A Study of Quizartinib Pharmacokinetics in Participants With Moderate Hepatic Impairment

Hepatic Impairment Clinical Trial

Official title:

An Open-label, Single-dose Study to Assess the Pharmacokinetics, Safety and Tolerability of Quizartinib in Subjects With Moderate Impaired Hepatic Function as Defined by NCI-ODWG Criteria

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04473664
• Other study ID #: AC220-A-U105
• Status: Completed
• Phase: Phase 1
• Start date: September 22, 2020
• Est. completion date: July 22, 2021

Study information

• Verified date: September 2022
• Source: Daiichi Sankyo, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: July 22, 2021
• Est. primary completion date: July 22, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Hepatic Impairment
• Liver Diseases
• Moderate Impaired Hepatic Function

Intervention

Drug:
• Quizartinib
Single oral dose, 30 mg tablet

Locations

Country	Name	City	State
United States	Advanced Pharma	Miami	Florida
United States	Clinical Pharmacology of Miami, LLC	Miami	Florida
United States	Orlando Clinical Research Center	Orlando	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Daiichi Sankyo, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	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
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.	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
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.	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
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.	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
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.	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
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.	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
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.	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
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.	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
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.	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
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.	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
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.	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
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.	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
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.	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
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.	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
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.	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
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.	Baseline up to 30 days after last dose, up to 2 months