 2 | Rosuvastatin | 1800 pg*hr/mL |
| Moderate Impairment | Effect of Rifampin on AUC0-inf Post-dose Period 2 | Pitavastatin | 3500 pg*hr/mL |
| Moderate Impairment | Effect of Rifampin on AUC0-inf Post-dose Period 2 | Midazolam | 359 pg*hr/mL |
| Moderate Impairment | Effect of Rifampin on AUC0-inf Post-dose Period 2 | Pitavastatin lactone (metabolite) | 2500 pg*hr/mL |
| Moderate Impairment | Effect of Rifampin on AUC0-inf Post-dose Period 2 | Atorvastatin | 2430 pg*hr/mL |
| Mild Impairment | Effect of Rifampin on AUC0-inf Post-dose Period 2 | Pitavastatin lactone (metabolite) | 1930 pg*hr/mL |
| Mild Impairment | Effect of Rifampin on AUC0-inf Post-dose Period 2 | Midazolam | 189 pg*hr/mL |
| Mild Impairment | Effect of Rifampin on AUC0-inf Post-dose Period 2 | Dabigatran | 3040 pg*hr/mL |
| Mild Impairment | Effect of Rifampin on AUC0-inf Post-dose Period 2 | Ortho-hydroxyatorvastatin (metabolite) | 1760 pg*hr/mL |
| Mild Impairment | Effect of Rifampin on AUC0-inf Post-dose Period 2 | Atorvastatin | 1710 pg*hr/mL |
| Mild Impairment | Effect of Rifampin on AUC0-inf Post-dose Period 2 | Pitavastatin | 2530 pg*hr/mL |
| Mild Impairment | Effect of Rifampin on AUC0-inf Post-dose Period 2 | Rosuvastatin | 1060 pg*hr/mL |
| Healthy Control | Effect of Rifampin on AUC0-inf Post-dose Period 2 | Rosuvastatin | 830 pg*hr/mL |
| Healthy Control | Effect of Rifampin on AUC0-inf Post-dose Period 2 | Dabigatran | 3290 pg*hr/mL |
| Healthy Control | Effect of Rifampin on AUC0-inf Post-dose Period 2 | Pitavastatin | 1910 pg*hr/mL |
| Healthy Control | Effect of Rifampin on AUC0-inf Post-dose Period 2 | Pitavastatin lactone (metabolite) | 1340 pg*hr/mL |
| Healthy Control | Effect of Rifampin on AUC0-inf Post-dose Period 2 | Atorvastatin | 1770 pg*hr/mL |
| Healthy Control | Effect of Rifampin on AUC0-inf Post-dose Period 2 | Ortho-hydroxyatorvastatin (metabolite) | 1650 pg*hr/mL |
| Healthy Control | Effect of Rifampin on AUC0-inf Post-dose Period 2 | Midazolam | 239 pg*hr/mL |
Primary
Maximum Plasma Concentration (Cmax) Post-dose Period 1
Cmax is the peak plasma concentration of study drug after administration. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail in healthy participants, participants with renal impairment, and 24 hours prior to hemodialysis in participants with end-stage renal disease requiring hemodialysis.
Time frame: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose
Population: All participants who were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of Cmax for the following reasons: non-compliance with the protocol or high pre-dose concentrations.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| End-Stage Renal Disease | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Midazolam | 39.9 pg/mL |
| End-Stage Renal Disease | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Rosuvastatin | 22.5 pg/mL |
| End-Stage Renal Disease | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 8.58 pg/mL |
| End-Stage Renal Disease | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Pitavastatin | 242 pg/mL |
| End-Stage Renal Disease | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Dabigatran | 132 pg/mL |
| End-Stage Renal Disease | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 78.5 pg/mL |
| End-Stage Renal Disease | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Atorvastatin | 63.7 pg/mL |
| Severe Impairment | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Atorvastatin | 46.7 pg/mL |
| Severe Impairment | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 95.4 pg/mL |
| Severe Impairment | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Dabigatran | 319 pg/mL |
| Severe Impairment | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Midazolam | 68.4 pg/mL |
| Severe Impairment | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 7.22 pg/mL |
| Severe Impairment | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Pitavastatin | 218 pg/mL |
| Severe Impairment | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Rosuvastatin | 24.4 pg/mL |
| Moderate Impairment | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 106 pg/mL |
| Moderate Impairment | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Midazolam | 77.2 pg/mL |
| Moderate Impairment | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Dabigatran | 312 pg/mL |
| Moderate Impairment | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Pitavastatin | 303 pg/mL |
| Moderate Impairment | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Atorvastatin | 55.0 pg/mL |
| Moderate Impairment | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 9.50 pg/mL |
| Moderate Impairment | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Rosuvastatin | 40.4 pg/mL |
| Mild Impairment | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Pitavastatin | 244 pg/mL |
| Mild Impairment | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Atorvastatin | 31.9 pg/mL |
| Mild Impairment | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Dabigatran | 153 pg/mL |
| Mild Impairment | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Rosuvastatin | 23.6 pg/mL |
| Mild Impairment | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 8.50 pg/mL |
| Mild Impairment | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Midazolam | 70.7 pg/mL |
| Mild Impairment | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 105 pg/mL |
| Healthy Control | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Pitavastatin | 164 pg/mL |
| Healthy Control | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Rosuvastatin | 21.5 pg/mL |
| Healthy Control | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 7.67 pg/mL |
| Healthy Control | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Atorvastatin | 21.6 pg/mL |
| Healthy Control | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Dabigatran | 183 pg/mL |
| Healthy Control | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Midazolam | 73.2 pg/mL |
| Healthy Control | Maximum Plasma Concentration (Cmax) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 88.1 pg/mL |
Comparison: Comparison of midazolam95% CI: [0.63, 1.48]
Comparison: Comparison of midazolam95% CI: [0.69, 1.62]
Comparison: Comparison of midazolam95% CI: [0.62, 1.41]
Comparison: Comparison of midazolam95% CI: [0.36, 0.83]
Comparison: Comparison of dabigatran95% CI: [0.44, 1.61]
Comparison: Comparison of dabigatran95% CI: [0.89, 3.27]
Comparison: Comparison of dabigatran95% CI: [0.93, 3.27]
Comparison: Comparison of dabigatran95% CI: [0.38, 1.38]
Comparison: Comparison of pitavastatin95% CI: [0.92, 2.4]
Comparison: Comparison of pitavastatin95% CI: [1.14, 2.98]
Comparison: Comparison of pitavastatin95% CI: [0.84, 2.11]
Comparison: Comparison of pitavastatin95% CI: [0.91, 2.38]
Comparison: Comparison of pitavastatin lactone95% CI: [0.81, 1.75]
Comparison: Comparison of pitavastatin lactone95% CI: [0.82, 1.76]
Comparison: Comparison of pitavastatin lactone95% CI: [0.75, 1.57]
Comparison: Comparison of pitavastatin lactone95% CI: [0.61, 1.31]
Comparison: Comparison of atorvastatin95% CI: [0.58, 3.75]
Comparison: Comparison of atorvastatin95% CI: [1.11, 5.85]
Comparison: Comparison of atorvastatin95% CI: [0.97, 4.81]
Comparison: Comparison of atorvastatin95% CI: [1.28, 6.77]
Comparison: Comparison of ortho-hydroxyatorvastatin95% CI: [0.59, 2.07]
Comparison: Comparison of ortho-hydroxyatorvastatin95% CI: [0.71, 2.17]
Comparison: Comparison of ortho-hydroxyatorvastatin95% CI: [0.55, 1.62]
Comparison: Comparison of ortho-hydroxyatorvastatin95% CI: [0.64, 1.96]
Comparison: Comparison of rosuvastatin95% CI: [0.46, 2.64]
Comparison: Comparison of rosuvastatin95% CI: [0.81, 4.32]
Comparison: Comparison of rosuvastatin95% CI: [0.51, 2.53]
Comparison: Comparison of rosuvastatin95% CI: [0.45, 2.41]
Primary
Plasma Concentration at 24 Hours (C24) Post-dose Period 1
C24hr is a measure of the plasma study drug concentration 24 hours post-dose. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail in healthy participants, participants with renal impairment, and 24 hours prior to hemodialysis in participants with end-stage renal disease requiring hemodialysis.
Time frame: 24 hours post-dose
Population: All participants who were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of C24 for the following reasons: non-compliance with the protocol or high pre-dose concentrations.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| End-Stage Renal Disease | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Midazolam | 0.283 pg/mL |
| End-Stage Renal Disease | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Rosuvastatin | 2.64 pg/mL |
| End-Stage Renal Disease | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 3.67 pg/mL |
| End-Stage Renal Disease | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Pitavastatin | 6.07 pg/mL |
| End-Stage Renal Disease | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Dabigatran | 70.2 pg/mL |
| End-Stage Renal Disease | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 12.9 pg/mL |
| End-Stage Renal Disease | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Atorvastatin | 4.28 pg/mL |
| Severe Impairment | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Atorvastatin | 5.73 pg/mL |
| Severe Impairment | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 23.2 pg/mL |
| Severe Impairment | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Dabigatran | 107 pg/mL |
| Severe Impairment | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Midazolam | 1.83 pg/mL |
| Severe Impairment | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 3.25 pg/mL |
| Severe Impairment | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Pitavastatin | 4.04 pg/mL |
| Severe Impairment | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Rosuvastatin | 3.40 pg/mL |
| Moderate Impairment | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 32.8 pg/mL |
| Moderate Impairment | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Midazolam | 2.64 pg/mL |
| Moderate Impairment | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Dabigatran | 59.3 pg/mL |
| Moderate Impairment | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Pitavastatin | 8.13 pg/mL |
| Moderate Impairment | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Atorvastatin | 6.03 pg/mL |
| Moderate Impairment | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 4.43 pg/mL |
| Moderate Impairment | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Rosuvastatin | 6.01 pg/mL |
| Mild Impairment | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Pitavastatin | 5.32 pg/mL |
| Mild Impairment | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Atorvastatin | 5.04 pg/mL |
| Mild Impairment | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Dabigatran | 18.7 pg/mL |
| Mild Impairment | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Rosuvastatin | 3.59 pg/mL |
| Mild Impairment | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 5.02 pg/mL |
| Mild Impairment | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Midazolam | 0.734 pg/mL |
| Mild Impairment | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 22.4 pg/mL |
| Healthy Control | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Pitavastatin | 4.10 pg/mL |
| Healthy Control | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Rosuvastatin | 1.94 pg/mL |
| Healthy Control | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 3.08 pg/mL |
| Healthy Control | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Atorvastatin | 3.85 pg/mL |
| Healthy Control | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Dabigatran | 7.70 pg/mL |
| Healthy Control | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Midazolam | 1.57 pg/mL |
| Healthy Control | Plasma Concentration at 24 Hours (C24) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 21.7 pg/mL |
Comparison: Comparison of midazolam95% CI: [0.78, 3.62]
Comparison: Comparison of pitavastatin95% CI: [0.75, 2.23]
Comparison: Comparison of pitavastatin95% CI: [1.15, 3.41]
Comparison: Comparison of pitavastatin95% CI: [0.58, 1.66]
Comparison: Comparison of pitavastatin lactone95% CI: [0.52, 2.03]
Comparison: Comparison of pitavastatin lactone95% CI: [0.77, 2.97]
Comparison: Comparison of pitavastatin lactone95% CI: [0.56, 2.05]
Comparison: Comparison of pitavastatin lactone95% CI: [0.3, 1.17]
Comparison: Comparison of atovastatin95% CI: [0.84, 2.94]
Comparison: Comparison of atovastatin95% CI: [0.81, 2.73]
Comparison: Comparison of ortho-hydroxyatorvastatin95% CI: [0.84, 2.47]
Comparison: Comparison of ortho-hydroxyatorvastatin95% CI: [0.63, 1.78]
Comparison: Comparison of rosuvastatin95% CI: [0.95, 3.61]
Comparison: Comparison of rosuvastatin95% CI: [1.64, 5.86]
Comparison: Comparison of rosuvastatin95% CI: [0.95, 3.24]
Primary
Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1
Tmax is the amount of time to reach maximum (peak) plasma drug concentration following drug administration. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail in healthy participants, participants with renal impairment, and 24 hours prior to hemodialysis in participants with end-stage renal disease requiring hemodialysis.
Time frame: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose
Population: All participants who were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of Tmax for the following reasons: non-compliance with the protocol or high pre-dose concentrations.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| End-Stage Renal Disease | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Midazolam | 0.50 hours |
| End-Stage Renal Disease | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Pitavastatin | 0.50 hours |
| End-Stage Renal Disease | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Rosuvastatin | 3.00 hours |
| End-Stage Renal Disease | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Dabigatran | 2.00 hours |
| End-Stage Renal Disease | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 5.00 hours |
| End-Stage Renal Disease | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Atorvastatin | 0.25 hours |
| End-Stage Renal Disease | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 2.50 hours |
| Severe Impairment | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Midazolam | 0.50 hours |
| Severe Impairment | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 6.00 hours |
| Severe Impairment | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Dabigatran | 3.00 hours |
| Severe Impairment | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Atorvastatin | 0.25 hours |
| Severe Impairment | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Pitavastatin | 0.50 hours |
| Severe Impairment | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Rosuvastatin | 4.00 hours |
| Severe Impairment | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 4.00 hours |
| Moderate Impairment | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Midazolam | 0.50 hours |
| Moderate Impairment | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 6.00 hours |
| Moderate Impairment | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Atorvastatin | 0.25 hours |
| Moderate Impairment | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 2.50 hours |
| Moderate Impairment | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Dabigatran | 2.50 hours |
| Moderate Impairment | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Rosuvastatin | 4.00 hours |
| Moderate Impairment | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Pitavastatin | 1.00 hours |
| Mild Impairment | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Pitavastatin | 0.52 hours |
| Mild Impairment | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Rosuvastatin | 2.00 hours |
| Mild Impairment | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Dabigatran | 1.50 hours |
| Mild Impairment | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 6.00 hours |
| Mild Impairment | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 2.00 hours |
| Mild Impairment | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Atorvastatin | 0.25 hours |
| Mild Impairment | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Midazolam | 0.50 hours |
| Healthy Control | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Rosuvastatin | 3.50 hours |
| Healthy Control | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Midazolam | 1.00 hours |
| Healthy Control | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Dabigatran | 1.50 hours |
| Healthy Control | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Pitavastatin lactone (metabolite) | 2.00 hours |
| Healthy Control | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Atorvastatin | 0.50 hours |
| Healthy Control | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Ortho-hydroxyatorvastatin (metabolite) | 6.00 hours |
| Healthy Control | Time to Maximum Plasma Concentration (Tmax) Post-dose Period 1 | Pitavastatin | 0.75 hours |
Secondary
Effect of Rifampin on AUC0-24 Post-dose Period 2
To evaluate the effect of a single oral dose of rifampin on the AUC0-24 of midazolam, dabigatran, pitavastatin, pitavastatin lactone, atorvastatin, ortho-hydroxyatorvastatin, and rosuvatatin. AUC0-24 is the area under the plasma concentration-time curve from time 0 to 24 hours post-dose. This is a measure of the average amount of study drug in the blood plasma over a period of 24 hours after the dose. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail and rifampin in healthy participants and participants with renal impairment. As pre-specified in the protocol, this outcome measure does not include end-stage renal disease participants as they did not receive rifampin during Period 2.
Time frame: Microdose cocktail: 0 hour (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post-dose; rifampin: 0 hour (pre-dose) and 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose
Population: All participants who received rifampin, were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of AUC0-24 for the following reasons: non-compliance with the protocol or high pre-dose concentrations. Per protocol, end-stage renal disease participants did not receive rifampin.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Severe Impairment | Effect of Rifampin on AUC0-24 Post-dose Period 2 | Midazolam | 238 pg*hr/mL |
| Severe Impairment | Effect of Rifampin on AUC0-24 Post-dose Period 2 | Atorvastatin | 2230 pg*hr/mL |
| Severe Impairment | Effect of Rifampin on AUC0-24 Post-dose Period 2 | Rosuvastatin | 1100 pg*hr/mL |
| Severe Impairment | Effect of Rifampin on AUC0-24 Post-dose Period 2 | Pitavastatin | 2760 pg*hr/mL |
| Severe Impairment | Effect of Rifampin on AUC0-24 Post-dose Period 2 | Dabigatran | 6540 pg*hr/mL |
| Severe Impairment | Effect of Rifampin on AUC0-24 Post-dose Period 2 | Ortho-hydroxyatorvastatin (metabolite) | 1580 pg*hr/mL |
| Severe Impairment | Effect of Rifampin on AUC0-24 Post-dose Period 2 | Pitavastatin lactone (metabolite) | 1070 pg*hr/mL |
| Moderate Impairment | Effect of Rifampin on AUC0-24 Post-dose Period 2 | Ortho-hydroxyatorvastatin (metabolite) | 1800 pg*hr/mL |
| Moderate Impairment | Effect of Rifampin on AUC0-24 Post-dose Period 2 | Midazolam | 346 pg*hr/mL |
| Moderate Impairment | Effect of Rifampin on AUC0-24 Post-dose Period 2 | Rosuvastatin | 1670 pg*hr/mL |
| Moderate Impairment | Effect of Rifampin on AUC0-24 Post-dose Period 2 | Pitavastatin lactone (metabolite) | 1780 pg*hr/mL |
| Moderate Impairment | Effect of Rifampin on AUC0-24 Post-dose Period 2 | Pitavastatin | 3360 pg*hr/mL |
| Moderate Impairment | Effect of Rifampin on AUC0-24 Post-dose Period 2 | Dabigatran | 5480 pg*hr/mL |
| Moderate Impairment | Effect of Rifampin on AUC0-24 Post-dose Period 2 | Atorvastatin | 2420 pg*hr/mL |
| Mild Impairment | Effect of Rifampin on AUC0-24 Post-dose Period 2 | Dabigatran | 2660 pg*hr/mL |
| Mild Impairment | Effect of Rifampin on AUC0-24 Post-dose Period 2 | Pitavastatin | 2460 pg*hr/mL |
| Mild Impairment | Effect of Rifampin on AUC0-24 Post-dose Period 2 | Pitavastatin lactone (metabolite) | 1490 pg*hr/mL |
| Mild Impairment | Effect of Rifampin on AUC0-24 Post-dose Period 2 | Atorvastatin | 1700 pg*hr/mL |
| Mild Impairment | Effect of Rifampin on AUC0-24 Post-dose Period 2 | Ortho-hydroxyatorvastatin (metabolite) | 1720 pg*hr/mL |
| Mild Impairment | Effect of Rifampin on AUC0-24 Post-dose Period 2 | Rosuvastatin | 1010 pg*hr/mL |
| Mild Impairment | Effect of Rifampin on AUC0-24 Post-dose Period 2 | Midazolam | 186 pg*hr/mL |
| Healthy Control | Effect of Rifampin on AUC0-24 Post-dose Period 2 | Ortho-hydroxyatorvastatin (metabolite) | 1620 pg*hr/mL |
| Healthy Control | Effect of Rifampin on AUC0-24 Post-dose Period 2 | Pitavastatin | 1860 pg*hr/mL |
| Healthy Control | Effect of Rifampin on AUC0-24 Post-dose Period 2 | Midazolam | 234 pg*hr/mL |
| Healthy Control | Effect of Rifampin on AUC0-24 Post-dose Period 2 | Atorvastatin | 1760 pg*hr/mL |
| Healthy Control | Effect of Rifampin on AUC0-24 Post-dose Period 2 | Dabigatran | 3030 pg*hr/mL |
| Healthy Control | Effect of Rifampin on AUC0-24 Post-dose Period 2 | Pitavastatin lactone (metabolite) | 1000 pg*hr/mL |
| Healthy Control | Effect of Rifampin on AUC0-24 Post-dose Period 2 | Rosuvastatin | 842 pg*hr/mL |
Secondary
Effect of Rifampin on AUC0-last Post-dose Period 2
To evaluate the effect of a single oral dose of rifampin on the AUC0-last of midazolam, dabigatran, pitavastatin, pitavastatin lactone, atorvastatin, ortho-hydroxyatorvastatin, and rosuvatatin. AUC0-last is the area under the plasma concentration-time curve from time zero to time of last measurable concentration. It is a measure of the amount of study drug in the blood plasma from pre-dose until the last measurable concentration of study drug could be determined. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail and rifampin in healthy participants and participants with renal impairment. As pre-specified in the protocol, this outcome measure does not include end-stage renal disease participants as they did not receive rifampin during Period 2.
Time frame: Microdose cocktail: 0 hour (pre-dose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose; rifampin: 0 hour (pre-dose) and 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose
Population: All participants who received rifampin, were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of AUC0-last for the following reasons: non-compliance with the protocol or high pre-dose concentrations. Per protocol, end-stage renal disease participants did not receive rifampin.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Severe Impairment | Effect of Rifampin on AUC0-last Post-dose Period 2 | Dabigatran | 10400 pg*hr/mL |
| Severe Impairment | Effect of Rifampin on AUC0-last Post-dose Period 2 | Midazolam | 236 pg*hr/mL |
| Severe Impairment | Effect of Rifampin on AUC0-last Post-dose Period 2 | Pitavastatin lactone (metabolite) | 1470 pg*hr/mL |
| Severe Impairment | Effect of Rifampin on AUC0-last Post-dose Period 2 | Rosuvastatin | 1150 pg*hr/mL |
| Severe Impairment | Effect of Rifampin on AUC0-last Post-dose Period 2 | Atorvastatin | 2220 pg*hr/mL |
| Severe Impairment | Effect of Rifampin on AUC0-last Post-dose Period 2 | Ortho-hydroxyatorvastatin (metabolite) | 1610 pg*hr/mL |
| Severe Impairment | Effect of Rifampin on AUC0-last Post-dose Period 2 | Pitavastatin | 2850 pg*hr/mL |
| Moderate Impairment | Effect of Rifampin on AUC0-last Post-dose Period 2 | Atorvastatin | 2420 pg*hr/mL |
| Moderate Impairment | Effect of Rifampin on AUC0-last Post-dose Period 2 | Dabigatran | 6830 pg*hr/mL |
| Moderate Impairment | Effect of Rifampin on AUC0-last Post-dose Period 2 | Pitavastatin | 3480 pg*hr/mL |
| Moderate Impairment | Effect of Rifampin on AUC0-last Post-dose Period 2 | Midazolam | 353 pg*hr/mL |
| Moderate Impairment | Effect of Rifampin on AUC0-last Post-dose Period 2 | Pitavastatin lactone (metabolite) | 2380 pg*hr/mL |
| Moderate Impairment | Effect of Rifampin on AUC0-last Post-dose Period 2 | Ortho-hydroxyatorvastatin (metabolite) | 1850 pg*hr/mL |
| Moderate Impairment | Effect of Rifampin on AUC0-last Post-dose Period 2 | Rosuvastatin | 1740 pg*hr/mL |
| Mild Impairment | Effect of Rifampin on AUC0-last Post-dose Period 2 | Pitavastatin lactone (metabolite) | 1850 pg*hr/mL |
| Mild Impairment | Effect of Rifampin on AUC0-last Post-dose Period 2 | Atorvastatin | 1690 pg*hr/mL |
| Mild Impairment | Effect of Rifampin on AUC0-last Post-dose Period 2 | Ortho-hydroxyatorvastatin (metabolite) | 1750 pg*hr/mL |
| Mild Impairment | Effect of Rifampin on AUC0-last Post-dose Period 2 | Dabigatran | 2830 pg*hr/mL |
| Mild Impairment | Effect of Rifampin on AUC0-last Post-dose Period 2 | Rosuvastatin | 1040 pg*hr/mL |
| Mild Impairment | Effect of Rifampin on AUC0-last Post-dose Period 2 | Pitavastatin | 2510 pg*hr/mL |
| Mild Impairment | Effect of Rifampin on AUC0-last Post-dose Period 2 | Midazolam | 182 pg*hr/mL |
| Healthy Control | Effect of Rifampin on AUC0-last Post-dose Period 2 | Rosuvastatin | 854 pg*hr/mL |
| Healthy Control | Effect of Rifampin on AUC0-last Post-dose Period 2 | Midazolam | 231 pg*hr/mL |
| Healthy Control | Effect of Rifampin on AUC0-last Post-dose Period 2 | Atorvastatin | 1760 pg*hr/mL |
| Healthy Control | Effect of Rifampin on AUC0-last Post-dose Period 2 | Dabigatran | 3140 pg*hr/mL |
| Healthy Control | Effect of Rifampin on AUC0-last Post-dose Period 2 | Pitavastatin | 1890 pg*hr/mL |
| Healthy Control | Effect of Rifampin on AUC0-last Post-dose Period 2 | Pitavastatin lactone (metabolite) | 1270 pg*hr/mL |
| Healthy Control | Effect of Rifampin on AUC0-last Post-dose Period 2 | Ortho-hydroxyatorvastatin (metabolite) | 1630 pg*hr/mL |
Secondary
Effect of Rifampin on C24 Post-dose Period 2
To evaluate the effect of a single oral dose of rifampin on the C24 of midazolam, dabigatran, pitavastatin, pitavastatin lactone, atorvastatin, ortho-hydroxyatorvastatin, and rosuvatatin. C24 is a measure of the plasma study drug concentration 24 hours post-dose. C24 is reported as median (minimum and maximum) in severe renal impairment arm due to zero values. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail and rifampin in healthy participants and participants with renal impairment. As pre-specified in the protocol, this outcome measure does not include end-stage renal disease participants as they did not receive rifampin during Period 2.
Time frame: 24 hours post-dose
Population: All participants who received rifampin, were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of C24 for the following reasons: non-compliance with the protocol or high pre-dose concentrations. Per protocol, end-stage renal disease participants did not receive rifampin.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Severe Impairment | Effect of Rifampin on C24 Post-dose Period 2 | Midazolam | 0.394 pg/mL |
| Severe Impairment | Effect of Rifampin on C24 Post-dose Period 2 | Pitavastatin | 7.01 pg/mL |
| Severe Impairment | Effect of Rifampin on C24 Post-dose Period 2 | Ortho-hydroxyatorvastatin (metabolite) | 7.23 pg/mL |
| Severe Impairment | Effect of Rifampin on C24 Post-dose Period 2 | Pitavastatin lactone (metabolite) | 21.3 pg/mL |
| Severe Impairment | Effect of Rifampin on C24 Post-dose Period 2 | Dabigatran | 174 pg/mL |
| Severe Impairment | Effect of Rifampin on C24 Post-dose Period 2 | Rosuvastatin | 4.47 pg/mL |
| Severe Impairment | Effect of Rifampin on C24 Post-dose Period 2 | Atorvastatin | 2.98 pg/mL |
| Moderate Impairment | Effect of Rifampin on C24 Post-dose Period 2 | Pitavastatin lactone (metabolite) | 34.0 pg/mL |
| Moderate Impairment | Effect of Rifampin on C24 Post-dose Period 2 | Midazolam | 1.42 pg/mL |
| Moderate Impairment | Effect of Rifampin on C24 Post-dose Period 2 | Dabigatran | 100 pg/mL |
| Moderate Impairment | Effect of Rifampin on C24 Post-dose Period 2 | Pitavastatin | 10.5 pg/mL |
| Moderate Impairment | Effect of Rifampin on C24 Post-dose Period 2 | Atorvastatin | 2.98 pg/mL |
| Moderate Impairment | Effect of Rifampin on C24 Post-dose Period 2 | Ortho-hydroxyatorvastatin (metabolite) | 9.96 pg/mL |
| Moderate Impairment | Effect of Rifampin on C24 Post-dose Period 2 | Rosuvastatin | 6.97 pg/mL |
| Mild Impairment | Effect of Rifampin on C24 Post-dose Period 2 | Dabigatran | 31.1 pg/mL |
| Mild Impairment | Effect of Rifampin on C24 Post-dose Period 2 | Rosuvastatin | 4.18 pg/mL |
| Mild Impairment | Effect of Rifampin on C24 Post-dose Period 2 | Ortho-hydroxyatorvastatin (metabolite) | 6.28 pg/mL |
| Mild Impairment | Effect of Rifampin on C24 Post-dose Period 2 | Midazolam | 0.00 pg/mL |
| Mild Impairment | Effect of Rifampin on C24 Post-dose Period 2 | Atorvastatin | 1.76 pg/mL |
| Mild Impairment | Effect of Rifampin on C24 Post-dose Period 2 | Pitavastatin | 4.70 pg/mL |
| Mild Impairment | Effect of Rifampin on C24 Post-dose Period 2 | Pitavastatin lactone (metabolite) | 20.7 pg/mL |
| Healthy Control | Effect of Rifampin on C24 Post-dose Period 2 | Rosuvastatin | 2.42 pg/mL |
| Healthy Control | Effect of Rifampin on C24 Post-dose Period 2 | Pitavastatin lactone (metabolite) | 17.1 pg/mL |
| Healthy Control | Effect of Rifampin on C24 Post-dose Period 2 | Atorvastatin | 1.35 pg/mL |
| Healthy Control | Effect of Rifampin on C24 Post-dose Period 2 | Midazolam | 0.601 pg/mL |
| Healthy Control | Effect of Rifampin on C24 Post-dose Period 2 | Ortho-hydroxyatorvastatin (metabolite) | 5.57 pg/mL |
| Healthy Control | Effect of Rifampin on C24 Post-dose Period 2 | Pitavastatin | 4.72 pg/mL |
| Healthy Control | Effect of Rifampin on C24 Post-dose Period 2 | Dabigatran | 27.5 pg/mL |
Secondary
Effect of Rifampin on CL/F Post-dose Period 2
To evaluate the effect of a single oral dose of rifampin on the CL/F of midazolam, dabigatran, pitavastatin, atorvastatin, and rosuvatatin. CL/F is the rate at which study drug was removed from the body. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail and rifampin in healthy participants and participants with renal impairment. As pre-specified in the protocol, this outcome measure does not include end-stage renal disease participants as they did not receive rifampin during Period 2.
Time frame: Microdose cocktail: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose; rifampin: 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose
Population: All participants who received rifampin, were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of CL/F for the following reasons: non-compliance with the protocol or high pre-dose concentrations. Per protocol, end-stage renal disease participants did not receive rifampin.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Severe Impairment | Effect of Rifampin on CL/F Post-dose Period 2 | Pitavastatin | 3.57 liters/hour | Geometric Coefficient of Variation 50 |
| Severe Impairment | Effect of Rifampin on CL/F Post-dose Period 2 | Atorvastatin | 44.2 liters/hour | Geometric Coefficient of Variation 57.6 |
| Severe Impairment | Effect of Rifampin on CL/F Post-dose Period 2 | Rosuvastatin | 38.6 liters/hour | Geometric Coefficient of Variation 37.7 |
| Severe Impairment | Effect of Rifampin on CL/F Post-dose Period 2 | Midazolam | 40.5 liters/hour | Geometric Coefficient of Variation 57.7 |
| Severe Impairment | Effect of Rifampin on CL/F Post-dose Period 2 | Dabigatran | 26.3 liters/hour | Geometric Coefficient of Variation 41.6 |
| Moderate Impairment | Effect of Rifampin on CL/F Post-dose Period 2 | Dabigatran | 38.9 liters/hour | Geometric Coefficient of Variation 58.7 |
| Moderate Impairment | Effect of Rifampin on CL/F Post-dose Period 2 | Rosuvastatin | 28.9 liters/hour | Geometric Coefficient of Variation 41.1 |
| Moderate Impairment | Effect of Rifampin on CL/F Post-dose Period 2 | Midazolam | 27.8 liters/hour | Geometric Coefficient of Variation 52 |
| Moderate Impairment | Effect of Rifampin on CL/F Post-dose Period 2 | Atorvastatin | 41.1 liters/hour | Geometric Coefficient of Variation 30.3 |
| Moderate Impairment | Effect of Rifampin on CL/F Post-dose Period 2 | Pitavastatin | 2.86 liters/hour | Geometric Coefficient of Variation 60.4 |
| Mild Impairment | Effect of Rifampin on CL/F Post-dose Period 2 | Rosuvastatin | 47.1 liters/hour | Geometric Coefficient of Variation 51.1 |
| Mild Impairment | Effect of Rifampin on CL/F Post-dose Period 2 | Atorvastatin | 58.6 liters/hour | Geometric Coefficient of Variation 49.4 |
| Mild Impairment | Effect of Rifampin on CL/F Post-dose Period 2 | Dabigatran | 92.8 liters/hour | Geometric Coefficient of Variation 41.5 |
| Mild Impairment | Effect of Rifampin on CL/F Post-dose Period 2 | Pitavastatin | 3.95 liters/hour | Geometric Coefficient of Variation 51.8 |
| Mild Impairment | Effect of Rifampin on CL/F Post-dose Period 2 | Midazolam | 53.0 liters/hour | Geometric Coefficient of Variation 34.8 |
| Healthy Control | Effect of Rifampin on CL/F Post-dose Period 2 | Rosuvastatin | 57.9 liters/hour | Geometric Coefficient of Variation 63.3 |
| Healthy Control | Effect of Rifampin on CL/F Post-dose Period 2 | Atorvastatin | 56.4 liters/hour | Geometric Coefficient of Variation 62.2 |
| Healthy Control | Effect of Rifampin on CL/F Post-dose Period 2 | Midazolam | 41.8 liters/hour | Geometric Coefficient of Variation 28.4 |
| Healthy Control | Effect of Rifampin on CL/F Post-dose Period 2 | Dabigatran | 85.6 liters/hour | Geometric Coefficient of Variation 40 |
| Healthy Control | Effect of Rifampin on CL/F Post-dose Period 2 | Pitavastatin | 5.24 liters/hour | Geometric Coefficient of Variation 75.8 |
Secondary
Effect of Rifampin on Cmax Post-dose Period 2
To evaluate the effect of a single oral dose of rifampin on the Cmax of midazolam, dabigatran, pitavastatin, pitavastatin lactone, atorvastatin, ortho-hydroxyatorvastatin, and rosuvatatin. Cmax is the peak plasma concentration of study drug after administration. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail and rifampin in healthy participants and participants with renal impairment. As pre-specified in the protocol, this outcome measure does not include end-stage renal disease participants as they did not receive rifampin during Period 2.
Time frame: Microdose cocktail: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose; rifampin: 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose
Population: All participants who received rifampin, were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of Cmax for the following reasons: non-compliance with the protocol or high pre-dose concentrations. Per protocol, end-stage renal disease participants did not receive rifampin.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Severe Impairment | Effect of Rifampin on Cmax Post-dose Period 2 | Midazolam | 75.4 pg/mL |
| Severe Impairment | Effect of Rifampin on Cmax Post-dose Period 2 | Ortho-hydroxyatorvastatin (metabolite) | 150 pg/mL |
| Severe Impairment | Effect of Rifampin on Cmax Post-dose Period 2 | Atorvastatin | 531 pg/mL |
| Severe Impairment | Effect of Rifampin on Cmax Post-dose Period 2 | Dabigatran | 422 pg/mL |
| Severe Impairment | Effect of Rifampin on Cmax Post-dose Period 2 | Rosuvastatin | 208 pg/mL |
| Severe Impairment | Effect of Rifampin on Cmax Post-dose Period 2 | Pitavastatin | 981 pg/mL |
| Severe Impairment | Effect of Rifampin on Cmax Post-dose Period 2 | Pitavastatin lactone (metabolite) | 88.4 pg/mL |
| Moderate Impairment | Effect of Rifampin on Cmax Post-dose Period 2 | Ortho-hydroxyatorvastatin (metabolite) | 174 pg/mL |
| Moderate Impairment | Effect of Rifampin on Cmax Post-dose Period 2 | Pitavastatin lactone (metabolite) | 119 pg/mL |
| Moderate Impairment | Effect of Rifampin on Cmax Post-dose Period 2 | Pitavastatin | 860 pg/mL |
| Moderate Impairment | Effect of Rifampin on Cmax Post-dose Period 2 | Atorvastatin | 508 pg/mL |
| Moderate Impairment | Effect of Rifampin on Cmax Post-dose Period 2 | Rosuvastatin | 396 pg/mL |
| Moderate Impairment | Effect of Rifampin on Cmax Post-dose Period 2 | Dabigatran | 443 pg/mL |
| Moderate Impairment | Effect of Rifampin on Cmax Post-dose Period 2 | Midazolam | 92.5 pg/mL |
| Mild Impairment | Effect of Rifampin on Cmax Post-dose Period 2 | Pitavastatin lactone (metabolite) | 131 pg/mL |
| Mild Impairment | Effect of Rifampin on Cmax Post-dose Period 2 | Midazolam | 73.0 pg/mL |
| Mild Impairment | Effect of Rifampin on Cmax Post-dose Period 2 | Dabigatran | 243 pg/mL |
| Mild Impairment | Effect of Rifampin on Cmax Post-dose Period 2 | Pitavastatin | 819 pg/mL |
| Mild Impairment | Effect of Rifampin on Cmax Post-dose Period 2 | Atorvastatin | 505 pg/mL |
| Mild Impairment | Effect of Rifampin on Cmax Post-dose Period 2 | Ortho-hydroxyatorvastatin (metabolite) | 215 pg/mL |
| Mild Impairment | Effect of Rifampin on Cmax Post-dose Period 2 | Rosuvastatin | 254 pg/mL |
| Healthy Control | Effect of Rifampin on Cmax Post-dose Period 2 | Pitavastatin | 599 pg/mL |
| Healthy Control | Effect of Rifampin on Cmax Post-dose Period 2 | Rosuvastatin | 236 pg/mL |
| Healthy Control | Effect of Rifampin on Cmax Post-dose Period 2 | Ortho-hydroxyatorvastatin (metabolite) | 198 pg/mL |
| Healthy Control | Effect of Rifampin on Cmax Post-dose Period 2 | Dabigatran | 351 pg/mL |
| Healthy Control | Effect of Rifampin on Cmax Post-dose Period 2 | Midazolam | 81.4 pg/mL |
| Healthy Control | Effect of Rifampin on Cmax Post-dose Period 2 | Atorvastatin | 405 pg/mL |
| Healthy Control | Effect of Rifampin on Cmax Post-dose Period 2 | Pitavastatin lactone (metabolite) | 102 pg/mL |
Secondary
Effect of Rifampin on t1/2 Post-dose Period 2
To evaluate the effect of a single oral dose of rifampin on the t1/2 of midazolam, dabigatran, pitavastatin, pitavastatin lactone, atorvastatin, ortho-hydroxyatorvastatin, and rosuvatatin. T1/2 is the elimination half-life of study drug. T1/2 is the time it takes for half of the study drug in the blood plasma to dissipate. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail and rifampin in healthy participants and participants with renal impairment. As pre-specified in the protocol, this outcome measure does not include end-stage renal disease participants as they did not receive rifampin during Period 2.
Time frame: Microdose cocktail: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose; rifampin: 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose
Population: All participants who received rifampin, were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of t1/2 for the following reasons: non-compliance with the protocol or high pre-dose concentrations. Per protocol, end-stage renal disease participants did not receive rifampin.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Severe Impairment | Effect of Rifampin on t1/2 Post-dose Period 2 | Pitavastatin | 6.99 hours | Geometric Coefficient of Variation 62.8 |
| Severe Impairment | Effect of Rifampin on t1/2 Post-dose Period 2 | Atorvastatin | 3.14 hours | Geometric Coefficient of Variation 18.9 |
| Severe Impairment | Effect of Rifampin on t1/2 Post-dose Period 2 | Ortho-hydroxyatorvastatin (metabolite) | 4.56 hours | Geometric Coefficient of Variation 43.7 |
| Severe Impairment | Effect of Rifampin on t1/2 Post-dose Period 2 | Rosuvastatin | 4.89 hours | Geometric Coefficient of Variation 49.9 |
| Severe Impairment | Effect of Rifampin on t1/2 Post-dose Period 2 | Midazolam | 4.14 hours | Geometric Coefficient of Variation 19.5 |
| Severe Impairment | Effect of Rifampin on t1/2 Post-dose Period 2 | Dabigatran | 19.4 hours | Geometric Coefficient of Variation 21.3 |
| Severe Impairment | Effect of Rifampin on t1/2 Post-dose Period 2 | Pitavastatin lactone (metabolite) | 17.2 hours | Geometric Coefficient of Variation 41 |
| Moderate Impairment | Effect of Rifampin on t1/2 Post-dose Period 2 | Atorvastatin | 2.99 hours | Geometric Coefficient of Variation 21.1 |
| Moderate Impairment | Effect of Rifampin on t1/2 Post-dose Period 2 | Midazolam | 5.49 hours | Geometric Coefficient of Variation 26.2 |
| Moderate Impairment | Effect of Rifampin on t1/2 Post-dose Period 2 | Ortho-hydroxyatorvastatin (metabolite) | 4.25 hours | Geometric Coefficient of Variation 39.7 |
| Moderate Impairment | Effect of Rifampin on t1/2 Post-dose Period 2 | Pitavastatin | 11.5 hours | Geometric Coefficient of Variation 71.6 |
| Moderate Impairment | Effect of Rifampin on t1/2 Post-dose Period 2 | Pitavastatin lactone (metabolite) | 17.7 hours | Geometric Coefficient of Variation 25.2 |
| Moderate Impairment | Effect of Rifampin on t1/2 Post-dose Period 2 | Dabigatran | 11.3 hours | Geometric Coefficient of Variation 33.1 |
| Moderate Impairment | Effect of Rifampin on t1/2 Post-dose Period 2 | Rosuvastatin | 7.48 hours | Geometric Coefficient of Variation 19.8 |
| Mild Impairment | Effect of Rifampin on t1/2 Post-dose Period 2 | Dabigatran | 7.57 hours | Geometric Coefficient of Variation 19 |
| Mild Impairment | Effect of Rifampin on t1/2 Post-dose Period 2 | Rosuvastatin | 9.64 hours | Geometric Coefficient of Variation 83.8 |
| Mild Impairment | Effect of Rifampin on t1/2 Post-dose Period 2 | Atorvastatin | 3.22 hours | Geometric Coefficient of Variation 8.6 |
| Mild Impairment | Effect of Rifampin on t1/2 Post-dose Period 2 | Ortho-hydroxyatorvastatin (metabolite) | 3.83 hours | Geometric Coefficient of Variation 19.7 |
| Mild Impairment | Effect of Rifampin on t1/2 Post-dose Period 2 | Pitavastatin lactone (metabolite) | 21.0 hours | Geometric Coefficient of Variation 22.5 |
| Mild Impairment | Effect of Rifampin on t1/2 Post-dose Period 2 | Midazolam | 4.12 hours | Geometric Coefficient of Variation 26.7 |
| Mild Impairment | Effect of Rifampin on t1/2 Post-dose Period 2 | Pitavastatin | 8.40 hours | Geometric Coefficient of Variation 75.8 |
| Healthy Control | Effect of Rifampin on t1/2 Post-dose Period 2 | Atorvastatin | 2.76 hours | Geometric Coefficient of Variation 8.4 |
| Healthy Control | Effect of Rifampin on t1/2 Post-dose Period 2 | Ortho-hydroxyatorvastatin (metabolite) | 3.49 hours | Geometric Coefficient of Variation 11.7 |
| Healthy Control | Effect of Rifampin on t1/2 Post-dose Period 2 | Rosuvastatin | 6.76 hours | Geometric Coefficient of Variation 94.3 |
| Healthy Control | Effect of Rifampin on t1/2 Post-dose Period 2 | Midazolam | 4.97 hours | Geometric Coefficient of Variation 22 |
| Healthy Control | Effect of Rifampin on t1/2 Post-dose Period 2 | Dabigatran | 6.48 hours | Geometric Coefficient of Variation 13.7 |
| Healthy Control | Effect of Rifampin on t1/2 Post-dose Period 2 | Pitavastatin lactone (metabolite) | 16.5 hours | Geometric Coefficient of Variation 33.9 |
| Healthy Control | Effect of Rifampin on t1/2 Post-dose Period 2 | Pitavastatin | 6.50 hours | Geometric Coefficient of Variation 30.3 |
Secondary
Effect of Rifampin on Tmax Post-dose Period 2
To evaluate the effect of a single oral dose of rifampin on the Tmax of midazolam, dabigatran, pitavastatin, pitavastatin lactone, atorvastatin, ortho-hydroxyatorvastatin, and rosuvatatin. Tmax is the amount of time to reach maximum (peak) plasma drug concentration following drug administration. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail and rifampin in healthy participants and participants with renal impairment. As pre-specified in the protocol, this outcome measure does not include end-stage renal disease participants as they did not receive rifampin during Period 2.
Time frame: Microdose cocktail: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose; rifampin: 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose
Population: All participants who received rifampin, were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of Tmax for the following reasons: non-compliance with the protocol or high pre-dose concentrations. Per protocol, end-stage renal disease participants did not receive rifampin.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Severe Impairment | Effect of Rifampin on Tmax Post-dose Period 2 | Pitavastatin lactone (metabolite) | 3.00 hours |
| Severe Impairment | Effect of Rifampin on Tmax Post-dose Period 2 | Pitavastatin | 1.00 hours |
| Severe Impairment | Effect of Rifampin on Tmax Post-dose Period 2 | Dabigatran | 3.50 hours |
| Severe Impairment | Effect of Rifampin on Tmax Post-dose Period 2 | Atorvastatin | 0.50 hours |
| Severe Impairment | Effect of Rifampin on Tmax Post-dose Period 2 | Rosuvastatin | 1.00 hours |
| Severe Impairment | Effect of Rifampin on Tmax Post-dose Period 2 | Midazolam | 0.50 hours |
| Severe Impairment | Effect of Rifampin on Tmax Post-dose Period 2 | Ortho-hydroxyatorvastatin (metabolite) | 1.75 hours |
| Moderate Impairment | Effect of Rifampin on Tmax Post-dose Period 2 | Pitavastatin lactone (metabolite) | 4.00 hours |
| Moderate Impairment | Effect of Rifampin on Tmax Post-dose Period 2 | Atorvastatin | 1.50 hours |
| Moderate Impairment | Effect of Rifampin on Tmax Post-dose Period 2 | Midazolam | 0.75 hours |
| Moderate Impairment | Effect of Rifampin on Tmax Post-dose Period 2 | Dabigatran | 3.00 hours |
| Moderate Impairment | Effect of Rifampin on Tmax Post-dose Period 2 | Pitavastatin | 1.00 hours |
| Moderate Impairment | Effect of Rifampin on Tmax Post-dose Period 2 | Ortho-hydroxyatorvastatin (metabolite) | 2.50 hours |
| Moderate Impairment | Effect of Rifampin on Tmax Post-dose Period 2 | Rosuvastatin | 2.00 hours |
| Mild Impairment | Effect of Rifampin on Tmax Post-dose Period 2 | Midazolam | 0.50 hours |
| Mild Impairment | Effect of Rifampin on Tmax Post-dose Period 2 | Pitavastatin | 1.00 hours |
| Mild Impairment | Effect of Rifampin on Tmax Post-dose Period 2 | Atorvastatin | 1.00 hours |
| Mild Impairment | Effect of Rifampin on Tmax Post-dose Period 2 | Rosuvastatin | 1.00 hours |
| Mild Impairment | Effect of Rifampin on Tmax Post-dose Period 2 | Ortho-hydroxyatorvastatin (metabolite) | 1.75 hours |
| Mild Impairment | Effect of Rifampin on Tmax Post-dose Period 2 | Pitavastatin lactone (metabolite) | 3.00 hours |
| Mild Impairment | Effect of Rifampin on Tmax Post-dose Period 2 | Dabigatran | 2.50 hours |
| Healthy Control | Effect of Rifampin on Tmax Post-dose Period 2 | Midazolam | 1.00 hours |
| Healthy Control | Effect of Rifampin on Tmax Post-dose Period 2 | Rosuvastatin | 2.00 hours |
| Healthy Control | Effect of Rifampin on Tmax Post-dose Period 2 | Dabigatran | 2.50 hours |
| Healthy Control | Effect of Rifampin on Tmax Post-dose Period 2 | Pitavastatin | 1.00 hours |
| Healthy Control | Effect of Rifampin on Tmax Post-dose Period 2 | Ortho-hydroxyatorvastatin (metabolite) | 3.00 hours |
| Healthy Control | Effect of Rifampin on Tmax Post-dose Period 2 | Atorvastatin | 1.50 hours |
| Healthy Control | Effect of Rifampin on Tmax Post-dose Period 2 | Pitavastatin lactone (metabolite) | 2.00 hours |
Secondary
Effect of Rifampin on Vz/F Post-dose Period 2
To evaluate the effect of a single oral dose of rifampin on the Vz/F of midazolam, dabigatran, pitavastatin, pitavastatin lactone, atorvastatin, ortho-hydroxyatorvastatin, and rosuvatatin. Vz/F is the distribution of study drug between the plasma and the rest of the body after the dose. Plasma pharmacokinetic data presented in the table below are following the administration of a single oral dose of a microdose cocktail and rifampin in healthy participants and participants with renal impairment. As pre-specified in the protocol, this outcome measure does not include end-stage renal disease participants as they did not receive rifampin during Period 2.
Time frame: Microdose cocktail: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, and 72 hours post-dose; rifampin: 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose
Population: All participants who received rifampin, were compliant with the study procedure and had available data. Per protocol, participants were excluded from this analysis of Vz/F for the following reasons: non-compliance with the protocol or high pre-dose concentrations. Per protocol, end-stage renal disease participants did not receive rifampin.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Severe Impairment | Effect of Rifampin on Vz/F Post-dose Period 2 | Midazolam | 242 liters | Geometric Coefficient of Variation 44.6 |
| Severe Impairment | Effect of Rifampin on Vz/F Post-dose Period 2 | Rosuvastatin | 272 liters | Geometric Coefficient of Variation 39.7 |
| Severe Impairment | Effect of Rifampin on Vz/F Post-dose Period 2 | Dabigatran | 733 liters | Geometric Coefficient of Variation 29.2 |
| Severe Impairment | Effect of Rifampin on Vz/F Post-dose Period 2 | Atorvastatin | 200 liters | Geometric Coefficient of Variation 55.4 |
| Severe Impairment | Effect of Rifampin on Vz/F Post-dose Period 2 | Pitavastatin | 36.0 liters | Geometric Coefficient of Variation 38.7 |
| Moderate Impairment | Effect of Rifampin on Vz/F Post-dose Period 2 | Pitavastatin | 47.3 liters | Geometric Coefficient of Variation 85.8 |
| Moderate Impairment | Effect of Rifampin on Vz/F Post-dose Period 2 | Atorvastatin | 177 liters | Geometric Coefficient of Variation 38.2 |
| Moderate Impairment | Effect of Rifampin on Vz/F Post-dose Period 2 | Rosuvastatin | 313 liters | Geometric Coefficient of Variation 58.2 |
| Moderate Impairment | Effect of Rifampin on Vz/F Post-dose Period 2 | Midazolam | 220 liters | Geometric Coefficient of Variation 56.5 |
| Moderate Impairment | Effect of Rifampin on Vz/F Post-dose Period 2 | Dabigatran | 632 liters | Geometric Coefficient of Variation 36.3 |
| Mild Impairment | Effect of Rifampin on Vz/F Post-dose Period 2 | Midazolam | 315 liters | Geometric Coefficient of Variation 30.8 |
| Mild Impairment | Effect of Rifampin on Vz/F Post-dose Period 2 | Pitavastatin | 47.8 liters | Geometric Coefficient of Variation 82.5 |
| Mild Impairment | Effect of Rifampin on Vz/F Post-dose Period 2 | Atorvastatin | 272 liters | Geometric Coefficient of Variation 58.4 |
| Mild Impairment | Effect of Rifampin on Vz/F Post-dose Period 2 | Dabigatran | 1010 liters | Geometric Coefficient of Variation 45.2 |
| Mild Impairment | Effect of Rifampin on Vz/F Post-dose Period 2 | Rosuvastatin | 654 liters | Geometric Coefficient of Variation 40.8 |
| Healthy Control | Effect of Rifampin on Vz/F Post-dose Period 2 | Pitavastatin | 49.2 liters | Geometric Coefficient of Variation 72.1 |
| Healthy Control | Effect of Rifampin on Vz/F Post-dose Period 2 | Dabigatran | 800 liters | Geometric Coefficient of Variation 41.1 |
| Healthy Control | Effect of Rifampin on Vz/F Post-dose Period 2 | Midazolam | 300 liters | Geometric Coefficient of Variation 36.3 |
| Healthy Control | Effect of Rifampin on Vz/F Post-dose Period 2 | Rosuvastatin | 565 liters | Geometric Coefficient of Variation 76.1 |
| Healthy Control | Effect of Rifampin on Vz/F Post-dose Period 2 | Atorvastatin | 225 liters | Geometric Coefficient of Variation 68.7 |