A Study of Quizartinib Pharmacokinetics in Participants With Moderate Hepatic Impairment

Phase 1

Completed

Conditions: Hepatic Impairment
Moderate Impaired Hepatic Function

Interventions: Drug: Quizartinib

Registration Number: NCT04473664

Lead Sponsor: Daiichi Sankyo

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 12

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 Exclusion Criteria for Matched Healthy Participants:

Any clinically relevant abnormality identified on the physical examination, ECG, vital signs, or laboratory tests at Screening
Liver function (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase of liver origin, gamma-glutamyl transferase, and total bilirubin) test results above the upper limit of normal at Screening and during Enrollment on Day -2 are exclusionary. If transaminase levels are >2 × upper limit of normal (ULN) at Screening the participant will be excluded and cannot be rescreened

Additional Exclusion Criteria for Participants with Hepatic Impairment:

Participants with active stage 3 or stage 4 encephalopathy
Fluctuating or rapidly deteriorating hepatic function as indicated by recent history or worsening of clinical and/or laboratory signs of HI as judged by the investigator
Participants with severe ascites and/or need of regular paracentesis

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Participants with Moderate Hepatic Impairment	Quizartinib	Participants with moderate hepatic impairment as defined by NCI-ODWG criteria who received a single, oral dose of quizartinib 30 mg on Day 1.
Control Participants with Normal Hepatic Function	Quizartinib	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.

Primary Outcome Measures

Name	Time	Method
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.
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.
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.
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.
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 Outcome Measures

Name	Time	Method
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.

Trial Locations

Locations (3): Clinical Pharmacology of Miami, LLC
🇺🇸
Miami, Florida, United States
Orlando Clinical Research Center
🇺🇸
Orlando, Florida, United States
Advanced Pharma
🇺🇸
Miami, Florida, United States