Healthy, Hepatic Insufficiency
Conditions
Brief summary
The main purpose of this study is to measure how much of pirtobrutinib (LOXO-305) gets into the bloodstream and how long it takes the body to eliminate it in participants with impaired liver function and healthy participants. The side effects and tolerability of pirtobrutinib will also be evaluated. Participation could last about 46 days.
Interventions
DRUGPirtobrutinib
Administered orally
Sponsors
Loxo Oncology, Inc.
Eli Lilly and Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
* Participants with mild, moderate or severe hepatic impairment and healthy participants with normal hepatic function * Males and females of non-childbearing potential. * Within body mass index (BMI) range 18.5 to 40.0 kilograms per square meter (kg/m²). * Participants will be in good health, based on medical history, physical examination findings, vital signs, 12 lead electrocardiogram (ECG), and clinical laboratory tests, as determined by the Investigator (or designee). * Able to comply with all study procedures, including the 8-night stay at the Clinical Research Unit and follow-up phone call.
Exclusion criteria
* History or presence of any of the following, deemed clinically significant by the Investigator (or designee), and/or Sponsor: 1. pancreatitis 2. peptic ulcer disease 3. intestinal malabsorption 4. gastric reduction surgery 5. history or presence of clinically significant cardiovascular disease. * Participants with out-of-range, at-rest vital signs. * Abnormal laboratory values determined to be clinically significant by the Investigator (or designee). * Clinically significant abnormality, as determined by the Investigator (or designee), from physical examination. * Participation in any other investigational study drug trial involving administration of any investigational drug in the past 30 days or 5 half-lives, whichever was longer, prior to the first dose administration (Day 1). * Use or intention to use any prescription or over-the-counter medications within 14 days prior to the first dose administration (Day 1) and through end of trial. * History or presence, upon clinical evaluation, of any illness that, in the opinion of the Investigator, would interfere with the ability to provide informed consent or comply with study instructions, or that might confound the interpretation of the study results, or put the participant at undue risk. * Donation of blood from 56 days prior to Screening, plasma or platelets from 4 weeks prior to Screening. * Receipt of blood products within 2 months prior to Check-in (Day -1). * Significant history or clinical manifestation of any metabolic, allergic, dermatological, hepatic, biliary, renal, hematological, pulmonary, cardiovascular (including any prior history of cardiomyopathy or cardiac failure), gastrointestinal (GI), neurological, or psychiatric disorder (as determined by the Investigator).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics (PK): Maximum Observed Concentration (Cmax) of Pirtobrutinib | Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose) | PK: Cmax of pirtobrutinib |
| PK: Area Under the Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Pirtobrutinib | Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose) | PK: AUC0-inf of pirtobrutinib |
| PK: Time to Maximum Observed Plasma Concentration (Tmax) of Pirtobrutinib | Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose) | PK: Tmax of pirtobrutinib |
| PK: Area Under the Concentration Versus Time Curve From Time Zero to the Last Measurable Concentration (AUC0-t) of Pirtobrutinib | Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose) | PK: AUC0-t of pirtobrutinib |
| PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Pirtobrutinib | Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose) | PK: %AUCextrap of pirtobrutinib |
| PK: Apparent Plasma Terminal Elimination Half-life (t½) of Pirtobrutinib | Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose) | PK: t½ of pirtobrutinib |
| PK: Apparent Systemic Clearance (CL/F) of Pirtobrutinib | Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose) | PK: CL/F of pirtobrutinib |
| PK: Apparent Volume of Distribution During the Terminal Phase (Vz/F) of Pirtobrutinib | Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose) | PK: Vz/F of pirtobrutinib |
| PK: Mean Residence Time (MRT) of Pirtobrutinib | Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose) | MRT is the average time a drug molecule stays in the body, calculated from the AUC0-inf. |
| PK: Unbound Cmax (Cmax,u) of Pirtobrutinib | Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose) | Cmax,u was calculated by multiplying Cmax by Fu (i.e., Cmax\*Fu). Fu represents the unbound fraction, which is the portion of the drug in the bloodstream that is unbound to plasma proteins. It is expressed as a decimal and will be calculated from protein binding concentration data as the unbound drug concentration divided by the total drug concentration in plasma. The concentrations of total and unbound drug were determined in a sample of predose plasma fortified with a known concentration of drug. |
| PK: Unbound AUC0-t (AUC0-t,u) of Pirtobrutinib | Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose) | AUC0-t,u was calculated by multiplying AUC0-t by Fu (i.e., AUC0-t\*Fu). Fu represents the unbound fraction, which is the portion of the drug in the bloodstream that is unbound to plasma proteins. It is expressed as a decimal and will be calculated from protein binding concentration data as the unbound drug concentration divided by the total drug concentration in plasma. The concentrations of total and unbound drug were determined in a sample of predose plasma fortified with a known concentration of drug. |
| PK: Unbound AUC0-inf (AUC0-inf,u) of Pirtobrutinib | Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose) | AUC0-inf,u was calculated by multiplying AUC0-inf by Fu (i.e., AUC0-inf\*Fu). Fu represents the unbound fraction, which is the portion of the drug in the bloodstream that is unbound to plasma proteins. It is expressed as a decimal and will be calculated from protein binding concentration data as the unbound drug concentration divided by the total drug concentration in plasma. The concentrations of total and unbound drug were determined in a sample of predose plasma fortified with a known concentration of drug. |
| PK: Unbound CL/F (CL/F,u) of Pirtobrutinib | Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose) | CL/F,u was calculated by multiplying CL/F by Fu (i.e., CL/F\*Fu). Fu represents the unbound fraction, which is the portion of the drug in the bloodstream that is unbound to plasma proteins. It is expressed as a decimal and will be calculated from protein binding concentration data as the unbound drug concentration divided by the total drug concentration in plasma. The concentrations of total and unbound drug were determined in a sample of predose plasma fortified with a known concentration of drug. |
| PK: Unbound Vz/F (Vz/F,u) of Pirtobrutinib | Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose) | Vz/F,u was calculated by multiplying Vz/F by Fu (i.e., Vz/F\*Fu). Fu represents the unbound fraction, which is the portion of the drug in the bloodstream that is unbound to plasma proteins. It is expressed as a decimal and will be calculated from protein binding concentration data as the unbound drug concentration divided by the total drug concentration in plasma. The concentrations of total and unbound drug were determined in a sample of predose plasma fortified with a known concentration of drug. |
| PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Mild Hepatic Function) | Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose) | PK: λZ of pirtobrutinib |
| PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Normal Hepatic Function) | Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose) | PK: λZ of pirtobrutinib |
| PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Moderate Hepatic Function) | Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose) | PK: λZ of pirtobrutinib |
| PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Severe Hepatic Function) | Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose) | PK: λZ of pirtobrutinib |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pirtobrutinib (Normal Hepatic Function) Participants received a single dose of Pirtobrutinib 200 mg administered orally on Day 1. | 14 |
| Pirtobrutinib (Mild Hepatic Impairment) Participants received a single dose of Pirtobrutinib 200 milligrams (mg) administered orally on Day 1. | 8 |
| Pirtobrutinib (Moderate Hepatic Impairment) Participants received a single dose of Pirtobrutinib 200 mg administered orally on Day 1. | 8 |
| Pirtobrutinib (Severe Hepatic Impairment) Participants received a single dose of Pirtobrutinib 200 mg administered orally on Day 1. | 6 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Pirtobrutinib (Normal Hepatic Function) | Total | Pirtobrutinib (Severe Hepatic Impairment) | Pirtobrutinib (Moderate Hepatic Impairment) | Pirtobrutinib (Mild Hepatic Impairment) |
|---|---|---|---|---|---|
| Age, Continuous | 54.4 years STANDARD_DEVIATION 8.22 | 55 years STANDARD_DEVIATION 6.88 | 52.3 years STANDARD_DEVIATION 9.35 | 56.3 years STANDARD_DEVIATION 3.92 | 56.8 years STANDARD_DEVIATION 4.56 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 19 Participants | 5 Participants | 4 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 17 Participants | 1 Participants | 4 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 5 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 11 Participants | 31 Participants | 6 Participants | 8 Participants | 6 Participants |
| Region of Enrollment United States | 14 Participants | 36 Participants | 6 Participants | 8 Participants | 8 Participants |
| Sex: Female, Male Female | 4 Participants | 10 Participants | 1 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 10 Participants | 26 Participants | 5 Participants | 6 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 8 | 0 / 8 | 0 / 6 |
| other Total, other adverse events | 3 / 14 | 2 / 8 | 0 / 8 | 1 / 6 |
| serious Total, serious adverse events | 0 / 14 | 0 / 8 | 0 / 8 | 0 / 6 |
Outcome results
Primary
Pharmacokinetics (PK): Maximum Observed Concentration (Cmax) of Pirtobrutinib
PK: Cmax of pirtobrutinib
Time frame: Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
Population: All participants who received a dose of Pirtobrutinib, had at least 1 quantifiable plasma concentration of Pirtobrutinib and had at least 1 PK parameter computed. Subjects were excluded from the analysis if they experienced an AE of vomiting that occurred at or before 2 times the median Tmax.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pirtobrutinib (Normal Hepatic Function) | Pharmacokinetics (PK): Maximum Observed Concentration (Cmax) of Pirtobrutinib | 4240 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 32.4 |
| Pirtobrutinib (Mild Hepatic Impairment) | Pharmacokinetics (PK): Maximum Observed Concentration (Cmax) of Pirtobrutinib | 4410 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 22.7 |
| Pirtobrutinib (Moderate Hepatic Impairment) | Pharmacokinetics (PK): Maximum Observed Concentration (Cmax) of Pirtobrutinib | 4140 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 20.8 |
| Pirtobrutinib (Severe Hepatic Impairment) | Pharmacokinetics (PK): Maximum Observed Concentration (Cmax) of Pirtobrutinib | 3270 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 22.8 |
Primary
PK: Apparent Plasma Terminal Elimination Half-life (t½) of Pirtobrutinib
PK: t½ of pirtobrutinib
Time frame: Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
Population: All participants who received a dose of Pirtobrutinib, had at least 1 quantifiable plasma concentration of Pirtobrutinib and had at least 1 PK parameter computed. Subjects were excluded from the analysis if they experienced an AE of vomiting that occurred at or before 2 times the median Tmax.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Plasma Terminal Elimination Half-life (t½) of Pirtobrutinib | 21.2 hours | Geometric Coefficient of Variation 20.9 |
| Pirtobrutinib (Mild Hepatic Impairment) | PK: Apparent Plasma Terminal Elimination Half-life (t½) of Pirtobrutinib | 19.8 hours | Geometric Coefficient of Variation 27.7 |
| Pirtobrutinib (Moderate Hepatic Impairment) | PK: Apparent Plasma Terminal Elimination Half-life (t½) of Pirtobrutinib | 18 hours | Geometric Coefficient of Variation 16.3 |
| Pirtobrutinib (Severe Hepatic Impairment) | PK: Apparent Plasma Terminal Elimination Half-life (t½) of Pirtobrutinib | 15.5 hours | Geometric Coefficient of Variation 26.6 |
Primary
PK: Apparent Systemic Clearance (CL/F) of Pirtobrutinib
PK: CL/F of pirtobrutinib
Time frame: Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
Population: All participants who received a dose of Pirtobrutinib, had at least 1 quantifiable plasma concentration of Pirtobrutinib and had at least 1 PK parameter computed. Subjects were excluded from the analysis if they experienced an AE of vomiting that occurred at or before 2 times the median Tmax.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Systemic Clearance (CL/F) of Pirtobrutinib | 2.04 liter per hour (L/h) | Geometric Coefficient of Variation 20.7 |
| Pirtobrutinib (Mild Hepatic Impairment) | PK: Apparent Systemic Clearance (CL/F) of Pirtobrutinib | 2.20 liter per hour (L/h) | Geometric Coefficient of Variation 42.7 |
| Pirtobrutinib (Moderate Hepatic Impairment) | PK: Apparent Systemic Clearance (CL/F) of Pirtobrutinib | 2.33 liter per hour (L/h) | Geometric Coefficient of Variation 31.1 |
| Pirtobrutinib (Severe Hepatic Impairment) | PK: Apparent Systemic Clearance (CL/F) of Pirtobrutinib | 2.77 liter per hour (L/h) | Geometric Coefficient of Variation 14.6 |
Primary
PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Mild Hepatic Function)
PK: λZ of pirtobrutinib
Time frame: Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
Population: All participants who received a dose of Pirtobrutinib, had at least 1 quantifiable plasma concentration of Pirtobrutinib and had at least 1 PK parameter computed. Subjects were excluded from the analysis if they experienced an AE of vomiting that occurred at or before 2 times the median Tmax.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Mild Hepatic Function) | Subject 15 | 0.0270 1/hour (1/h) |
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Mild Hepatic Function) | Subject 16 | 0.0448 1/hour (1/h) |
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Mild Hepatic Function) | Subject 17 | 0.0453 1/hour (1/h) |
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Mild Hepatic Function) | Subject 18 | 0.0336 1/hour (1/h) |
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Mild Hepatic Function) | Subject 19 | 0.0234 1/hour (1/h) |
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Mild Hepatic Function) | Subject 20 | 0.0273 1/hour (1/h) |
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Mild Hepatic Function) | Subject 21 | 0.0432 1/hour (1/h) |
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Mild Hepatic Function) | Subject 22 | 0.0440 1/hour (1/h) |
Primary
PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Moderate Hepatic Function)
PK: λZ of pirtobrutinib
Time frame: Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
Population: All participants who received a dose of Pirtobrutinib, had at least 1 quantifiable plasma concentration of Pirtobrutinib and had at least 1 PK parameter computed. Subjects were excluded from the analysis if they experienced an AE of vomiting that occurred at or before 2 times the median Tmax.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Moderate Hepatic Function) | Subject 23 | 0.0377 1/hour (1/h) |
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Moderate Hepatic Function) | Subject 24 | 0.0387 1/hour (1/h) |
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Moderate Hepatic Function) | Subject 25 | 0.0364 1/hour (1/h) |
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Moderate Hepatic Function) | Subject 26 | 0.0430 1/hour (1/h) |
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Moderate Hepatic Function) | Subject 27 | 0.0395 1/hour (1/h) |
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Moderate Hepatic Function) | Subject 28 | 0.0467 1/hour (1/h) |
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Moderate Hepatic Function) | Subject 29 | 0.0419 1/hour (1/h) |
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Moderate Hepatic Function) | Subject 30 | 0.0272 1/hour (1/h) |
Primary
PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Normal Hepatic Function)
PK: λZ of pirtobrutinib
Time frame: Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
Population: All participants who received a dose of Pirtobrutinib, had at least 1 quantifiable plasma concentration of Pirtobrutinib and had at least 1 PK parameter computed. Subjects were excluded from the analysis if they experienced an AE of vomiting that occurred at or before 2 times the median Tmax.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Normal Hepatic Function) | Subject 1 | 0.0334 1/hour (1/h) |
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Normal Hepatic Function) | Subject 2 | 0.0323 1/hour (1/h) |
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Normal Hepatic Function) | Subject 3 | 0.0418 1/hour (1/h) |
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Normal Hepatic Function) | Subject 4 | 0.0287 1/hour (1/h) |
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Normal Hepatic Function) | Subject 5 | 0.0231 1/hour (1/h) |
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Normal Hepatic Function) | Subject 6 | 0.0319 1/hour (1/h) |
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Normal Hepatic Function) | Subject 7 | 0.0420 1/hour (1/h) |
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Normal Hepatic Function) | Subject 8 | 0.0262 1/hour (1/h) |
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Normal Hepatic Function) | Subject 9 | 0.0292 1/hour (1/h) |
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Normal Hepatic Function) | Subject 10 | 0.0291 1/hour (1/h) |
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Normal Hepatic Function) | Subject 11 | 0.0299 1/hour (1/h) |
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Normal Hepatic Function) | Subject 12 | 0.0308 1/hour (1/h) |
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Normal Hepatic Function) | Subject 13 | 0.0399 1/hour (1/h) |
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Normal Hepatic Function) | Subject 14 | 0.0491 1/hour (1/h) |
Primary
PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Severe Hepatic Function)
PK: λZ of pirtobrutinib
Time frame: Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
Population: All participants who received a dose of Pirtobrutinib, had at least 1 quantifiable plasma concentration of Pirtobrutinib and had at least 1 PK parameter computed. Subjects were excluded from the analysis if they experienced an AE of vomiting that occurred at or before 2 times the median Tmax.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Severe Hepatic Function) | Subject 31 | 0.0401 1/hour (1/h) |
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Severe Hepatic Function) | Subject 32 | 0.0526 1/hour (1/h) |
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Severe Hepatic Function) | Subject 33 | 0.0279 1/hour (1/h) |
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Severe Hepatic Function) | Subject 34 | 0.0522 1/hour (1/h) |
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Severe Hepatic Function) | Subject 35 | 0.0465 1/hour (1/h) |
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Severe Hepatic Function) | Subject 36 | 0.0567 1/hour (1/h) |
Primary
PK: Apparent Volume of Distribution During the Terminal Phase (Vz/F) of Pirtobrutinib
PK: Vz/F of pirtobrutinib
Time frame: Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
Population: All participants who received a dose of Pirtobrutinib, had at least 1 quantifiable plasma concentration of Pirtobrutinib and had at least 1 PK parameter computed. Subjects were excluded from the analysis if they experienced an AE of vomiting that occurred at or before 2 times the median Tmax.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pirtobrutinib (Normal Hepatic Function) | PK: Apparent Volume of Distribution During the Terminal Phase (Vz/F) of Pirtobrutinib | 62.4 Liter (L) | Geometric Coefficient of Variation 29.5 |
| Pirtobrutinib (Mild Hepatic Impairment) | PK: Apparent Volume of Distribution During the Terminal Phase (Vz/F) of Pirtobrutinib | 62.9 Liter (L) | Geometric Coefficient of Variation 45.1 |
| Pirtobrutinib (Moderate Hepatic Impairment) | PK: Apparent Volume of Distribution During the Terminal Phase (Vz/F) of Pirtobrutinib | 60.6 Liter (L) | Geometric Coefficient of Variation 30.1 |
| Pirtobrutinib (Severe Hepatic Impairment) | PK: Apparent Volume of Distribution During the Terminal Phase (Vz/F) of Pirtobrutinib | 61.8 Liter (L) | Geometric Coefficient of Variation 30.5 |
Primary
PK: Area Under the Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Pirtobrutinib
PK: AUC0-inf of pirtobrutinib
Time frame: Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
Population: All participants who received a dose of Pirtobrutinib, had at least 1 quantifiable plasma concentration of Pirtobrutinib and had at least 1 PK parameter computed. Subjects were excluded from the analysis if they experienced an AE of vomiting that occurred at or before 2 times the median Tmax.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pirtobrutinib (Normal Hepatic Function) | PK: Area Under the Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Pirtobrutinib | 98000 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 20.7 |
| Pirtobrutinib (Mild Hepatic Impairment) | PK: Area Under the Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Pirtobrutinib | 90900 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 42.7 |
| Pirtobrutinib (Moderate Hepatic Impairment) | PK: Area Under the Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Pirtobrutinib | 85700 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 31.1 |
| Pirtobrutinib (Severe Hepatic Impairment) | PK: Area Under the Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Pirtobrutinib | 72200 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 14.6 |
Primary
PK: Area Under the Concentration Versus Time Curve From Time Zero to the Last Measurable Concentration (AUC0-t) of Pirtobrutinib
PK: AUC0-t of pirtobrutinib
Time frame: Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
Population: All participants who received a dose of Pirtobrutinib, had at least 1 quantifiable plasma concentration of Pirtobrutinib and had at least 1 PK parameter computed. Subjects were excluded from the analysis if they experienced an AE of vomiting that occurred at or before 2 times the median Tmax.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pirtobrutinib (Normal Hepatic Function) | PK: Area Under the Concentration Versus Time Curve From Time Zero to the Last Measurable Concentration (AUC0-t) of Pirtobrutinib | 96800 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 21.2 |
| Pirtobrutinib (Mild Hepatic Impairment) | PK: Area Under the Concentration Versus Time Curve From Time Zero to the Last Measurable Concentration (AUC0-t) of Pirtobrutinib | 89900 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 43 |
| Pirtobrutinib (Moderate Hepatic Impairment) | PK: Area Under the Concentration Versus Time Curve From Time Zero to the Last Measurable Concentration (AUC0-t) of Pirtobrutinib | 84600 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 31.7 |
| Pirtobrutinib (Severe Hepatic Impairment) | PK: Area Under the Concentration Versus Time Curve From Time Zero to the Last Measurable Concentration (AUC0-t) of Pirtobrutinib | 71500 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 14.8 |
Primary
PK: Mean Residence Time (MRT) of Pirtobrutinib
MRT is the average time a drug molecule stays in the body, calculated from the AUC0-inf.
Time frame: Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
Population: All participants who received a dose of Pirtobrutinib, had at least 1 quantifiable plasma concentration of Pirtobrutinib and had at least 1 PK parameter computed. Subjects were excluded from the analysis if they experienced an AE of vomiting that occurred at or before 2 times the median Tmax.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pirtobrutinib (Normal Hepatic Function) | PK: Mean Residence Time (MRT) of Pirtobrutinib | 28.8 hours | Geometric Coefficient of Variation 17.6 |
| Pirtobrutinib (Mild Hepatic Impairment) | PK: Mean Residence Time (MRT) of Pirtobrutinib | 27.7 hours | Geometric Coefficient of Variation 26.3 |
| Pirtobrutinib (Moderate Hepatic Impairment) | PK: Mean Residence Time (MRT) of Pirtobrutinib | 25 hours | Geometric Coefficient of Variation 14 |
| Pirtobrutinib (Severe Hepatic Impairment) | PK: Mean Residence Time (MRT) of Pirtobrutinib | 24 hours | Geometric Coefficient of Variation 26.2 |
Primary
PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Pirtobrutinib
PK: %AUCextrap of pirtobrutinib
Time frame: Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
Population: All participants who received a dose of Pirtobrutinib, had at least 1 quantifiable plasma concentration of Pirtobrutinib and had at least 1 PK parameter computed. Subjects were excluded from the analysis if they experienced an AE of vomiting that occurred at or before 2 times the median Tmax.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pirtobrutinib (Normal Hepatic Function) | PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Pirtobrutinib | 0.978 percentage of AUCextrap | Geometric Coefficient of Variation 67.3 |
| Pirtobrutinib (Mild Hepatic Impairment) | PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Pirtobrutinib | 1.13 percentage of AUCextrap | Geometric Coefficient of Variation 34.4 |
| Pirtobrutinib (Moderate Hepatic Impairment) | PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Pirtobrutinib | 1.14 percentage of AUCextrap | Geometric Coefficient of Variation 54.7 |
| Pirtobrutinib (Severe Hepatic Impairment) | PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Pirtobrutinib | 0.921 percentage of AUCextrap | Geometric Coefficient of Variation 50.4 |
Primary
PK: Time to Maximum Observed Plasma Concentration (Tmax) of Pirtobrutinib
PK: Tmax of pirtobrutinib
Time frame: Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
Population: All participants who received a dose of Pirtobrutinib, had at least 1 quantifiable plasma concentration of Pirtobrutinib and had at least 1 PK parameter computed. Subjects were excluded from the analysis if they experienced an AE of vomiting that occurred at or before 2 times the median Tmax.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pirtobrutinib (Normal Hepatic Function) | PK: Time to Maximum Observed Plasma Concentration (Tmax) of Pirtobrutinib | 2.50 hours |
| Pirtobrutinib (Mild Hepatic Impairment) | PK: Time to Maximum Observed Plasma Concentration (Tmax) of Pirtobrutinib | 2.25 hours |
| Pirtobrutinib (Moderate Hepatic Impairment) | PK: Time to Maximum Observed Plasma Concentration (Tmax) of Pirtobrutinib | 2.25 hours |
| Pirtobrutinib (Severe Hepatic Impairment) | PK: Time to Maximum Observed Plasma Concentration (Tmax) of Pirtobrutinib | 2.78 hours |
Primary
PK: Unbound AUC0-inf (AUC0-inf,u) of Pirtobrutinib
AUC0-inf,u was calculated by multiplying AUC0-inf by Fu (i.e., AUC0-inf\*Fu). Fu represents the unbound fraction, which is the portion of the drug in the bloodstream that is unbound to plasma proteins. It is expressed as a decimal and will be calculated from protein binding concentration data as the unbound drug concentration divided by the total drug concentration in plasma. The concentrations of total and unbound drug were determined in a sample of predose plasma fortified with a known concentration of drug.
Time frame: Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
Population: All participants who received a dose of Pirtobrutinib, had at least 1 quantifiable plasma concentration of Pirtobrutinib and had at least 1 PK parameter computed. Subjects were excluded from the analysis if they experienced an AE of vomiting that occurred at or before 2 times the median Tmax.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pirtobrutinib (Normal Hepatic Function) | PK: Unbound AUC0-inf (AUC0-inf,u) of Pirtobrutinib | 2470 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 22.6 |
| Pirtobrutinib (Mild Hepatic Impairment) | PK: Unbound AUC0-inf (AUC0-inf,u) of Pirtobrutinib | 2740 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 32.1 |
| Pirtobrutinib (Moderate Hepatic Impairment) | PK: Unbound AUC0-inf (AUC0-inf,u) of Pirtobrutinib | 2440 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 39.1 |
| Pirtobrutinib (Severe Hepatic Impairment) | PK: Unbound AUC0-inf (AUC0-inf,u) of Pirtobrutinib | 2440 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 28.5 |
Primary
PK: Unbound AUC0-t (AUC0-t,u) of Pirtobrutinib
AUC0-t,u was calculated by multiplying AUC0-t by Fu (i.e., AUC0-t\*Fu). Fu represents the unbound fraction, which is the portion of the drug in the bloodstream that is unbound to plasma proteins. It is expressed as a decimal and will be calculated from protein binding concentration data as the unbound drug concentration divided by the total drug concentration in plasma. The concentrations of total and unbound drug were determined in a sample of predose plasma fortified with a known concentration of drug.
Time frame: Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
Population: All participants who received a dose of Pirtobrutinib, had at least 1 quantifiable plasma concentration of Pirtobrutinib and had at least 1 PK parameter computed. Subjects were excluded from the analysis if they experienced an AE of vomiting that occurred at or before 2 times the median Tmax.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pirtobrutinib (Normal Hepatic Function) | PK: Unbound AUC0-t (AUC0-t,u) of Pirtobrutinib | 2440 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 22.8 |
| Pirtobrutinib (Mild Hepatic Impairment) | PK: Unbound AUC0-t (AUC0-t,u) of Pirtobrutinib | 2710 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 32.3 |
| Pirtobrutinib (Moderate Hepatic Impairment) | PK: Unbound AUC0-t (AUC0-t,u) of Pirtobrutinib | 2410 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 39.6 |
| Pirtobrutinib (Severe Hepatic Impairment) | PK: Unbound AUC0-t (AUC0-t,u) of Pirtobrutinib | 2410 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 28.5 |
Primary
PK: Unbound CL/F (CL/F,u) of Pirtobrutinib
CL/F,u was calculated by multiplying CL/F by Fu (i.e., CL/F\*Fu). Fu represents the unbound fraction, which is the portion of the drug in the bloodstream that is unbound to plasma proteins. It is expressed as a decimal and will be calculated from protein binding concentration data as the unbound drug concentration divided by the total drug concentration in plasma. The concentrations of total and unbound drug were determined in a sample of predose plasma fortified with a known concentration of drug.
Time frame: Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
Population: All participants who received a dose of Pirtobrutinib, had at least 1 quantifiable plasma concentration of Pirtobrutinib and had at least 1 PK parameter computed. Subjects were excluded from the analysis if they experienced an AE of vomiting that occurred at or before 2 times the median Tmax.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pirtobrutinib (Normal Hepatic Function) | PK: Unbound CL/F (CL/F,u) of Pirtobrutinib | 80.9 liter per hour (L/h) | Geometric Coefficient of Variation 22.6 |
| Pirtobrutinib (Mild Hepatic Impairment) | PK: Unbound CL/F (CL/F,u) of Pirtobrutinib | 73 liter per hour (L/h) | Geometric Coefficient of Variation 32.1 |
| Pirtobrutinib (Moderate Hepatic Impairment) | PK: Unbound CL/F (CL/F,u) of Pirtobrutinib | 81.9 liter per hour (L/h) | Geometric Coefficient of Variation 39.1 |
| Pirtobrutinib (Severe Hepatic Impairment) | PK: Unbound CL/F (CL/F,u) of Pirtobrutinib | 82 liter per hour (L/h) | Geometric Coefficient of Variation 28.5 |
Primary
PK: Unbound Cmax (Cmax,u) of Pirtobrutinib
Cmax,u was calculated by multiplying Cmax by Fu (i.e., Cmax\*Fu). Fu represents the unbound fraction, which is the portion of the drug in the bloodstream that is unbound to plasma proteins. It is expressed as a decimal and will be calculated from protein binding concentration data as the unbound drug concentration divided by the total drug concentration in plasma. The concentrations of total and unbound drug were determined in a sample of predose plasma fortified with a known concentration of drug.
Time frame: Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
Population: All participants who received a dose of Pirtobrutinib, had at least 1 quantifiable plasma concentration of Pirtobrutinib and had at least 1 PK parameter computed. Subjects were excluded from the analysis if they experienced an AE of vomiting that occurred at or before 2 times the median Tmax.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pirtobrutinib (Normal Hepatic Function) | PK: Unbound Cmax (Cmax,u) of Pirtobrutinib | 107 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 31.2 |
| Pirtobrutinib (Mild Hepatic Impairment) | PK: Unbound Cmax (Cmax,u) of Pirtobrutinib | 133 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 16.3 |
| Pirtobrutinib (Moderate Hepatic Impairment) | PK: Unbound Cmax (Cmax,u) of Pirtobrutinib | 118 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 26.5 |
| Pirtobrutinib (Severe Hepatic Impairment) | PK: Unbound Cmax (Cmax,u) of Pirtobrutinib | 111 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 27.5 |
Primary
PK: Unbound Vz/F (Vz/F,u) of Pirtobrutinib
Vz/F,u was calculated by multiplying Vz/F by Fu (i.e., Vz/F\*Fu). Fu represents the unbound fraction, which is the portion of the drug in the bloodstream that is unbound to plasma proteins. It is expressed as a decimal and will be calculated from protein binding concentration data as the unbound drug concentration divided by the total drug concentration in plasma. The concentrations of total and unbound drug were determined in a sample of predose plasma fortified with a known concentration of drug.
Time frame: Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
Population: All participants who received a dose of Pirtobrutinib, had at least 1 quantifiable plasma concentration of Pirtobrutinib and had at least 1 PK parameter computed. Subjects were excluded from the analysis if they experienced an AE of vomiting that occurred at or before 2 times the median Tmax.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pirtobrutinib (Normal Hepatic Function) | PK: Unbound Vz/F (Vz/F,u) of Pirtobrutinib | 2470 Liter (L) | Geometric Coefficient of Variation 26 |
| Pirtobrutinib (Mild Hepatic Impairment) | PK: Unbound Vz/F (Vz/F,u) of Pirtobrutinib | 2090 Liter (L) | Geometric Coefficient of Variation 34 |
| Pirtobrutinib (Moderate Hepatic Impairment) | PK: Unbound Vz/F (Vz/F,u) of Pirtobrutinib | 2130 Liter (L) | Geometric Coefficient of Variation 33.1 |
| Pirtobrutinib (Severe Hepatic Impairment) | PK: Unbound Vz/F (Vz/F,u) of Pirtobrutinib | 1830 Liter (L) | Geometric Coefficient of Variation 36.3 |