A Study to Determine the Absolute Oral Bioavailability of Quizartinib Using a Radiolabeled Microtracer in Healthy Subjects

Phase 1

Completed

Conditions: Healthy Subjects

Interventions: Drug: Quizartinib dihydrochloride
Drug: 14C-Quizartinib solution for infusion

Registration Number: NCT04796831

Lead Sponsor: Daiichi Sankyo

Brief Summary: Quizartinib, a selective FLT3 inhibitor, is being developed as a treatment for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The absolute oral bioavailability of quizartinib has not yet been studied. This study is designed to estimate quizartinib bioavailability of quizartinib following oral and intravenous (IV) administration.

Detailed Description: Quizartinib bioavailability based on the dose-adjusted exposure of quizartinib following oral and IV administration will be assessed in healthy male subjects. The primary objective of this study is to determine the absolute oral bioavailability of quizartinib. Secondary objectives will include characterizing the plasma PK of quizartinib, radiolabeled quizartinib, and the major circulating metabolite after a single oral dose and IV administration. Safety and tolerability of quizartinib will also be assessed.

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 8

Inclusion Criteria

Healthy males aged 18 years to 55 years of age (inclusive) at the time of signing informed consent
Body mass index (BMI) of 18.0 kg/m^2 to 32.0 kg/m^2 (inclusive) at screening

Exclusion Criteria

History or presence of:
- Clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal (GI), endocrine, immunologic, dermatologic, neurologic, oncologic, or psychiatric disease, as judged by the Investigator.
- Any other condition, including laboratory abnormality, that in the opinion of the Investigator, would jeopardize the safety of the subject, obtaining informed consent, compliance to the study procedures, or the validity of the study results.
History of a clinically significant illness, in the opinion of the Investigator, within 4 weeks prior to administration of quizartinib.
History, or presence in the average of triplicate ECGs at screening and admission (Day -1), of any of the following cardiac conduction abnormalities:
- QT interval corrected with Fridericia's formula (QTcF) > 450 milliseconds (ms).
- Evidence of second- or third-degree atrioventricular block.
- Evidence of complete left or right bundle branch block.
- QRS or T wave morphology that could, in the Investigator's opinion, render QT interval assessment unreliable (confirmed with triplicate ECG).
Laboratory results (serum chemistry, hematology, coagulation, and urinalysis) outside the normal range, if considered clinically significant by the Investigator at screening or admission (Day -1).
Estimated creatinine clearance (CrCl) <90 mL/min (calculated using Cockcroft-Gault Equation) at screening.
Use of drugs with a risk of QT interval prolongation or Torsades de Pointes (TdP) within 14 days of admission (Day -1) (or 5 drug half-lives, if 5 drug half-lives are expected to exceed 14 days).

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
All Participants	Quizartinib dihydrochloride	Participants who will receive a single, oral dose of 60 mg quizartinib and a single, IV administration of 50 μg 14C-quizartinib solution for infusion at 4 hours post-oral dosing.
All Participants	14C-Quizartinib solution for infusion	Participants who will receive a single, oral dose of 60 mg quizartinib and a single, IV administration of 50 μg 14C-quizartinib solution for infusion at 4 hours post-oral dosing.

Primary Outcome Measures

Name	Time	Method
Percentage of Absolute Oral Bioavailability for Quizartinib As Assessed By Pharmacokinetic Parameters for Area Under the Plasma Concentration-Time Curve Following Intravenous and Oral Administrations of Quizartinib	Relative to oral dosing: Pre-dose and at 1, 2, 4, 4.25, 4.5, 4.75, 5, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240, 288, 336, 384, 432, 480, and 504 hours	The absolute bioavailability assessment for quizartinib was based on the pharmacokinetic parameters area under the curve (AUC) from the time of dosing to time Tlast (AUClast) and AUC from the time of dosing extrapolated to infinity (AUCinf) for quizartinib following intravenous and oral administrations. Pharmacokinetic parameters were calculated using a non-compartmental approach. PK parameters were computed using Phoenix™ WinNonlin® (Version 8.0).

Secondary Outcome Measures

Name	Time	Method
Pharmacokinetic Parameter of Maximum (Peak) Observed Plasma Concentration (Cmax) Following Intravenous Administrations of Quizartinib	Relative to oral dosing: 4, 4.25, 4.5, 4.75, 5, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240, 288, 336, 384, 432, 480, and 504 hours	Maximum (peak) plasma concentration (Cmax) was an observed value from the study. Cmax was assessed for 14C-Quizartinib and 14C-AC886.
Pharmacokinetic Parameter of Terminal Half-Life (t1/2) Following Intravenous and Oral Administrations of Quizartinib	Relative to oral dosing: Pre-dose, 1, 2, 4, 4.25, 4.5, 4.75, 5, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240, 288, 336, 384, 432, 480, and 504 hours	Pharmacokinetic parameters were calculated using a non-compartmental approach. PK parameters were computed using Phoenix™ WinNonlin® (Version 8.0). Half-life (t1/2) was assessed for Quizartinib, 14C-Quizartinib, AC886, 14C-AC886.
Pharmacokinetic Parameter of Maximum (Peak) Observed Plasma Concentration (Cmax) Following Oral Administrations of Quizartinib	Relative to oral dosing: Pre-dose, 1, 2, 4, 4.25, 4.5, 4.75, 5, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240, 288, 336, 384, 432, 480, and 504 hours	Maximum (peak) plasma concentration (Cmax) was an observed value from the study. Cmax was assessed for Quizartinib and active metabolite AC886.
Pharmacokinetic Parameter for Volume of Distribution (Vz) Following Following Single-Dose Intravenous Administration of Quizartinib	Relative to oral dosing: 4, 4.25, 4.5, 4.75, 5, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240, 288, 336, 384, 432, 480, and 504 hours	Pharmacokinetic parameters were calculated using a non-compartmental approach. PK parameters were computed using Phoenix™ WinNonlin® (Version 8.0). Volume of distribution based on the terminal phase (Vz) was assessed following single-dose IV administration for 14C-quizartinib.
Pharmacokinetic Parameter of Metabolite to Parent Ratio (MPR) Based on Area Under the Curve Following Intravenous and Oral Administrations of Quizartinib	Relative to oral dosing: Pre-dose (AC886 only), 1 hour (AC886 only), 2 hours (AC886 only), 4, 4.25, 4.5, 4.75, 5, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240, 288, 336, 384, 432, 480, and 504 hours	Pharmacokinetic parameters were calculated using a non-compartmental approach. PK parameters were computed using Phoenix™ WinNonlin® (Version 8.0). MPR was assessed for AC886 and 14C-AC886.
Number of Participants With Any Treatment-emergent Adverse Event Following Intravenous and Oral Administrations of Quizartinib	Baseline up to approximately 6 weeks post-dose	Treatment-emergent adverse events were coded using Medical Dictionary for Regulatory Activities (MedDRA) version 24.0.
Pharmacokinetic Parameter of Time to Maximum Plasma Concentration (Tmax) Following Intravenous and Oral Administrations of Quizartinib	Relative to oral dosing: Pre-dose, 1, 2, 4, 4.25, 4.5, 4.75, 5, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240, 288, 336, 384, 432, 480, and 504 hours	Time to maximum plasma concentration (Tmax) was an observed value from the study. Tmax was assessed for Quizartinib and AC886.
Pharmacokinetic Parameter for Area Under the Plasma Concentration-Time Curve (AUC) Following Oral Administrations of Quizartinib	Relative to oral dosing: Pre-dose, 1, 2, 4, 4.25, 4.5, 4.75, 5, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240, 288, 336, 384, 432, 480, and 504 hours	Pharmacokinetic parameters were calculated using a non-compartmental approach. PK parameters were computed using Phoenix™ WinNonlin® (Version 8.0). Area under the concentration-time curve from the time of dosing to time (AUClast) and area under the concentration-time curve from the time of dosing extrapolated to infinity (AUCinf) were assessed for Quizartinib and AC886.
Pharmacokinetic Parameter for Area Under the Plasma Concentration-Time Curve (AUC) Following Intravenous Administrations of Quizartinib	Relative to oral dosing: 4, 4.25, 4.5, 4.75, 5, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240, 288, 336, 384, 432, 480, and 504 hours	Pharmacokinetic parameters were calculated using a non-compartmental approach. PK parameters were computed using Phoenix™ WinNonlin® (Version 8.0). Area under the concentration-time curve from the time of dosing to time (AUClast) and area under the concentration-time curve from the time of dosing extrapolated to infinity (AUCinf) were assessed for 14C-Quizartinib and 14C-AC886.
Pharmacokinetic Parameter for Total Body Clearance (CL) Following Single-Dose Intravenous Administration of Quizartinib	Relative to oral dosing: 4, 4.25, 4.5, 4.75, 5, 6, 8, 12, 24, 48, 72, 96, 144, 192, 240, 288, 336, 384, 432, 480, and 504 hours	Pharmacokinetic parameters were calculated using a non-compartmental approach. PK parameters were computed using Phoenix™ WinNonlin® (Version 8.0). Total body clearance (CL) was assessed following single-dose IV administration for 14C-quizartinib.