Healthy
Conditions
Brief summary
The main purpose of this study is to assess the effect of Pirtobrutinib (LOXO-305) on how fast different formulations of midazolam gets into the blood stream and how long it takes the body to remove it when administered in healthy participants. The study will also access how much endogenous coproporphyrins I and III as biomarkers of OATP1B1 and OATP1B3 is in the bloodstream and how the body handles and eliminates them following single and multiple oral doses of Pirtobrutinib. Safety and tolerability of Pirtobrutinib will also be evaluated. For each participant, the total duration of the study will be 59 days, including screening.
Interventions
DRUGMidazolam Syrup
Administered Orally.
DRUGMidazolam Solution
Administered IV bolus.
DRUGPirtobrutinib
Administered Orally.
Sponsors
Loxo Oncology, Inc.
Eli Lilly and Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Must have Body mass index (BMI) within the range of 18.0 to 32.0 kilograms per square meter (kg/m²), inclusive * Male and female participants in good health, determined by no clinically significant findings from medical history, 12-lead Electrocardiogram (ECG), vital sign measurements, or clinical laboratory evaluations as assessed by the investigator * Female participants of non-childbearing potential and male participants who follow standard contraceptive methods * Must have comply with all study procedures, including the 8-night stay at the Clinical Research Unit (CRU) and follow-up phone call
Exclusion criteria
* History or presence of any diseases or conditions of clinical significance by the Investigator (or designee) and/or Sponsor * Positive serologic test for hepatitis B surface antigen (HBsAg), hepatitis B virus immunoglobulin M (HBV IgM) core antibody, hepatitis C virus (HCV) antibody, or human immunodeficiency virus (HIV) antibody at Screening * Positive polymerase chain reaction (PCR) test for COVID-19 at Screening or Check-in (Day -1) * Known ongoing alcohol and/or drug abuse within 2 years prior to Screening * History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the Investigator (or designee) * Have previously completed or withdrawn from any other study investigating Pirtobrutinib (LOXO-305) and have previously received the investigational product
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PK: Apparent Plasma Terminal Elimination Half-life (t½) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) | PK: t1/2 of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported. |
| PK: Volume of Distribution at Steady State (Vss) of Midazolam Following Intravenous Dose Administration | Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) | PK: Vss of midazolam following intravenous dose administration was reported. |
| PK: Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) | PK: AUC0-t of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported. |
| PK: Area Under the Concentration-Time From Time 0 Extrapolated To Infinity (AUC0-inf) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) | PK: AUC0-inf of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported. |
| PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) | PK: %AUCextrap of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported. |
| PK: Maximum Observed Plasma Concentration (Cmax) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) | PK: Cmax of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported. |
| PK: Time to Maximum Observed Plasma Concentration (Tmax) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) | PK: tmax of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported. |
| PK: Apparent Terminal Elimination Rate Constant (λz) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) | PK: λz of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported. |
| PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) | PK: %AUCextrap of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported. |
| Pharmacokinetics (PK): Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Midazolam and Its Metabolite 1-hydroxymidazolam (1-OH-midazolam) Following Oral Dose Administration | Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) | PK: AUC0-t of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported. |
| PK: Area Under the Concentration-Time From Time 0 Extrapolated To Infinity (AUC0-inf) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) | PK: AUC(0-inf) of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported. |
| PK: Maximum Observed Plasma Concentration (Cmax) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) | PK: Cmax of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported. |
| PK: Time to Maximum Observed Plasma Concentration (Tmax) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) | PK: tmax of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported. |
| PK: Apparent Terminal Elimination Rate Constant (Lambda [λ] z) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) | PK: λz of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported. |
| PK: Apparent Systemic Clearance (CL/F) of Midazolam Following Oral Dose Administration | Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) | PK: CL/F of midazolam following oral dose administration was reported. |
| PK: Apparent Volume of Distribution (Vz/F) of Midazolam Following Oral Dose Administration | Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) | PK: Vz/F of midazolam following oral dose administration was reported. |
| PK: Apparent Plasma Terminal Elimination Half-life (t½) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) | PK: t½ of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported. |
| PK: Total Clearance (CL) of Midazolam Following Intravenous Dose Administration | Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) | PK: CL of midazolam following intravenous dose administration was reported. |
| PK: Volume of Distribution (Vz) of Midazolam Following Intravenous Dose Administration | Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) | PK: Vz of midazolam following intravenous dose administration was reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PK: Area Under the Concentration-time Curve During a Dosing Interval (AUCtau) of Pirtobrutinib | Period 2: Day 5, Day 14 and Day 15 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose), Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 100 hours post-dose) | PK: AUCtau of Pirtobrutinib was reported. |
| PK: Maximum Observed Plasma Concentration (Cmax) of Pirtobrutinib | Period 2: Day 5, Day 14 and Day 15 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose), Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 100 hours post-dose) | PK: Cmax of Pirtobrutinib was reported. |
| PK: Concentration Observed at the End Of the Dosing Interval (Ctrough) of Pirtobrutinib | Period 2: 24-hour post-dose on Day 14, Day 15, and Day 17 | PK: Ctrough of Pirtobrutinib before multiple oral doses administration was reported. |
| PK: Time To Maximum Observed Plasma Concentration (Tmax) of Pirtobrutinib | Period 2: Day 5, Day 14 and Day 15 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose), Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 100 hours post-dose) | PK: tmax of Pirtobrutinib was reported. |
| PK: Apparent Systemic Plasma Clearance at Steady State (CL,ss/F) of Pirtobrutinib | Period 2: Day 14 and Day 15 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose), Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 100 hours post-dose) | PK: CL,ss/F of Pirtobrutinib was reported. |
| PK: Accumulation Ratio (RAUC) of Pirtobrutinib | Period 2: Day 5 and Day 14 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose) | RAUC was ratio of Day 14 AUCtau to Day 5 AUCtau. |
| PK: Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Pirtobrutinib | Period 2: Day 5, Day 14 and Day 15 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose), Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 100 hours post-dose) | PK: AUC0-t of Pirtobrutinib was reported. |
Countries
United States
Participant flow
Pre-assignment details
The study consisted of 2 periods: Period 1 and Period 2. A total of 15 healthy participants were enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| All Participants: Midazolam (IV + Oral Dose) + Pirtobrutinib All participants in the study who received:
* Period 1, Day 1: Participants received a single intravenous (IV) bolus dose of midazolam 250 micrograms (mcg) solution on Day 1.
* Period 1 Day 3: Participants received a single oral dose of midazolam 500 mcg syrup on Day 3. A washout period of 2 days between midazolam IV dose and midazolam oral dose on Day 1 and Day 3 was observed.
* Period 2, Day 5-17: Participants received Pirtobrutinib 200 mg tablets orally once daily (QD) in the morning from Day 5 through Day 17
* Period 2, Day 15: Participants received single IV bolus dose of Midazolam 250 mcg followed by Pirtobrutinib intake on Day 15.
* Period 2, Day 17: Participants received a single oral dose of midazolam 500 mcg syrup followed by Pirtobrutinib intake on Day 17. A washout period of 2 days between midazolam IV dose and midazolam oral dose on Day 15 and Day 17 was observed. | 15 |
| Total | 15 |
Baseline characteristics
| Characteristic | All Participants: Midazolam (IV + Oral Dose) + Pirtobrutinib |
|---|---|
| Age, Continuous | 33.9 years STANDARD_DEVIATION 9.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 10 Participants |
| Region of Enrollment United States | 15 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 12 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 15 | 0 / 15 | 0 / 15 | 0 / 15 |
| other Total, other adverse events | 1 / 15 | 0 / 15 | 3 / 15 | 1 / 15 | 0 / 15 |
| serious Total, serious adverse events | 0 / 15 | 0 / 15 | 0 / 15 | 0 / 15 | 0 / 15 |
Outcome results
Primary
Pharmacokinetics (PK): Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Midazolam and Its Metabolite 1-hydroxymidazolam (1-OH-midazolam) Following Oral Dose Administration
PK: AUC0-t of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported.
Time frame: Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)
Population: All participants who received at least 1 dose of oral midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Period 1: Oral Midazolam 500 mcg (Day 3) | Pharmacokinetics (PK): Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Midazolam and Its Metabolite 1-hydroxymidazolam (1-OH-midazolam) Following Oral Dose Administration | Midazolam | 4.81 Hours*nanograms per milliliter (h*ng/mL) | Geometric Coefficient of Variation 40.8 |
| Period 1: Oral Midazolam 500 mcg (Day 3) | Pharmacokinetics (PK): Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Midazolam and Its Metabolite 1-hydroxymidazolam (1-OH-midazolam) Following Oral Dose Administration | Metabolite: 1-OH-medazolam | 2.24 Hours*nanograms per milliliter (h*ng/mL) | Geometric Coefficient of Variation 41.9 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | Pharmacokinetics (PK): Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Midazolam and Its Metabolite 1-hydroxymidazolam (1-OH-midazolam) Following Oral Dose Administration | Midazolam | 8.30 Hours*nanograms per milliliter (h*ng/mL) | Geometric Coefficient of Variation 43.2 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | Pharmacokinetics (PK): Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Midazolam and Its Metabolite 1-hydroxymidazolam (1-OH-midazolam) Following Oral Dose Administration | Metabolite: 1-OH-medazolam | 2.52 Hours*nanograms per milliliter (h*ng/mL) | Geometric Coefficient of Variation 40.6 |
Primary
PK: Apparent Plasma Terminal Elimination Half-life (t½) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration
PK: t1/2 of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported.
Time frame: Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)
Population: All participants who received at least 1 dose of IV midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Apparent Plasma Terminal Elimination Half-life (t½) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Midazolam | 3.02 hours | Geometric Coefficient of Variation 37 |
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Apparent Plasma Terminal Elimination Half-life (t½) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Metabolite: 1-OH-medazolam | 3.09 hours | Geometric Coefficient of Variation 55.7 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Apparent Plasma Terminal Elimination Half-life (t½) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Midazolam | 3.13 hours | Geometric Coefficient of Variation 49.5 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Apparent Plasma Terminal Elimination Half-life (t½) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Metabolite: 1-OH-medazolam | 2.46 hours | Geometric Coefficient of Variation 47.8 |
Primary
PK: Apparent Plasma Terminal Elimination Half-life (t½) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration
PK: t½ of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported.
Time frame: Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)
Population: All participants who received at least 1 dose of oral midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Apparent Plasma Terminal Elimination Half-life (t½) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | Midazolam | 2.20 hours | Geometric Coefficient of Variation 50.7 |
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Apparent Plasma Terminal Elimination Half-life (t½) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | Metabolite: 1-OH-midazolam | 1.57 hours | Geometric Coefficient of Variation 35.4 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Apparent Plasma Terminal Elimination Half-life (t½) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | Midazolam | 3.05 hours | Geometric Coefficient of Variation 50.2 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Apparent Plasma Terminal Elimination Half-life (t½) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | Metabolite: 1-OH-midazolam | 1.65 hours | Geometric Coefficient of Variation 61.2 |
Primary
PK: Apparent Systemic Clearance (CL/F) of Midazolam Following Oral Dose Administration
PK: CL/F of midazolam following oral dose administration was reported.
Time frame: Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)
Population: All participants who received at least 1 dose of oral midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Apparent Systemic Clearance (CL/F) of Midazolam Following Oral Dose Administration | 94.2 Liters per hour (L/h) | Geometric Coefficient of Variation 43.1 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Apparent Systemic Clearance (CL/F) of Midazolam Following Oral Dose Administration | 55.5 Liters per hour (L/h) | Geometric Coefficient of Variation 44 |
Primary
PK: Apparent Terminal Elimination Rate Constant (Lambda [λ] z) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration
PK: λz of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported.
Time frame: Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)
Population: All participants who received at least 1 dose of oral midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Apparent Terminal Elimination Rate Constant (Lambda [λ] z) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | Midazolam | 0.316 one per hour (1/h) | Geometric Coefficient of Variation 50.7 |
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Apparent Terminal Elimination Rate Constant (Lambda [λ] z) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | Metabolite: 1-OH-midazolam | 0.441 one per hour (1/h) | Geometric Coefficient of Variation 35.4 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Apparent Terminal Elimination Rate Constant (Lambda [λ] z) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | Midazolam | 0.227 one per hour (1/h) | Geometric Coefficient of Variation 50.2 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Apparent Terminal Elimination Rate Constant (Lambda [λ] z) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | Metabolite: 1-OH-midazolam | 0.419 one per hour (1/h) | Geometric Coefficient of Variation 61.2 |
Primary
PK: Apparent Terminal Elimination Rate Constant (λz) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration
PK: λz of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported.
Time frame: Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)
Population: All participants who received at least 1 dose of IV midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Apparent Terminal Elimination Rate Constant (λz) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Midazolam | 0.229 1/h | Geometric Coefficient of Variation 37 |
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Apparent Terminal Elimination Rate Constant (λz) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Metabolite: 1-OH-medazolam | 0.224 1/h | Geometric Coefficient of Variation 55.7 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Apparent Terminal Elimination Rate Constant (λz) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Midazolam | 0.221 1/h | Geometric Coefficient of Variation 49.5 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Apparent Terminal Elimination Rate Constant (λz) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Metabolite: 1-OH-medazolam | 0.282 1/h | Geometric Coefficient of Variation 47.8 |
Primary
PK: Apparent Volume of Distribution (Vz/F) of Midazolam Following Oral Dose Administration
PK: Vz/F of midazolam following oral dose administration was reported.
Time frame: Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)
Population: All participants who received at least 1 dose of oral midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Apparent Volume of Distribution (Vz/F) of Midazolam Following Oral Dose Administration | 298 Liters | Geometric Coefficient of Variation 29.7 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Apparent Volume of Distribution (Vz/F) of Midazolam Following Oral Dose Administration | 244 Liters | Geometric Coefficient of Variation 29.6 |
Primary
PK: Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration
PK: AUC0-t of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported.
Time frame: Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)
Population: All participants who received at least 1 dose of IV midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Midazolam | 8.89 h*ng/mL | Geometric Coefficient of Variation 21.6 |
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Metabolite: 1-OH-medazolam | 1.39 h*ng/mL | Geometric Coefficient of Variation 41.7 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Midazolam | 10.1 h*ng/mL | Geometric Coefficient of Variation 25.1 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Metabolite: 1-OH-medazolam | 1.21 h*ng/mL | Geometric Coefficient of Variation 35.7 |
Primary
PK: Area Under the Concentration-Time From Time 0 Extrapolated To Infinity (AUC0-inf) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration
PK: AUC0-inf of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported.
Time frame: Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)
Population: All participants who received at least 1 dose of IV midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed. Here, 'Number analyzed' signifies participants with available data for each specified category.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Area Under the Concentration-Time From Time 0 Extrapolated To Infinity (AUC0-inf) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Midazolam | 9.62 h*ng/mL | Geometric Coefficient of Variation 21.4 |
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Area Under the Concentration-Time From Time 0 Extrapolated To Infinity (AUC0-inf) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Metabolite: 1-OH-medazolam | 2.13 h*ng/mL | Geometric Coefficient of Variation 43 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Area Under the Concentration-Time From Time 0 Extrapolated To Infinity (AUC0-inf) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Midazolam | 10.8 h*ng/mL | Geometric Coefficient of Variation 26.5 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Area Under the Concentration-Time From Time 0 Extrapolated To Infinity (AUC0-inf) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Metabolite: 1-OH-medazolam | 1.62 h*ng/mL | Geometric Coefficient of Variation 25.2 |
Primary
PK: Area Under the Concentration-Time From Time 0 Extrapolated To Infinity (AUC0-inf) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration
PK: AUC(0-inf) of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported.
Time frame: Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)
Population: All participants who received at least 1 dose of oral midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Area Under the Concentration-Time From Time 0 Extrapolated To Infinity (AUC0-inf) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | Midazolam | 5.31 h*ng/mL | Geometric Coefficient of Variation 43.1 |
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Area Under the Concentration-Time From Time 0 Extrapolated To Infinity (AUC0-inf) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | Metabolite: 1-OH-midazolam | 2.60 h*ng/mL | Geometric Coefficient of Variation 39.9 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Area Under the Concentration-Time From Time 0 Extrapolated To Infinity (AUC0-inf) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | Midazolam | 9.01 h*ng/mL | Geometric Coefficient of Variation 44 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Area Under the Concentration-Time From Time 0 Extrapolated To Infinity (AUC0-inf) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | Metabolite: 1-OH-midazolam | 2.92 h*ng/mL | Geometric Coefficient of Variation 42.2 |
Primary
PK: Maximum Observed Plasma Concentration (Cmax) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration
PK: Cmax of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported.
Time frame: Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)
Population: All participants who received at least 1 dose of IV midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Maximum Observed Plasma Concentration (Cmax) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Midazolam | 6.96 ng/mL | Geometric Coefficient of Variation 34.8 |
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Maximum Observed Plasma Concentration (Cmax) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Metabolite: 1-OH-medazolam | 0.512 ng/mL | Geometric Coefficient of Variation 31.7 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Maximum Observed Plasma Concentration (Cmax) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Midazolam | 6.91 ng/mL | Geometric Coefficient of Variation 27.8 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Maximum Observed Plasma Concentration (Cmax) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Metabolite: 1-OH-medazolam | 0.475 ng/mL | Geometric Coefficient of Variation 28.6 |
Primary
PK: Maximum Observed Plasma Concentration (Cmax) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration
PK: Cmax of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported.
Time frame: Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)
Population: All participants who received at least 1 dose of oral midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Maximum Observed Plasma Concentration (Cmax) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | Midazolam | 2.33 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 36.7 |
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Maximum Observed Plasma Concentration (Cmax) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | Metabolite: 1-OH-midazolam | 1.25 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 42.2 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Maximum Observed Plasma Concentration (Cmax) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | Midazolam | 3.68 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 34.3 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Maximum Observed Plasma Concentration (Cmax) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | Metabolite: 1-OH-midazolam | 1.41 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 40.2 |
Primary
PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration
PK: %AUCextrap of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported.
Time frame: Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)
Population: All participants who received at least 1 dose of IV midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed. Here, 'Number analyzed' signifies participants with available data for each specified category.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Midazolam | 7.13 percentage of AUC0-inf | Geometric Coefficient of Variation 37.1 |
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Metabolite: 1-OH-medazolam | 19.6 percentage of AUC0-inf | Geometric Coefficient of Variation 24.7 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Midazolam | 6.44 percentage of AUC0-inf | Geometric Coefficient of Variation 42 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Metabolite: 1-OH-medazolam | 24.7 percentage of AUC0-inf | Geometric Coefficient of Variation 11.5 |
Primary
PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration
PK: %AUCextrap of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported.
Time frame: Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)
Population: All participants who received at least 1 dose of oral midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | Midazolam | 8.84 percentage of AUC0-inf | Geometric Coefficient of Variation 33.7 |
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | Metabolite: 1-OH-midazolam | 12.9 percentage of AUC0-inf | Geometric Coefficient of Variation 37.5 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | Midazolam | 7.42 percentage of AUC0-inf | Geometric Coefficient of Variation 35.3 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | Metabolite: 1-OH-midazolam | 12.2 percentage of AUC0-inf | Geometric Coefficient of Variation 48.6 |
Primary
PK: Time to Maximum Observed Plasma Concentration (Tmax) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration
PK: tmax of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported.
Time frame: Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)
Population: All participants who received at least 1 dose of IV midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Time to Maximum Observed Plasma Concentration (Tmax) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Midazolam | 0.0833 hours |
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Time to Maximum Observed Plasma Concentration (Tmax) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Metabolite: 1-OH-medazolam | 0.750 hours |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Time to Maximum Observed Plasma Concentration (Tmax) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Midazolam | 0.0833 hours |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Time to Maximum Observed Plasma Concentration (Tmax) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | Metabolite: 1-OH-medazolam | 0.750 hours |
Primary
PK: Time to Maximum Observed Plasma Concentration (Tmax) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration
PK: tmax of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported.
Time frame: Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)
Population: All participants who received at least 1 dose of oral midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Time to Maximum Observed Plasma Concentration (Tmax) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | Midazolam | 0.750 Hours |
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Time to Maximum Observed Plasma Concentration (Tmax) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | Metabolite: 1-OH-midazolam | 0.750 Hours |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Time to Maximum Observed Plasma Concentration (Tmax) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | Midazolam | 0.500 Hours |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Time to Maximum Observed Plasma Concentration (Tmax) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | Metabolite: 1-OH-midazolam | 0.500 Hours |
Primary
PK: Total Clearance (CL) of Midazolam Following Intravenous Dose Administration
PK: CL of midazolam following intravenous dose administration was reported.
Time frame: Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)
Population: All participants who received at least 1 dose of IV midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Total Clearance (CL) of Midazolam Following Intravenous Dose Administration | 26.0 L/h | Geometric Coefficient of Variation 21.4 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Total Clearance (CL) of Midazolam Following Intravenous Dose Administration | 23.1 L/h | Geometric Coefficient of Variation 26.5 |
Primary
PK: Volume of Distribution at Steady State (Vss) of Midazolam Following Intravenous Dose Administration
PK: Vss of midazolam following intravenous dose administration was reported.
Time frame: Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)
Population: All participants who received at least 1 dose of IV midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Volume of Distribution at Steady State (Vss) of Midazolam Following Intravenous Dose Administration | 78.2 Liters | Geometric Coefficient of Variation 29.4 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Volume of Distribution at Steady State (Vss) of Midazolam Following Intravenous Dose Administration | 76.1 Liters | Geometric Coefficient of Variation 31 |
Primary
PK: Volume of Distribution (Vz) of Midazolam Following Intravenous Dose Administration
PK: Vz of midazolam following intravenous dose administration was reported.
Time frame: Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose)
Population: All participants who received at least 1 dose of IV midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Volume of Distribution (Vz) of Midazolam Following Intravenous Dose Administration | 113 Liters | Geometric Coefficient of Variation 34.2 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Volume of Distribution (Vz) of Midazolam Following Intravenous Dose Administration | 105 Liters | Geometric Coefficient of Variation 37.8 |
Secondary
PK: Accumulation Ratio (RAUC) of Pirtobrutinib
RAUC was ratio of Day 14 AUCtau to Day 5 AUCtau.
Time frame: Period 2: Day 5 and Day 14 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose)
Population: The PK population included all participants who received at least 1 dose of pirtobrutinib had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Accumulation Ratio (RAUC) of Pirtobrutinib | 2.08 Ratio | Geometric Coefficient of Variation 15.9 |
Secondary
PK: Apparent Systemic Plasma Clearance at Steady State (CL,ss/F) of Pirtobrutinib
PK: CL,ss/F of Pirtobrutinib was reported.
Time frame: Period 2: Day 14 and Day 15 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose), Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 100 hours post-dose)
Population: The PK population included all participants who received at least 1 dose of pirtobrutinib had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Apparent Systemic Plasma Clearance at Steady State (CL,ss/F) of Pirtobrutinib | 1.75 L/h | Geometric Coefficient of Variation 26.1 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Apparent Systemic Plasma Clearance at Steady State (CL,ss/F) of Pirtobrutinib | 1.72 L/h | Geometric Coefficient of Variation 25 |
| Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg (Day 15) | PK: Apparent Systemic Plasma Clearance at Steady State (CL,ss/F) of Pirtobrutinib | 1.69 L/h | Geometric Coefficient of Variation 25.5 |
Secondary
PK: Area Under the Concentration-time Curve During a Dosing Interval (AUCtau) of Pirtobrutinib
PK: AUCtau of Pirtobrutinib was reported.
Time frame: Period 2: Day 5, Day 14 and Day 15 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose), Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 100 hours post-dose)
Population: The PK population included all participants who received at least 1 dose of pirtobrutinib had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Area Under the Concentration-time Curve During a Dosing Interval (AUCtau) of Pirtobrutinib | 55000 h*ng/mL | Geometric Coefficient of Variation 20 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Area Under the Concentration-time Curve During a Dosing Interval (AUCtau) of Pirtobrutinib | 114000 h*ng/mL | Geometric Coefficient of Variation 26.1 |
| Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg (Day 15) | PK: Area Under the Concentration-time Curve During a Dosing Interval (AUCtau) of Pirtobrutinib | 116000 h*ng/mL | Geometric Coefficient of Variation 25 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Area Under the Concentration-time Curve During a Dosing Interval (AUCtau) of Pirtobrutinib | 118000 h*ng/mL | Geometric Coefficient of Variation 25.5 |
Secondary
PK: Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Pirtobrutinib
PK: AUC0-t of Pirtobrutinib was reported.
Time frame: Period 2: Day 5, Day 14 and Day 15 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose), Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 100 hours post-dose)
Population: The PK population included all participants who received at least 1 dose of pirtobrutinib had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Pirtobrutinib | 54800 h*ng/mL | Geometric Coefficient of Variation 20 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Pirtobrutinib | 114000 h*ng/mL | Geometric Coefficient of Variation 26 |
| Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg (Day 15) | PK: Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Pirtobrutinib | 115000 h*ng/mL | Geometric Coefficient of Variation 25 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Pirtobrutinib | 211000 h*ng/mL | Geometric Coefficient of Variation 33.8 |
Secondary
PK: Concentration Observed at the End Of the Dosing Interval (Ctrough) of Pirtobrutinib
PK: Ctrough of Pirtobrutinib before multiple oral doses administration was reported.
Time frame: Period 2: 24-hour post-dose on Day 14, Day 15, and Day 17
Population: The PK population included all participants who received at least 1 dose of pirtobrutinib had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Concentration Observed at the End Of the Dosing Interval (Ctrough) of Pirtobrutinib | 3060 ng/mL | Geometric Coefficient of Variation 32.1 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Concentration Observed at the End Of the Dosing Interval (Ctrough) of Pirtobrutinib | 3180 ng/mL | Geometric Coefficient of Variation 36.4 |
| Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg (Day 15) | PK: Concentration Observed at the End Of the Dosing Interval (Ctrough) of Pirtobrutinib | 3050 ng/mL | Geometric Coefficient of Variation 32.7 |
Secondary
PK: Maximum Observed Plasma Concentration (Cmax) of Pirtobrutinib
PK: Cmax of Pirtobrutinib was reported.
Time frame: Period 2: Day 5, Day 14 and Day 15 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose), Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 100 hours post-dose)
Population: The PK population included all participants who received at least 1 dose of pirtobrutinib had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Maximum Observed Plasma Concentration (Cmax) of Pirtobrutinib | 4880 ng/mL | Geometric Coefficient of Variation 18.5 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Maximum Observed Plasma Concentration (Cmax) of Pirtobrutinib | 8120 ng/mL | Geometric Coefficient of Variation 27.1 |
| Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg (Day 15) | PK: Maximum Observed Plasma Concentration (Cmax) of Pirtobrutinib | 8620 ng/mL | Geometric Coefficient of Variation 23.1 |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Maximum Observed Plasma Concentration (Cmax) of Pirtobrutinib | 8750 ng/mL | Geometric Coefficient of Variation 27.2 |
Secondary
PK: Time To Maximum Observed Plasma Concentration (Tmax) of Pirtobrutinib
PK: tmax of Pirtobrutinib was reported.
Time frame: Period 2: Day 5, Day 14 and Day 15 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose), Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 100 hours post-dose)
Population: The PK population included all participants who received at least 1 dose of pirtobrutinib had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Period 1: Oral Midazolam 500 mcg (Day 3) | PK: Time To Maximum Observed Plasma Concentration (Tmax) of Pirtobrutinib | 2.50 hours |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Time To Maximum Observed Plasma Concentration (Tmax) of Pirtobrutinib | 3.00 hours |
| Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg (Day 15) | PK: Time To Maximum Observed Plasma Concentration (Tmax) of Pirtobrutinib | 3.00 hours |
| Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | PK: Time To Maximum Observed Plasma Concentration (Tmax) of Pirtobrutinib | 3.00 hours |