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

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

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.

Study Overview

• Status: Completed
• Conditions: Healthy Subjects
• Intervention / Treatment: Drug: Quizartinib dihydrochloride; Drug: 14C-Quizartinib solution for infusion

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.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Nottingham, United Kingdom, NG11 6JS
    • Quotient Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: All Participants; 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.	Drug: Quizartinib dihydrochloride; Single oral dose of 60 mg quizartinib (2 x 30 mg tablets); Other Names: Quizartinib; Drug: 14C-Quizartinib solution for infusion; 50 μg solution for infusion containing NMT 22.84 kBq 14C in 5 mL; administered once as a 15-minute infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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).	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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic Parameter of Maximum (Peak) Observed Plasma Concentration (Cmax) Following Oral Administrations of Quizartinib	Maximum (peak) plasma concentration (Cmax) was an observed value from the study. Cmax was assessed for Quizartinib and active metabolite AC886.	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 Parameter of Maximum (Peak) Observed Plasma Concentration (Cmax) Following Intravenous Administrations of Quizartinib	Maximum (peak) plasma concentration (Cmax) was an observed value from the study. Cmax was assessed for 14C-Quizartinib and 14C-AC886.	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 Parameter of Time to Maximum Plasma Concentration (Tmax) Following Intravenous and Oral Administrations of Quizartinib	Time to maximum plasma concentration (Tmax) was an observed value from the study. Tmax was assessed for Quizartinib and AC886.	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 Parameter of Terminal Half-Life (t1/2) Following Intravenous and Oral Administrations of Quizartinib	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.	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 Parameter for Area Under the Plasma Concentration-Time Curve (AUC) Following Oral Administrations of Quizartinib	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.	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 Parameter for Area Under the Plasma Concentration-Time Curve (AUC) Following Intravenous Administrations of Quizartinib	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.	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 Parameter for Total Body Clearance (CL) Following Single-Dose Intravenous Administration of Quizartinib	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.	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 Parameter for Volume of Distribution (Vz) Following Following Single-Dose Intravenous Administration of Quizartinib	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.	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 Parameter of Metabolite to Parent Ratio (MPR) Based on Area Under the Curve Following Intravenous and Oral Administrations of Quizartinib	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.	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
Number of Participants With Any Treatment-emergent Adverse Event Following Intravenous and Oral Administrations of Quizartinib	Treatment-emergent adverse events were coded using Medical Dictionary for Regulatory Activities (MedDRA) version 24.0.	Baseline up to approximately 6 weeks post-dose

Collaborators and Investigators

• Sponsor: Daiichi Sankyo, Inc.
• Collaborators: Quotient Sciences

Study record dates

Study Major Dates

• Study Start (Actual): April 26, 2021
• Primary Completion (Actual): June 11, 2021
• Study Completion (Actual): June 11, 2021

Study Registration Dates

• First Submitted: March 5, 2021
• First Submitted That Met QC Criteria: March 9, 2021
• First Posted (Actual): March 15, 2021

Study Record Updates

• Last Update Posted (Estimate): January 11, 2023
• Last Update Submitted That Met QC Criteria: April 15, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Healthy Subjects; Quizartinib; Microtracer; Oral Bioavailability
• Other Study ID Numbers: AC220-A-U107; 2021-000198-10 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No