Trial Outcomes & Findings for A Study to Determine the Absolute Oral Bioavailability of Quizartinib Using a Radiolabeled Microtracer in Healthy Subjects (NCT NCT04796831)

Results Overview

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).

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

8 participants

Primary outcome timeframe

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

Results posted on

2023-01-11

Participant Flow

A total of 8 participants who met all inclusion criteria and no exclusion criteria were included in this study and were enrolled at 1 clinic center in the United Kingdom.

Participants underwent preliminary screening procedures up to 21 days before investigational medicinal product (IMP) administration (Day -21 to Day-2). Participants were admitted in the morning on the day prior to IMP administration (i.e., Day -1), at which time admission procedures were undertaken to confirm eligibility. Participants were dosed in the morning of Day 1 following an overnight fast of a minimum of 8 hours for the oral dose (a minimum of 12 hours for the intravenous dose).

Participant milestones

Participant milestones
Measure	All Participants Participants who received 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.
Overall Study STARTED	8
Overall Study COMPLETED	8
Overall Study NOT COMPLETED	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	All Participants n=8 Participants Participants who received 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.
Age, Categorical <=18 years	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	8 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants
Age, Continuous	35.1 years STANDARD_DEVIATION 9.2 • n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants
Sex: Female, Male Male	8 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants
Race (NIH/OMB) White	8 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Region of Enrollment United Kingdom	8 participants n=5 Participants

PRIMARY outcome

Timeframe: 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

Population: Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable Population.

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).

Outcome measures

Outcome measures
Measure	All Participants n=8 Participants Participants who received 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.
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 Area under the concentration-time curve from the time of dosing to time Tlast (AUClast)	72.12 percentage of oral bioavailability Standard Deviation 7.18
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 Area under the concentration-time curve from the time of dosing extrapolated to infinity (AUCinf)	71.47 percentage of oral bioavailability Standard Deviation 7.34

SECONDARY outcome

Timeframe: 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

Population: Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable Population.

Maximum (peak) plasma concentration (Cmax) was an observed value from the study. Cmax was assessed for Quizartinib and active metabolite AC886.

Outcome measures

Outcome measures
Measure	All Participants n=8 Participants Participants who received 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.
Pharmacokinetic Parameter of Maximum (Peak) Observed Plasma Concentration (Cmax) Following Oral Administrations of Quizartinib Oral (plasma): Quizartinib	209 ng/mL Standard Deviation 33.4
Pharmacokinetic Parameter of Maximum (Peak) Observed Plasma Concentration (Cmax) Following Oral Administrations of Quizartinib Oral (plasma): AC886	40.7 ng/mL Standard Deviation 24.0

SECONDARY outcome

Timeframe: 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

Population: Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable Population.

Maximum (peak) plasma concentration (Cmax) was an observed value from the study. Cmax was assessed for 14C-Quizartinib and 14C-AC886.

Outcome measures

Outcome measures
Measure	All Participants n=7 Participants Participants who received 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.
Pharmacokinetic Parameter of Maximum (Peak) Observed Plasma Concentration (Cmax) Following Intravenous Administrations of Quizartinib 14C-Quizartinib	1030 pg/mL Standard Deviation 317
Pharmacokinetic Parameter of Maximum (Peak) Observed Plasma Concentration (Cmax) Following Intravenous Administrations of Quizartinib 14C-AC886	31.9 pg/mL Standard Deviation 11.4

SECONDARY outcome

Timeframe: 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

Population: Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable Population.

Time to maximum plasma concentration (Tmax) was an observed value from the study. Tmax was assessed for Quizartinib and AC886.

Outcome measures

Outcome measures
Measure	All Participants n=8 Participants Participants who received 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.
Pharmacokinetic Parameter of Time to Maximum Plasma Concentration (Tmax) Following Intravenous and Oral Administrations of Quizartinib Oral (plasma): Quizartinib	4.75 hours Interval 2.0 to 5.02
Pharmacokinetic Parameter of Time to Maximum Plasma Concentration (Tmax) Following Intravenous and Oral Administrations of Quizartinib Oral (plasma): AC886	5.51 hours Interval 4.75 to 72.12
Pharmacokinetic Parameter of Time to Maximum Plasma Concentration (Tmax) Following Intravenous and Oral Administrations of Quizartinib Intravenous: Quizartinib	0.25 hours Interval 0.23 to 0.27
Pharmacokinetic Parameter of Time to Maximum Plasma Concentration (Tmax) Following Intravenous and Oral Administrations of Quizartinib Intravenous: AC886	44.02 hours Interval 20.02 to 68.12

SECONDARY outcome

Timeframe: 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

Population: Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable Population.

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.

Outcome measures

Outcome measures
Measure	All Participants n=8 Participants Participants who received 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.
Pharmacokinetic Parameter of Terminal Half-Life (t1/2) Following Intravenous and Oral Administrations of Quizartinib Oral (plasma): Quizartinib	94.2 hours Standard Deviation 23.7
Pharmacokinetic Parameter of Terminal Half-Life (t1/2) Following Intravenous and Oral Administrations of Quizartinib Oral (plasma): AC886	111 hours Standard Deviation 45.4
Pharmacokinetic Parameter of Terminal Half-Life (t1/2) Following Intravenous and Oral Administrations of Quizartinib Intravenous: Quizartinib	95.7 hours Standard Deviation 29.7
Pharmacokinetic Parameter of Terminal Half-Life (t1/2) Following Intravenous and Oral Administrations of Quizartinib Intravenous: AC886	90.4 hours Standard Deviation 31.2

SECONDARY outcome

Timeframe: 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

Population: Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable Population.

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.

Outcome measures

Outcome measures
Measure	All Participants n=8 Participants Participants who received 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.
Pharmacokinetic Parameter for Area Under the Plasma Concentration-Time Curve (AUC) Following Oral Administrations of Quizartinib Oral (plasma): Quizartinib, AUClast	17000 ng*h/mL Standard Deviation 4990
Pharmacokinetic Parameter for Area Under the Plasma Concentration-Time Curve (AUC) Following Oral Administrations of Quizartinib Oral (plasma): AC886, AUClast	5300 ng*h/mL Standard Deviation 1310
Pharmacokinetic Parameter for Area Under the Plasma Concentration-Time Curve (AUC) Following Oral Administrations of Quizartinib Oral (plasma): Quizartinib, AUCinf	17600 ng*h/mL Standard Deviation 5500
Pharmacokinetic Parameter for Area Under the Plasma Concentration-Time Curve (AUC) Following Oral Administrations of Quizartinib Oral (plasma): AC886, AUCinf	5580 ng*h/mL Standard Deviation 1200

SECONDARY outcome

Timeframe: 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

Population: Pharmacokinetic parameters were assessed in patients with available data in the Pharmacokinetic Evaluable Population.

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.

Outcome measures

Outcome measures
Measure	All Participants n=7 Participants Participants who received 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.
Pharmacokinetic Parameter for Area Under the Plasma Concentration-Time Curve (AUC) Following Intravenous Administrations of Quizartinib Intravenous: 14C-Quizartinib, AUClast	18800 pg*h/mL Standard Deviation 4950
Pharmacokinetic Parameter for Area Under the Plasma Concentration-Time Curve (AUC) Following Intravenous Administrations of Quizartinib Intravenous: 14C-AC886, AUClast	5170 pg*h/mL Standard Deviation 1330
Pharmacokinetic Parameter for Area Under the Plasma Concentration-Time Curve (AUC) Following Intravenous Administrations of Quizartinib Intravenous: 14C-Quizartinib, AUCinf	19600 pg*h/mL Standard Deviation 5390
Pharmacokinetic Parameter for Area Under the Plasma Concentration-Time Curve (AUC) Following Intravenous Administrations of Quizartinib Intravenous: 14C-AC886, AUCinf	5620 pg*h/mL Standard Deviation 1270

SECONDARY outcome

Timeframe: 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

Population: Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable Population.

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.

Outcome measures

Outcome measures
Measure	All Participants n=8 Participants Participants who received 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.
Pharmacokinetic Parameter for Total Body Clearance (CL) Following Single-Dose Intravenous Administration of Quizartinib	2.31 L/h Standard Deviation 0.624

SECONDARY outcome

Timeframe: 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

Population: Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable Population.

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.

Outcome measures

Outcome measures
Measure	All Participants n=8 Participants Participants who received 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.
Pharmacokinetic Parameter for Volume of Distribution (Vz) Following Following Single-Dose Intravenous Administration of Quizartinib	318 Liters Standard Deviation 142

SECONDARY outcome

Timeframe: 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

Population: Pharmacokinetic parameters were assessed in the Pharmacokinetic Evaluable Population.

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.

Outcome measures

Outcome measures
Measure	All Participants n=8 Participants Participants who received 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.
Pharmacokinetic Parameter of Metabolite to Parent Ratio (MPR) Based on Area Under the Curve Following Intravenous and Oral Administrations of Quizartinib Oral (plasma): MPR(AUClast), AC886	0.35 metabolite-to-parent ratio Standard Deviation 0.164
Pharmacokinetic Parameter of Metabolite to Parent Ratio (MPR) Based on Area Under the Curve Following Intravenous and Oral Administrations of Quizartinib Oral (plasma): MPR(AUCinf), AC886	0.35 metabolite-to-parent ratio Standard Deviation 0.158
Pharmacokinetic Parameter of Metabolite to Parent Ratio (MPR) Based on Area Under the Curve Following Intravenous and Oral Administrations of Quizartinib Intravenous: MPR(AUClast), 14C-AC886	0.29 metabolite-to-parent ratio Standard Deviation 0.098
Pharmacokinetic Parameter of Metabolite to Parent Ratio (MPR) Based on Area Under the Curve Following Intravenous and Oral Administrations of Quizartinib Intravenous: MPR(AUCinf), 14C-AC886	0.30 metabolite-to-parent ratio Standard Deviation 0.093

SECONDARY outcome

Timeframe: Baseline up to approximately 6 weeks post-dose

Population: Treatment-emergent adverse events were assessed in the Safety Population.

Treatment-emergent adverse events were coded using Medical Dictionary for Regulatory Activities (MedDRA) version 24.0.

Outcome measures

Outcome measures
Measure	All Participants n=8 Participants Participants who received 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.
Number of Participants With Any Treatment-emergent Adverse Event Following Intravenous and Oral Administrations of Quizartinib	1 Participants

Adverse Events

All Participants

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	All Participants n=8 participants at risk 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.
Ear and labyrinth disorders Cerumen impaction	12.5% 1/8 • Treatment-emergent adverse events were collected from baseline up to 6 weeks post-dose.

Additional Information

Contact for Clinical Trial Information

Daiichi Sankyo

Phone: 908-992-6400

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place