Hepatic Impairment, Moderate Impaired Hepatic Function
Conditions
Keywords
Hepatic Impairment, Healthy Subjects, Drug-drug Interaction, Pharmacokinetics, Quizartinib
Brief summary
Quizartinib is a novel oral Class III receptor tyrosine kinase (RTK) inhibitor exhibiting highly potent and selective but reversible inhibition of Feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3). Quizartinib is currently being studied alone or in combination with other agents as a treatment for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) in adult and pediatric populations.
Detailed description
The primary objective of this study is to determine the plasma pharmacokinetics (PK) of quizartinib and its pharmacologically active metabolite AC886 after a single oral dose of 30 mg in participants with moderate hepatic impairment (HI) (as defined by National Cancer Institute-Organ Dysfunction Working Group \[NCI-ODWG\] criteria) compared to the healthy control participants with normal hepatic function.
Interventions
DRUGQuizartinib
Single oral dose, 30 mg tablet
Sponsors
Daiichi Sankyo
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
* Male and female subjects 18 years to 75 years of age (inclusive), with a body mass index (BMI) of 18 kg/m\^2 to 36 kg/m\^2 (inclusive) * In females, documented surgical sterilization, postmenopausal status for at least 1 year (follicle stimulating hormone \[FSH\] \> 40 mIU/mL serum at Screening), or agreement to use an approved form of contraception * In males, documented surgical sterilization, sexual abstinence, or agreement to use an approved form of contraception from Screening until 6 months after the dose of quizartinib * In males, agreement to avoid sperm donation for 6 months days after the dose of quizartinib * Participants must agree to refrain from donation of blood from 56 days prior to Screening, plasma from 2 weeks prior to Screening, and platelets from 6 weeks prior to Screening. * All participants must be willing to refrain from consuming grapefruit/grapefruit juice, Seville oranges, and pomegranates/pomegranate juice 10 days before the dose of the study drug is given on Day 1 until end-of-study.
Exclusion criteria
* Any serious and/or unstable pre-existing medical, psychiatric disorder, or other conditions (including lab abnormality) that could interfere with participant's safety, obtaining informed consent or compliance to the study procedures * Laboratory results (serum chemistry, hematology, and urinalysis) outside the normal range, if considered clinically significant by the investigator Estimated glomerular filtration rate (eGFR) \< 90 mL/min at screening. * Women who are pregnant or breastfeeding * Use of any drugs or substances known to be inhibitors or inducers of CYP3A4/5 within 28 days from the first dose or 5 half-lives, if known, of the drugs or substances, whichever is greater, prior to quizartinib administration and during the study. * Receipt of any prescribed or over-the-counter (OTC) systemic, herbal (including St John's wort), or topical medication within 14 days of quizartinib administration, or any expectation of requiring use of such medication while participating in the study is prohibited. * A positive drugs of abuse screen from a urine ethanol test (unless the drug is medically prescribed by a licensed health care provider) or alcohol breath test at Screening or at Check-in on Day -1 or a participant who will not agree to smoke ≤10 cigarettes or equivalent per day from Screening up to Enrollment, and is unable to be restricted to ≤5 cigarettes per day and for 6 hours post dose during their period of residence in the clinical unit * Concomitant use of medications known to affect the elimination of serum creatinine (e.g., trimethoprim or cimetidine) and inhibitors of renal tubular secretion (eg, probenecid) within 14 days or 5 half-lives, if known, of the drugs, whichever is greater, prior to quizartinib administration * Diagnosis of or suspicion of long QT syndrome (including family history of long QT syndrome. * Use of drugs with a risk of QT interval prolongation or torsade de pointes within 14 days of Day -1 (or 5 drug half-lives, if 5 drug half-lives are expected to exceed 14 days) * Consumption of alcohol- and caffeine-containing beverages within 72 hours prior to check-in and during confinement * Positive serology for hepatitis B surface antigen (HBsAg) and HCV (healthy subjects), hepatitis A virus (HAV) immunoglobulin M, or anti-human immunodeficiency virus (HIV) Type 1 and Type 2 (all participants) * Current enrollment in or have not yet completed at least 30 days or 5 elimination half-lives, whichever is longer, since receiving an investigational device or product, or receipt of other investigational agents within 30 days of quizartinib Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) of Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | Day 1 through 22: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose | Maximum Plasma Concentration (Cmax) is defined as the maximum observed plasma concentration and was an observed value for the study. |
| Time to Maximum Plasma Concentration (Tmax) for Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | Day 1 through 22: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose | Time of Maximum Plasma Concentration (Tmax) is defined as time of maximum observed plasma concentration and was an observed value from the study. |
| Area Under the Plasma Concentration-Time Curve (AUC) for Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | Day 1 through 22: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose | Area Under the Plasma Concentration-Time Curve up to the Last Quantifiable Concentration Post-Dose (AUClast) is defined as AUC from time 0 to the last measurable concentration, as calculated by the linear up-log down trapezoidal method. Area Under the Plasma Concentration-Time Curve up to Infinity (AUCinf) is defined as area under the plasma concentration-time curve from the time of dosing extrapolated to infinity. AUClast and AUCinf was assessed. |
| Total Apparent Clearance (CL/F) for Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | Day 1 through 22: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose | Total Apparent Clearance (CL/F) is defined as total apparent clearance and was calculated using non-compartmental analysis. |
| Volume of Distribution in the Terminal Phase (Vz/F) for Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | Day 1 through 22: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose | Volume of Distribution in the Terminal Phase (Vz/F) is defined as volume of distribution in the terminal phase and was calculated using non-compartmental analysis. |
| Terminal Half-Life (t1/2) for Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | Day 1 through 22: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose | Terminal Elimination Half-Life (t1/2) is defined as terminal elimination half-life and was calculated using noncompartmental analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-Time Curve (AUC) of Unbound Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | Day 1 through 22: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose | Area Under the Plasma Concentration-Time Curve up to the Last Quantifiable Concentration Post-Dose (AUClast) is defined as AUC from time 0 to the last measurable concentration, as calculated by the linear up-log down trapezoidal method. Area Under the Plasma Concentration-Time Curve up to Infinity (AUCinf) is defined as area under the plasma concentration-time curve from the time of dosing extrapolated to infinity. AUClast and AUCinf was assessed. |
| Maximum Plasma Concentration (Cmax) of Unbound Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | Day 1 through 22: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose | Maximum Plasma Concentration (Cmax) is defined as the maximum observed plasma concentration and was an observed value for the study. |
| Maximum Plasma Concentration (Cmax) of Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | Day 1 through 22: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose | Maximum Plasma Concentration (Cmax) is defined as the maximum observed plasma concentration and was an observed value for the study. |
| Number of Participants With Treatment-emergent Adverse Events Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | Baseline up to 30 days after last dose, up to 2 months | A Treatment-Emergent Adverse Events (TEAE) is defined as any event not present prior to the initiation of the drug treatment of the drug treatment or any event already present that worsens in either intensity or frequency following exposure to the drug treatment. Number of any TEAE that is related and unrelated to study medication is presented. |
| Area Under the Plasma Concentration-Time Curve (AUC) of Unbound Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | Day 1 through 22: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose | Area Under the Plasma Concentration-Time Curve up to the Last Quantifiable Concentration Post-Dose (AUClast) is defined as AUC from time 0 to the last measurable concentration, as calculated by the linear up-log down trapezoidal method. Area Under the Plasma Concentration-Time Curve up to Infinity (AUCinf) is defined as area under the plasma concentration-time curve from the time of dosing extrapolated to infinity. AUClast and AUCinf was assessed. |
| Time to Maximum Plasma Concentration (Tmax) for Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | Day 1 through 22: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose | Time of Maximum Plasma Concentration (Tmax) is defined as time of maximum observed plasma concentration and was an observed value from the study. |
| Area Under the Plasma Concentration-Time Curve (AUC) for Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | Day 1 through 22: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose | Area Under the Plasma Concentration-Time Curve up to the Last Quantifiable Concentration Post-Dose (AUClast) is defined as AUC from time 0 to the last measurable concentration, as calculated by the linear up-log down trapezoidal method. Area Under the Plasma Concentration-Time Curve up to Infinity (AUCinf) is defined as area under the plasma concentration-time curve from the time of dosing extrapolated to infinity. AUClast and AUCinf was assessed. |
| Terminal Half-Life (t1/2) for Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | Day 1 through 22: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose | Terminal Elimination Half-Life (t1/2) is defined as terminal elimination half-life and was calculated using noncompartmental analysis. |
| Metabolite to Parent Ratio (MPR) Based on Area Under the Curve for Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | Day 1 through 22: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose | AUCinf is defined as area under the plasma concentration-time curve from the time of dosing extrapolated to infinity and AUClast is defined as AUC from time 0 to the last measurable concentration, as calculated by the linear up-log down trapezoidal method. MPR is defined as a metabolite to parent ratio with metabolite as the numerator and the parent as the denominator. MPR corrected for molecular weight of AC886 of AUCinf and AUClast are reported and were calculated using non-compartmental analysis. AUClast and AUCinf was assessed. |
| Maximum Plasma Concentration (Cmax) of Unbound Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | Day 1 through 22: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose | Maximum Plasma Concentration (Cmax) is defined as the maximum observed plasma concentration and was an observed value for the study. |
Countries
United States
Participant flow
Recruitment details
A total of 12 participants who met all inclusion criteria and no exclusion criteria were enrolled from 22 Sep 2020 to 22 Jul 2021 at 3 clinics in the United States.
Pre-assignment details
This study included a screening period up to 22 days prior to the enrolment and a 22 day in-clinic period, including screening.
Participants by arm
| Arm | Count |
|---|---|
| Participants With Moderate Hepatic Impairment Participants with moderate hepatic impairment as defined by NCI-ODWG criteria who received a single, oral dose of quizartinib 30 mg on Day 1. | 6 |
| Control Participants With Normal Hepatic Function Healthy participants with normal hepatic function matched as a group by sex, age (±10 years), and weight (±20%) who received a single, oral dose of quizartinib 30 mg on Day 1 | 6 |
| Total | 12 |
Baseline characteristics
| Characteristic | Control Participants With Normal Hepatic Function | Total | Participants With Moderate Hepatic Impairment |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 2 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 10 Participants | 4 Participants |
| Age, Continuous | 55.3 years STANDARD_DEVIATION 3.88 | 56.2 years STANDARD_DEVIATION 5.34 | 57.0 years STANDARD_DEVIATION 6.78 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 11 Participants | 6 Participants |
| Region of Enrollment United States | 6 participants | 12 participants | 6 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 6 Participants | 12 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 1 / 6 | 2 / 6 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 |
Outcome results
Primary
Area Under the Plasma Concentration-Time Curve (AUC) for Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function
Area Under the Plasma Concentration-Time Curve up to the Last Quantifiable Concentration Post-Dose (AUClast) is defined as AUC from time 0 to the last measurable concentration, as calculated by the linear up-log down trapezoidal method. Area Under the Plasma Concentration-Time Curve up to Infinity (AUCinf) is defined as area under the plasma concentration-time curve from the time of dosing extrapolated to infinity. AUClast and AUCinf was assessed.
Time frame: Day 1 through 22: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose
Population: Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Participants With Moderate Hepatic Impairment | Area Under the Plasma Concentration-Time Curve (AUC) for Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | AUClast | 7480 ng*h/mL | Standard Deviation 2930 |
| Participants With Moderate Hepatic Impairment | Area Under the Plasma Concentration-Time Curve (AUC) for Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | AUCinf | 7880 ng*h/mL | Standard Deviation 3540 |
| Control Participants With Normal Hepatic Function | Area Under the Plasma Concentration-Time Curve (AUC) for Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | AUClast | 7720 ng*h/mL | Standard Deviation 4750 |
| Control Participants With Normal Hepatic Function | Area Under the Plasma Concentration-Time Curve (AUC) for Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | AUCinf | 8110 ng*h/mL | Standard Deviation 5120 |
Comparison: AUClast statistical comparison was analyzed for Quizartinib.90% CI: [59.5, 201]
Comparison: AUCinf statistical comparison was analyzed for Quizartinib.90% CI: [57.9, 207]
Primary
Maximum Plasma Concentration (Cmax) of Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function
Maximum Plasma Concentration (Cmax) is defined as the maximum observed plasma concentration and was an observed value for the study.
Time frame: Day 1 through 22: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose
Population: Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Participants With Moderate Hepatic Impairment | Maximum Plasma Concentration (Cmax) of Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | 86.2 ng/mL | Standard Deviation 15.8 |
| Control Participants With Normal Hepatic Function | Maximum Plasma Concentration (Cmax) of Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | 90.7 ng/mL | Standard Deviation 17.7 |
Comparison: Statistical comparison was analyzed for Quizartinib.90% CI: [77.1, 117]
Primary
Terminal Half-Life (t1/2) for Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function
Terminal Elimination Half-Life (t1/2) is defined as terminal elimination half-life and was calculated using noncompartmental analysis.
Time frame: Day 1 through 22: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose
Population: Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Participants With Moderate Hepatic Impairment | Terminal Half-Life (t1/2) for Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | 93.7 hours | Standard Deviation 36 |
| Control Participants With Normal Hepatic Function | Terminal Half-Life (t1/2) for Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | 96.3 hours | Standard Deviation 34.7 |
Primary
Time to Maximum Plasma Concentration (Tmax) for Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function
Time of Maximum Plasma Concentration (Tmax) is defined as time of maximum observed plasma concentration and was an observed value from the study.
Time frame: Day 1 through 22: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose
Population: Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Participants With Moderate Hepatic Impairment | Time to Maximum Plasma Concentration (Tmax) for Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | 4.0 hours |
| Control Participants With Normal Hepatic Function | Time to Maximum Plasma Concentration (Tmax) for Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | 4.0 hours |
Primary
Total Apparent Clearance (CL/F) for Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function
Total Apparent Clearance (CL/F) is defined as total apparent clearance and was calculated using non-compartmental analysis.
Time frame: Day 1 through 22: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose
Population: Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Participants With Moderate Hepatic Impairment | Total Apparent Clearance (CL/F) for Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | 4.0 L/h | Standard Deviation 1.9 |
| Control Participants With Normal Hepatic Function | Total Apparent Clearance (CL/F) for Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | 5.0 L/h | Standard Deviation 3.3 |
Primary
Volume of Distribution in the Terminal Phase (Vz/F) for Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function
Volume of Distribution in the Terminal Phase (Vz/F) is defined as volume of distribution in the terminal phase and was calculated using non-compartmental analysis.
Time frame: Day 1 through 22: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose
Population: Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Participants With Moderate Hepatic Impairment | Volume of Distribution in the Terminal Phase (Vz/F) for Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | 479 Liters | Standard Deviation 121 |
| Control Participants With Normal Hepatic Function | Volume of Distribution in the Terminal Phase (Vz/F) for Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | 577 Liters | Standard Deviation 269 |
Secondary
Area Under the Plasma Concentration-Time Curve (AUC) for Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function
Area Under the Plasma Concentration-Time Curve up to the Last Quantifiable Concentration Post-Dose (AUClast) is defined as AUC from time 0 to the last measurable concentration, as calculated by the linear up-log down trapezoidal method. Area Under the Plasma Concentration-Time Curve up to Infinity (AUCinf) is defined as area under the plasma concentration-time curve from the time of dosing extrapolated to infinity. AUClast and AUCinf was assessed.
Time frame: Day 1 through 22: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose
Population: Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set. For AUCinf, 1 participant was excluded from the Moderate Hepatic Impairment group where AUCinf based on extrapolation was greater than 20% and 1 participant was excluded from the Normal Hepatic Function group where Adjusted r-squared value was greater than 0.9.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Participants With Moderate Hepatic Impairment | Area Under the Plasma Concentration-Time Curve (AUC) for Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | AUClast | 2180 ng*h/mL | Standard Deviation 1110 |
| Participants With Moderate Hepatic Impairment | Area Under the Plasma Concentration-Time Curve (AUC) for Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | AUCinf | 2610 ng*h/mL | Standard Deviation 878 |
| Control Participants With Normal Hepatic Function | Area Under the Plasma Concentration-Time Curve (AUC) for Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | AUClast | 3240 ng*h/mL | Standard Deviation 1280 |
| Control Participants With Normal Hepatic Function | Area Under the Plasma Concentration-Time Curve (AUC) for Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | AUCinf | 3700 ng*h/mL | Standard Deviation 1130 |
Comparison: AUClast statistical comparison was analyzed for AC886.90% CI: [35.3, 111]
Comparison: AUCinf statistical comparison was analyzed for AC886.90% CI: [46.8, 104]
Secondary
Area Under the Plasma Concentration-Time Curve (AUC) of Unbound Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function
Area Under the Plasma Concentration-Time Curve up to the Last Quantifiable Concentration Post-Dose (AUClast) is defined as AUC from time 0 to the last measurable concentration, as calculated by the linear up-log down trapezoidal method. Area Under the Plasma Concentration-Time Curve up to Infinity (AUCinf) is defined as area under the plasma concentration-time curve from the time of dosing extrapolated to infinity. AUClast and AUCinf was assessed.
Time frame: Day 1 through 22: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose
Population: Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Participants With Moderate Hepatic Impairment | Area Under the Plasma Concentration-Time Curve (AUC) of Unbound Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | Unbound AC886 AUClast | 4.06 ng*h/mL | — |
| Participants With Moderate Hepatic Impairment | Area Under the Plasma Concentration-Time Curve (AUC) of Unbound Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | Unbound AC886 AUCinf | 4.18 ng*h/mL | — |
| Control Participants With Normal Hepatic Function | Area Under the Plasma Concentration-Time Curve (AUC) of Unbound Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | Unbound AC886 AUClast | 7.17 ng*h/mL | Standard Deviation 3.53 |
| Control Participants With Normal Hepatic Function | Area Under the Plasma Concentration-Time Curve (AUC) of Unbound Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | Unbound AC886 AUCinf | 7.35 ng*h/mL | Standard Deviation 3.56 |
Secondary
Area Under the Plasma Concentration-Time Curve (AUC) of Unbound Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function
Area Under the Plasma Concentration-Time Curve up to the Last Quantifiable Concentration Post-Dose (AUClast) is defined as AUC from time 0 to the last measurable concentration, as calculated by the linear up-log down trapezoidal method. Area Under the Plasma Concentration-Time Curve up to Infinity (AUCinf) is defined as area under the plasma concentration-time curve from the time of dosing extrapolated to infinity. AUClast and AUCinf was assessed.
Time frame: Day 1 through 22: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose
Population: Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Participants With Moderate Hepatic Impairment | Area Under the Plasma Concentration-Time Curve (AUC) of Unbound Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | Unbound Quizartinib AUClast | 35.8 ng*h/mL | Standard Deviation 30.4 |
| Participants With Moderate Hepatic Impairment | Area Under the Plasma Concentration-Time Curve (AUC) of Unbound Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | Unbound Quizartinib AUCinf | 37.4 ng*h/mL | Standard Deviation 31.3 |
| Control Participants With Normal Hepatic Function | Area Under the Plasma Concentration-Time Curve (AUC) of Unbound Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | Unbound Quizartinib AUClast | 84.5 ng*h/mL | Standard Deviation 86.5 |
| Control Participants With Normal Hepatic Function | Area Under the Plasma Concentration-Time Curve (AUC) of Unbound Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | Unbound Quizartinib AUCinf | 88.4 ng*h/mL | Standard Deviation 90 |
Comparison: AUClast statistical comparison was analyzed for Quizartinib.90% CI: [16, 165]
Comparison: AUCinf statistical comparison was analyzed for Quizartinib.90% CI: [15.8, 168]
Secondary
Maximum Plasma Concentration (Cmax) of Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function
Maximum Plasma Concentration (Cmax) is defined as the maximum observed plasma concentration and was an observed value for the study.
Time frame: Day 1 through 22: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose
Population: Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Participants With Moderate Hepatic Impairment | Maximum Plasma Concentration (Cmax) of Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | 17.3 ng/mL | Standard Deviation 12.1 |
| Control Participants With Normal Hepatic Function | Maximum Plasma Concentration (Cmax) of Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | 24.7 ng/mL | Standard Deviation 18.2 |
Comparison: Statistical comparison was analyzed for AC886.90% CI: [32, 173]
Secondary
Maximum Plasma Concentration (Cmax) of Unbound Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function
Maximum Plasma Concentration (Cmax) is defined as the maximum observed plasma concentration and was an observed value for the study.
Time frame: Day 1 through 22: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose
Population: Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set. Unbound AC886 concentration were below the level of quantification for 5 participants in the moderate hepatic impairment group and 2 participants in the normal hepatic function group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Participants With Moderate Hepatic Impairment | Maximum Plasma Concentration (Cmax) of Unbound Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | 0.0553 ng/mL | — |
| Control Participants With Normal Hepatic Function | Maximum Plasma Concentration (Cmax) of Unbound Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | 0.0658 ng/mL | Standard Deviation 0.049 |
Secondary
Maximum Plasma Concentration (Cmax) of Unbound Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function
Maximum Plasma Concentration (Cmax) is defined as the maximum observed plasma concentration and was an observed value for the study.
Time frame: Day 1 through 22: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose
Population: Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Participants With Moderate Hepatic Impairment | Maximum Plasma Concentration (Cmax) of Unbound Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | 0.412 ng/mL | Standard Deviation 0.32 |
| Control Participants With Normal Hepatic Function | Maximum Plasma Concentration (Cmax) of Unbound Quizartinib Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | 0.881 ng/mL | Standard Deviation 0.692 |
Comparison: Statistical comparison was analyzed for Quizartinib.90% CI: [18, 111]
Secondary
Metabolite to Parent Ratio (MPR) Based on Area Under the Curve for Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function
AUCinf is defined as area under the plasma concentration-time curve from the time of dosing extrapolated to infinity and AUClast is defined as AUC from time 0 to the last measurable concentration, as calculated by the linear up-log down trapezoidal method. MPR is defined as a metabolite to parent ratio with metabolite as the numerator and the parent as the denominator. MPR corrected for molecular weight of AC886 of AUCinf and AUClast are reported and were calculated using non-compartmental analysis. AUClast and AUCinf was assessed.
Time frame: Day 1 through 22: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose
Population: Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set. For AUCinf, 1 participant was excluded from the Moderate Hepatic Impairment group where AUCinf based on extrapolation was greater than 20% and 1 participant was excluded from the Normal Hepatic Function group where Adjusted r-squared value was greater than 0.9.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Participants With Moderate Hepatic Impairment | Metabolite to Parent Ratio (MPR) Based on Area Under the Curve for Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | MPR AUClast | 0.363 ratio | Standard Deviation 0.269 |
| Participants With Moderate Hepatic Impairment | Metabolite to Parent Ratio (MPR) Based on Area Under the Curve for Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | MPR AUCinf | 0.428 ratio | Standard Deviation 0.261 |
| Control Participants With Normal Hepatic Function | Metabolite to Parent Ratio (MPR) Based on Area Under the Curve for Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | MPR AUClast | 0.653 ratio | Standard Deviation 0.496 |
| Control Participants With Normal Hepatic Function | Metabolite to Parent Ratio (MPR) Based on Area Under the Curve for Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | MPR AUCinf | 0.762 ratio | Standard Deviation 0.467 |
Secondary
Number of Participants With Treatment-emergent Adverse Events Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function
A Treatment-Emergent Adverse Events (TEAE) is defined as any event not present prior to the initiation of the drug treatment of the drug treatment or any event already present that worsens in either intensity or frequency following exposure to the drug treatment. Number of any TEAE that is related and unrelated to study medication is presented.
Time frame: Baseline up to 30 days after last dose, up to 2 months
Population: TEAEs were assessed using the Safety Analysis Set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Participants With Moderate Hepatic Impairment | Number of Participants With Treatment-emergent Adverse Events Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | 1 Participants |
| Control Participants With Normal Hepatic Function | Number of Participants With Treatment-emergent Adverse Events Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | 2 Participants |
Secondary
Terminal Half-Life (t1/2) for Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function
Terminal Elimination Half-Life (t1/2) is defined as terminal elimination half-life and was calculated using noncompartmental analysis.
Time frame: Day 1 through 22: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose
Population: Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Participants With Moderate Hepatic Impairment | Terminal Half-Life (t1/2) for Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | 111.1 hours | Standard Deviation 48.7 |
| Control Participants With Normal Hepatic Function | Terminal Half-Life (t1/2) for Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | 81.4 hours | Standard Deviation 20.7 |
Secondary
Time to Maximum Plasma Concentration (Tmax) for Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function
Time of Maximum Plasma Concentration (Tmax) is defined as time of maximum observed plasma concentration and was an observed value from the study.
Time frame: Day 1 through 22: Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose
Population: Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Participants With Moderate Hepatic Impairment | Time to Maximum Plasma Concentration (Tmax) for Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | 7.00 hours |
| Control Participants With Normal Hepatic Function | Time to Maximum Plasma Concentration (Tmax) for Active Metabolite AC886 Following Single Dose of Quizartinib in Participants With Moderate Hepatic Impairment Compared to Participants With Normal Hepatic Function | 7.00 hours |