A Study of the Effect of a Moderate CYP3A Inducer Efavirenz on Quizartinib Pharmacokinetics in Healthy Participants

• Sponsor: Daiichi Sankyo Co., Ltd. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT04459598
• Collaborator: (none)
• Enrollment: 32
• Location: 1
• Arms: 2
• Actual Duration (Months): 1.8
• Patients Per Site Per Month: 17.4

Study Details

Study Description

Brief Summary

This drug-drug interaction (DDI) study has been designed to investigate the effect of a moderate CYP3A inducer efavirenz on the pharmacokinetics of quizartinib and its major circulating active metabolite AC886.

Condition or Disease	Intervention/Treatment	Phase
Healthy Subjects; Drug-drug Interaction; Pharmacokinetics; Quizartinib	Drug: Efavirenz; Drug: Quizartinib	Phase 1

Detailed Description

In vitro, quizartinib is metabolized primarily by CYP3A. Therefore, co-administration of quizartinib with CYP3A inducers may decrease quizartinib exposure. This study will assess the effect of a moderate CYP3A inducer efavirenz on the single dose (60 mg) quizartinib pharmacokinetics in healthy participants.

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Parallel Drug Interaction Study to Evaluate the Effect of a CYP3A Moderate Inducer Efavirenz on the Pharmacokinetics of Quizartinib in Healthy Subjects
• Actual Study Start Date: Aug 19, 2020
• Actual Primary Completion Date: Oct 14, 2020
• Actual Study Completion Date: Oct 14, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Efavirenz 600 mg + Quizartinib 60 mg Participants who received efavirenz 600 mg once daily (QD) for 34 days and a single, oral dose of quizartinib 60 mg on Day 15 concurrently with efavirenz.	Drug: Efavirenz; Single oral dose, 600-mg tablet; Drug: Quizartinib; Single oral dose, 60 mg (2 x 30 mg) tablets
Active Comparator: Quizartinib 60 mg Participants who received a single, oral dose of quizartinib 60 mg on Day 1.	Drug: Quizartinib; Single oral dose, 60 mg (2 x 30 mg) tablets

Outcome Measures

Primary Outcome Measures

1. Maximum Plasma Concentration (Cmax) Following Single Dose of Quizartinib With or Without Efavirenz [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. Cmax was assessed for Quizartinib and active metabolite AC886.

2. Time to Maximum Plasma Concentration (Tmax) Following Single Dose of Quizartinib With or Without Efavirenz [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. Tmax was assessed for Quizartinib and active metabolite AC886.

3. Area Under the Plasma Concentration-Time Curve up to the Last Quantifiable Concentration Post-Dose (AUClast) Following Single Dose of Quizartinib With or Without Efavirenz [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 and was calculated using non-compartmental analysis. AUClast was assessed for Quizartinib and active metabolite AC886.

4. Area Under the Plasma Concentration-Time Curve up to Infinity (AUCinf) Following Single Dose of Quizartinib With or Without Efavirenz [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 Infinity (AUCinf) is defined as area under the plasma concentration-time curve from the time of dosing extrapolated to infinity and was calculated using non-compartmental analysis. AUCinf was assessed for Quizartinib and active metabolite AC886.

5. Terminal Half-Life (t1/2) Following Single Dose of Quizartinib With or Without Efavirenz [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 non-compartmental analysis. AUClast was assessed for Quizartinib and active metabolite AC886. Half-life (t1/2) was assessed for Quizartinib and active metabolite AC886.

6. Metabolite to Parent Ratio (MPR) Based on Area Under the Curve for Active Metabolite AC886 Following Single Dose of Quizartinib With or Without Efavirenz [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.

7. Total Apparent Clearance (CL/F) for Quizartinib Following Single Dose of Quizartinib With or Without Efavirenz [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.

8. Volume of Distribution in the Terminal Phase (Vz/F) for Quizartinib Following Single Dose of Quizartinib With or Without Efavirenz [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.

Secondary Outcome Measures

1. Number of Participants With Treatment-emergent Adverse Events Following Single Dose of Quizartinib With or Without Efavirenz [Baseline up to 30 days post last dose, up to approximately 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Male and female participants 18 to 55 years of age (inclusive), with a body mass index (BMI) of 18 kg/m^{2 to 32 kg/m}2 (inclusive) and with a minimum body weight of 45 kg at Screening.

• 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, 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.

• Liver function test results must be below the upper limit of normal. Hemoglobin levels must be ≥ 11.5 g/dL for female participants and ≥ 12.5 g/dL for male participants.

• 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.

• Presence or history of clinically severe adverse reaction to any drug

• History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered drugs (with the exception of appendectomy, hernia repair, and/or cholecystectomy)

• History of any cancer, except non-melanoma skin cancer, or resected nonmetastatic cancer with no evidence of disease accepted by the Investigator and Sponsor medical monitor

• 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

• History or presence of an abnormal electrocardiogram (ECG), which, in the investigator's opinion, is clinically significant and/or a QT interval corrected for heart rate using Fridericia's formula >450 milliseconds (ms) at Screening.

• 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 h prior to check-in and during confinement

• Positive serology for hepatitis B surface antigen (HBsAg) and HCV (healthy participants), hepatitis A virus (HAV) immunoglobulin M, or antihuman immunodeficiency virus (HIV) Type 1 and Type 2 (all subjects)

• Loss of more than 450 mL blood during the 3 months before the trial (eg, as a blood donor)

• 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Worldwide Clinical Trials	San Antonio	Texas	United States	78217

Sponsors and Collaborators

• Daiichi Sankyo Co., Ltd.

Investigators

• Study Director: Global Clinical Leader, Daiichi Sankyo, Inc.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 4, 2020

More Information

Publications

None provided.

• Responsible Party: Daiichi Sankyo Co., Ltd.
• ClinicalTrials.gov Identifier: NCT04459598
• Other Study ID Numbers: AC220-A-U106
• First Posted: Jul 7, 2020
• Last Update Posted: Jun 28, 2022
• Last Verified: Jun 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Daiichi Sankyo Co., Ltd.: Healthy Subjects; Drug-drug Interaction; Pharmacokinetics; Quizartinib; CYP3A Inducer
• Additional relevant MeSH terms: Efavirenz

Study Results

Participant Flow

Recruitment Details	A total of 32 participants who met all inclusion criteria and no exclusion criteria were enrolled from 19 Aug 2020 to 14 Oct 2020 at 1 clinic in the United States.
Pre-assignment Detail	This study consisted of two treatment periods. Following a Screening Period of 21 days, eligible participants were randomized in a 1:1 ratio to 1 of 2 treatment groups. Treatment Group A received efavirenz once daily on Day 1 and continued the regimen through Day 35 and a single dose of quizartinib on Day 15. Treatment Group B received a single dose of quizartinib on Day 1.

Arm/Group Title	Efavirenz 600 mg + Quizartinib 60 mg	Quizartinib 60 mg
Arm/Group Description	Participants who received efavirenz 600 mg once daily (QD) for 34 days and a single, oral dose of quizartinib 60 mg on Day 15 concurrently with efavirenz.	Participants who received a single, oral dose of quizartinib 60 mg on Day 1.
Period Title: Overall Study
STARTED	16	16
COMPLETED	15	15
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	Efavirenz 600 mg + Quizartinib 60 mg	Quizartinib 60 mg	Total
Arm/Group Description	Participants who received efavirenz 600 mg once daily (QD) for 34 days and a single, oral dose of quizartinib 60 mg on Day 15 concurrently with efavirenz.	Participants who received a single, oral dose of quizartinib 60 mg on Day 1.	Total of all reporting groups
Overall Participants	16	16	32
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	16 100%	16 100%	32 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40 (10.05)	38.7 (10.22)	39.6 (10.01)
Sex: Female, Male (Count of Participants)
Female	1 6.3%	5 31.3%	6 18.8%
Male	15 93.8%	11 68.8%	26 81.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 12.5%	0 0%	2 6.3%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	9 56.3%	9 56.3%	18 56.3%
White	5 31.3%	7 43.8%	12 37.5%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Maximum Plasma Concentration (Cmax) Following Single Dose of Quizartinib With or Without Efavirenz
Description	Maximum Plasma Concentration (Cmax) is defined as the maximum observed plasma concentration and was an observed value for the study. Cmax was assessed for Quizartinib and active metabolite AC886.
Time Frame	Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set except for 1 participant from the Efavirenz 600 mg + Quizartinib 60 mg group due to insufficient data.

Arm/Group Title	Efavirenz 600 mg + Quizartinib 60 mg	Quizartinib 60 mg
Arm/Group Description	Participants who received efavirenz 600 mg once daily (QD) for 34 days and a single, oral dose of quizartinib 60 mg on Day 15 concurrently with efavirenz.	Participants who received a single, oral dose of quizartinib 60 mg on Day 1.
Measure Participants	15	16
Quizartinib	130.0 (36.1)	238.0 (76.9)
AC886	11.0 (5.35)	34.4 (18.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Efavirenz 600 mg + Quizartinib 60 mg, Quizartinib 60 mg
	Comments	Statistical comparison was analyzed for Quizartinib.
	Type of Statistical Test	Other
	Comments	Least squares (LS) means were calculated from an analysis of variance (ANOVA) model on log-transformed scale. The LS means for each treatment were back transformed from the log scale to provide estimates of the geometric means (GMS). The ratio (%) of GMS was calculated and 90% Confidence Intervals (CIs) for the ratio (%) of GMS were presented.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (%) of Geometric LS Mean
	Estimated Value	55.24
	Confidence Interval	(2-Sided) 90%; 45.24 to 67.46
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the comparison, the Efavirenz + Quizartinib treatment group represents the numerator and Quizartinib only treatment group represents the denominator.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Efavirenz 600 mg + Quizartinib 60 mg, Quizartinib 60 mg
	Comments	Statistical comparison was analyzed for AC886.
	Type of Statistical Test	Other
	Comments	Least squares (LS) means were calculated from an analysis of variance (ANOVA) model on log-transformed scale. The LS means for each treatment were back transformed from the log scale to provide estimates of the geometric means (GMS). The ratio (%) of GMS was calculated and 90% Confidence Intervals (CIs) for the ratio (%) of GMS were presented.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (%) of Geometric LS Mean
	Estimated Value	32.37
	Confidence Interval	(2-Sided) 90%; 23.79 to 44.05
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the comparison, the Efavirenz + Quizartinib treatment group represents the numerator and Quizartinib only treatment group represents the denominator.

2. Primary Outcome

Title	Time to Maximum Plasma Concentration (Tmax) Following Single Dose of Quizartinib With or Without Efavirenz
Description	Time of Maximum Plasma Concentration (Tmax) is defined as time of maximum observed plasma concentration and was an observed value from the study. Tmax was assessed for Quizartinib and active metabolite AC886.
Time Frame	Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set except for 1 participant from the Efavirenz 600 mg + Quizartinib 60 mg group due to insufficient data.

Arm/Group Title	Efavirenz 600 mg + Quizartinib 60 mg	Quizartinib 60 mg
Arm/Group Description	Participants who received efavirenz 600 mg once daily (QD) for 34 days and a single, oral dose of quizartinib 60 mg on Day 15 concurrently with efavirenz.	Participants who received a single, oral dose of quizartinib 60 mg on Day 1.
Measure Participants	15	16
Quizartinib	2.0	4.0
AC886	4.0	4.0

3. Primary Outcome

Title	Area Under the Plasma Concentration-Time Curve up to the Last Quantifiable Concentration Post-Dose (AUClast) Following Single Dose of Quizartinib With or Without Efavirenz
Description	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 and was calculated using non-compartmental analysis. AUClast was assessed for Quizartinib and active metabolite AC886.
Time Frame	Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set except for 1 participant from the Efavirenz 600 mg + Quizartinib 60 mg group due to insufficient data.

Arm/Group Title	Efavirenz 600 mg + Quizartinib 60 mg	Quizartinib 60 mg
Arm/Group Description	Participants who received efavirenz 600 mg once daily (QD) for 34 days and a single, oral dose of quizartinib 60 mg on Day 15 concurrently with efavirenz.	Participants who received a single, oral dose of quizartinib 60 mg on Day 1.
Measure Participants	15	16
Quizartinib	2730 (1160)	23600 (8420)
AC886	185 (177)	4110 (1320)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Efavirenz 600 mg + Quizartinib 60 mg, Quizartinib 60 mg
	Comments	Statistical comparison was analyzed for Quizartinib.
	Type of Statistical Test	Other
	Comments	Least squares (LS) means were calculated from an analysis of variance (ANOVA) model on log-transformed scale. The LS means for each treatment were back transformed from the log scale to provide estimates of the geometric means (GMS). The ratio (%) of GMS was calculated and 90% Confidence Intervals (CIs) for the ratio (%) of GMS were presented.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (%) of Geometric LS Mean
	Estimated Value	11.11
	Confidence Interval	(2-Sided) 90%; 8.47 to 14.56
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the comparison, the Efavirenz + Quizartinib treatment group represents the numerator and Quizartinib only treatment group represents the denominator.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Efavirenz 600 mg + Quizartinib 60 mg, Quizartinib 60 mg
	Comments	Statistical comparison was analyzed for AC886.
	Type of Statistical Test	Other
	Comments	Least squares (LS) means were calculated from an analysis of variance (ANOVA) model on log-transformed scale. The LS means for each treatment were back transformed from the log scale to provide estimates of the geometric means (GMS). The ratio (%) of GMS was calculated and 90% Confidence Intervals (CIs) for the ratio (%) of GMS were presented.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (%) of Geometric LS Mean
	Estimated Value	3.67
	Confidence Interval	(2-Sided) 90%; 2.47 to 5.45
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the comparison, the Efavirenz + Quizartinib treatment group represents the numerator and Quizartinib only treatment group represents the denominator.

4. Primary Outcome

Title	Area Under the Plasma Concentration-Time Curve up to Infinity (AUCinf) Following Single Dose of Quizartinib With or Without Efavirenz
Description	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 and was calculated using non-compartmental analysis. AUCinf was assessed for Quizartinib and active metabolite AC886.
Time Frame	Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set except for 1 participant from the Efavirenz 600 mg + Quizartinib 60 mg group due to insufficient data. Data from participants where AUCinf based on extrapolation was greater than 20% was also excluded from the Efavirenz 600 mg + Quizartinib 60 mg group and Quizartinib 60 mg group.

Arm/Group Title	Efavirenz 600 mg + Quizartinib 60 mg	Quizartinib 60 mg
Arm/Group Description	Participants who received efavirenz 600 mg once daily (QD) for 34 days and a single, oral dose of quizartinib 60 mg on Day 15 concurrently with efavirenz.	Participants who received a single, oral dose of quizartinib 60 mg on Day 1.
Measure Participants	15	16
Quizartinib	2760 (1170)	26000 (9880)
AC886	208 (183)	4540 (1410)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Efavirenz 600 mg + Quizartinib 60 mg, Quizartinib 60 mg
	Comments	Statistical comparison was analyzed for Quizartinib.
	Type of Statistical Test	Other
	Comments	Least squares (LS) means were calculated from an analysis of variance (ANOVA) model on log-transformed scale. The LS means for each treatment were back transformed from the log scale to provide estimates of the geometric means (GMS). The ratio (%) of GMS was calculated and 90% Confidence Intervals (CIs) for the ratio (%) of GMS were presented.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (%) of Geometric LS Mean
	Estimated Value	10.29
	Confidence Interval	(2-Sided) 90%; 7.73 to 13.70
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the comparison, the Efavirenz + Quizartinib treatment group represents the numerator and Quizartinib only treatment group represents the denominator.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Efavirenz 600 mg + Quizartinib 60 mg, Quizartinib 60 mg
	Comments	Statistical comparison was analyzed for AC886.
	Type of Statistical Test	Other
	Comments	Least squares (LS) means were calculated from an analysis of variance (ANOVA) model on log-transformed scale. The LS means for each treatment were back transformed from the log scale to provide estimates of the geometric means (GMS). The ratio (%) of GMS was calculated and 90% Confidence Intervals (CIs) for the ratio (%) of GMS were presented.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (%) of Geometric LS Mean
	Estimated Value	3.88
	Confidence Interval	(2-Sided) 90%; 2.62 to 5.76
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the comparison, the Efavirenz + Quizartinib treatment group represents the numerator and Quizartinib only treatment group represents the denominator.

5. Primary Outcome

Title	Terminal Half-Life (t1/2) Following Single Dose of Quizartinib With or Without Efavirenz
Description	Terminal Elimination Half-Life (t1/2) is defined as terminal elimination half-life and was calculated using non-compartmental analysis. AUClast was assessed for Quizartinib and active metabolite AC886. Half-life (t1/2) was assessed for Quizartinib and active metabolite AC886.
Time Frame	Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set except for 1 participant from the Efavirenz 600 mg + Quizartinib 60 mg group due to insufficient data.

Arm/Group Title	Efavirenz 600 mg + Quizartinib 60 mg	Quizartinib 60 mg
Arm/Group Description	Participants who received efavirenz 600 mg once daily (QD) for 34 days and a single, oral dose of quizartinib 60 mg on Day 15 concurrently with efavirenz.	Participants who received a single, oral dose of quizartinib 60 mg on Day 1.
Measure Participants	15	16
Quizartinib	23.8 (7.4)	136 (40.1)
AC886	11.9 (5.5)	135 (33.5)

6. Primary Outcome

Title	Metabolite to Parent Ratio (MPR) Based on Area Under the Curve for Active Metabolite AC886 Following Single Dose of Quizartinib With or Without Efavirenz
Description	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.
Time Frame	Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set except for 1 participant from the Efavirenz 600 mg + Quizartinib 60 mg group due to insufficient data. Data from participants where AUCinf based on extrapolation was greater than 20% was also excluded from MPR AUCinf.

Arm/Group Title	Efavirenz 600 mg + Quizartinib 60 mg	Quizartinib 60 mg
Arm/Group Description	Participants who received efavirenz 600 mg once daily (QD) for 34 days and a single, oral dose of quizartinib 60 mg on Day 15 concurrently with efavirenz.	Participants who received a single, oral dose of quizartinib 60 mg on Day 1.
Measure Participants	15	16
MPR AUClast	0.0675 (0.0403)	0.186 (0.0753)
MPR AUCinf	0.0762 (0.0395)	0.1880 (0.0777)

7. Primary Outcome

Title	Total Apparent Clearance (CL/F) for Quizartinib Following Single Dose of Quizartinib With or Without Efavirenz
Description	Total Apparent Clearance (CL/F) is defined as total apparent clearance and was calculated using non-compartmental analysis.
Time Frame	Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set except for 1 participant from the Efavirenz 600 mg + Quizartinib 60 mg group due to insufficient data.

Arm/Group Title	Efavirenz 600 mg + Quizartinib 60 mg	Quizartinib 60 mg
Arm/Group Description	Participants who received efavirenz 600 mg once daily (QD) for 34 days and a single, oral dose of quizartinib 60 mg on Day 15 concurrently with efavirenz.	Participants who received a single, oral dose of quizartinib 60 mg on Day 1.
Measure Participants	15	16
Mean (Standard Deviation) [L/h]	12.210 (7.6937)	1.1849 (0.51388)

8. Primary Outcome

Title	Volume of Distribution in the Terminal Phase (Vz/F) for Quizartinib Following Single Dose of Quizartinib With or Without Efavirenz
Description	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.
Time Frame	Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set except for 1 participant from the Efavirenz 600 mg + Quizartinib 60 mg group due to insufficient data.

Arm/Group Title	Efavirenz 600 mg + Quizartinib 60 mg	Quizartinib 60 mg
Arm/Group Description	Participants who received efavirenz 600 mg once daily (QD) for 34 days and a single, oral dose of quizartinib 60 mg on Day 15 concurrently with efavirenz.	Participants who received a single, oral dose of quizartinib 60 mg on Day 1.
Measure Participants	15	16
Mean (Standard Deviation) [L]	359.9 (102.23)	214.9 (59.82)

9. Secondary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events Following Single Dose of Quizartinib With or Without Efavirenz
Description	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.
Time Frame	Baseline up to 30 days post last dose, up to approximately 2 months

Outcome Measure Data

Analysis Population Description

TEAEs were assessed using the Safety Analysis Set.

Arm/Group Title	Efavirenz 600 mg + Quizartinib 60 mg	Quizartinib 60 mg
Arm/Group Description	Participants who received efavirenz 600 mg once daily (QD) for 34 days and a single, oral dose of quizartinib 60 mg on Day 15 concurrently with efavirenz.	Participants who received a single, oral dose of quizartinib 60 mg on Day 1.
Measure Participants	16	16
Count of Participants [Participants]	13 81.3%	5 31.3%

Adverse Events

Time Frame	Adverse events were collected from the date of signing the informed consent form up to 30 days after last dose, up to 2 months.
Adverse Event Reporting Description	Adverse events were defined as any untoward, unfavorable, unintended medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. All-cause mortality includes all deaths that occurred during the study and within the 30 days after the last dose of the study drug.
Arm/Group Title	Efavirenz 600 mg + Quizartinib 60 mg		Quizartinib 60 mg
Arm/Group Description	Participants who received efavirenz 600 mg once daily (QD) for 34 days and a single, oral dose of quizartinib 60 mg on Day 15 concurrently with efavirenz.		Participants who received a single, oral dose of quizartinib 60 mg on Day 1.
All Cause Mortality
	Efavirenz 600 mg + Quizartinib 60 mg		Quizartinib 60 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/16 (0%)
Serious Adverse Events
	Efavirenz 600 mg + Quizartinib 60 mg		Quizartinib 60 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/16 (0%)
Other (Not Including Serious) Adverse Events
	Efavirenz 600 mg + Quizartinib 60 mg		Quizartinib 60 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/16 (81.3%)		5/16 (31.3%)
Blood and lymphatic system disorders
Neutropenia	1/16 (6.3%)		0/16 (0%)
Cardiac disorders
Palpitations	1/16 (6.3%)		0/16 (0%)
Eye disorders
Blepharospasm	1/16 (6.3%)		0/16 (0%)
Conjunctivitis allergic	1/16 (6.3%)		0/16 (0%)
Eye pruritus	1/16 (6.3%)		0/16 (0%)
Eyelid irritation	1/16 (6.3%)		0/16 (0%)
Gastrointestinal disorders
Nausea	3/16 (18.8%)		1/16 (6.3%)
Flatulence	3/16 (18.8%)		0/16 (0%)
Constipation	0/16 (0%)		1/16 (6.3%)
Diarrhoea	0/16 (0%)		1/16 (6.3%)
Dyspepsia	0/16 (0%)		1/16 (6.3%)
Gastrooesophageal reflux disease	1/16 (6.3%)		0/16 (0%)
General disorders
Chest discomfort	1/16 (6.3%)		0/16 (0%)
Fatigue	1/16 (6.3%)		0/16 (0%)
Vessel puncture site pain	1/16 (6.3%)		0/16 (0%)
Infections and infestations
Cellulitis	1/16 (6.3%)		0/16 (0%)
Syphilis	0/16 (0%)		1/16 (6.3%)
Injury, poisoning and procedural complications
Arthropod bite	2/16 (12.5%)		0/16 (0%)
Musculoskeletal and connective tissue disorders
Back pain	1/16 (6.3%)		0/16 (0%)
Musculoskeletal chest pain	1/16 (6.3%)		0/16 (0%)
Rhabdomyolysis	1/16 (6.3%)		0/16 (0%)
Nervous system disorders
Headache	6/16 (37.5%)		2/16 (12.5%)
Dizziness	5/16 (31.3%)		0/16 (0%)
Paraesthesia	1/16 (6.3%)		1/16 (6.3%)
Disturbance in attention	1/16 (6.3%)		0/16 (0%)
Dizziness postural	1/16 (6.3%)		0/16 (0%)
Psychiatric disorders
Abnormal dreams	2/16 (12.5%)		0/16 (0%)
Insomnia	1/16 (6.3%)		0/16 (0%)
Nightmare	1/16 (6.3%)		0/16 (0%)
Restlessness	1/16 (6.3%)		0/16 (0%)
Respiratory, thoracic and mediastinal disorders
Throat tightness	0/16 (0%)		1/16 (6.3%)
Skin and subcutaneous tissue disorders
Skin irritation	1/16 (6.3%)		1/16 (6.3%)
Pruritus	0/16 (0%)		1/16 (6.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.