A Study of the Effect of Quizartinib on the Pharmacokinetics of the P-gp Substrate Dabigatran Etexilate in Healthy Participants

• Sponsor: Daiichi Sankyo Co., Ltd. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT04459585
• Collaborator: (none)
• Enrollment: 20
• Location: 1
• Arm: 1
• Actual Duration (Months): 1.7
• Patients Per Site Per Month: 11.5

Study Details

Study Description

Brief Summary

The purpose of this study is to investigate the one-way drug-drug interaction potential of quizartinib on dabigatran etexilate in healthy adult participants.

Condition or Disease	Intervention/Treatment	Phase
Healthy Subjects; Drug-drug Interaction; Pharmacokinetics; Quizartinib	Drug: Dabigatran Etexilate Mesylate; Drug: Quizartinib	Early Phase 1

Detailed Description

This study will evaluate the potential intestinal inhibitory effect of quizartinib on the pharmacokinetics of a Pgp substrate dabigatran etexilate in healthy participants.

The hypothesis for this clinical study is that quizartinib, as a P-gp inhibitor, may increase the systemic exposure (measured by area under the concentration-time curve [AUC] and maximum concentration [Cmax]) of P-gp substrates that may be sensitive to intestinal P-gp inhibition.

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1, Open-Label, Fixed Sequence Drug Interaction Study to Evaluate the Potential Intestinal Inhibitory Effect of Quizartinib on the Pharmacokinetics of a Pgp Substrate Dabigatran Etexilate in Healthy Subjects
• Actual Study Start Date: Aug 28, 2020
• Actual Primary Completion Date: Oct 20, 2020
• Actual Study Completion Date: Oct 20, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dabigatran + Quizartinib Participants who will receive a single oral dose of 150mg dabigatran etexilate on Day 1 of Period 1 and then will receive a single oral dose of 60mg quizartinib 2 hours prior to the administration of a single oral dose of 150mg dabigatran etexilate on the morning of Day 5 of Period 2.	Drug: Dabigatran Etexilate Mesylate; Single oral 150 mg capsule dose; Other Names: Pradaxa ; Drug: Quizartinib; Single oral 60 mg dose of quizartinib administered as two 30 mg tablets (26.5 mg free base per tablet)

Outcome Measures

Primary Outcome Measures

1. Maximum Plasma Concentration (Cmax) of Total Dabigatran and of Free Dabigatran Following a Single Dose in Participants Without and With Concomitant Quizartinib [Period 1 Day 1 (Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60 and 72 hours post-dose) and Period 2 Day 5 (pre-dose and 1, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 14, 26, 38, 50, 62, and 74 hours post-dose)]

   Maximum Plasma Concentration (Cmax) is defined as the maximum observed plasma concentration and was calculated using non-compartmental analysis.

2. Area Under the Plasma Concentration-Time Curve up to the Last Quantifiable Concentration Post-Dose (AUClast) of Total Dabigatran and of Free Dabigatran Following a Single Dose in Participants Without and With Concomitant Quizartinib [Period 1 Day 1 (Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60 and 72 hours post-dose) and Period 2 Day 5 (pre-dose and 1, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 14, 26, 38, 50, 62, and 74 hours post-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.

3. Area Under the Plasma Concentration-Time Curve up to Infinity (AUCinf) of Total Dabigatran and of Free Dabigatran Following a Single Dose in Participants Without and With Concomitant Quizartinib [Period 1 Day 1 (Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60 and 72 hours post-dose) and Period 2 Day 5 (pre-dose and 1, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 14, 26, 38, 50, 62, and 74 hours post-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.

Secondary Outcome Measures

1. Time of Maximum Plasma Concentration (Tmax) of Total Dabigatran and of Free Dabigatran Following a Single Dose in Participants Without and With Concomitant Quizartinib [Period 1 Day 1 (Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60 and 72 hours post-dose) and Period 2 Day 5 (pre-dose and 1, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 14, 26, 38, 50, 62, and 74 hours post-dose)]

   Time of Maximum Plasma Concentration (Tmax) is defined as time of maximum observed plasma concentration and was calculated using non-compartmental analysis.

2. Terminal Elimination Half-Life (T1/2) of Total Dabigatran and of Free Dabigatran Following a Single Dose in Participants Without and With Concomitant Quizartinib [Period 1 Day 1 (Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60 and 72 hours post-dose) and Period 2 Day 5 (pre-dose and 1, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 14, 26, 38, 50, 62, and 74 hours post-dose)]

   Terminal Elimination Half-Life (T1/2) is defined as terminal elimination half-life and was calculated using non-compartmental analysis.

3. Maximum Plasma Concentration (Cmax) of Quizartinib and the Metabolite ACC886 Following Single Dose of Dabigatran With Quizartinib in Participants [Period 2 Day 5 (Pre-dose and 1, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 14, 26, 38, 50, 62, and 74 hours post-dose)]

   Maximum Plasma Concentration (Cmax) is defined as the maximum observed plasma concentration and was calculated using non-compartmental analysis. Cmax was assessed for Quizartinib and Metabolite AC886.

4. Time of Maximum Plasma Concentration (Tmax) of Quizartinib and the Metabolite ACC886 Following Single Dose of Dabigatran With Quizartinib in Participants [Period 2 Day 5 (Pre-dose and 1, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 14, 26, 38, 50, 62, and 74 hours post-dose)]

   Time of Maximum Plasma Concentration (Tmax) is defined as time of maximum observed plasma concentration and was calculated using non-compartmental analysis. Tmax was assessed for Quizartinib and Metabolite AC886.

5. Area Under the Plasma Concentration-Time Curve From Time 0 to 74 Hours (AUClast,74) of Quizartinib and the Metabolite ACC886 Following Single Dose of Dabigatran With Quizartinib in Participants [Period 2 Day 5 (Pre-dose and 1, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 14, 26, 38, 50, 62, and 74 hours post-dose)]

   Area Under the Plasma Concentration-Time Curve From Time 0 to 74 Hours (AUClast,74) is defined as area under the plasma concentration-time curve to the last quantifiable concentration post dose at 74 hours and was calculated using non-compartmental analysis. AUClast,74 was assessed for Quizartinib and Metabolite AC886.

6. Number of Participants Reporting Treatment-Emergent Adverse Events (TEAE) Relatedness to Study Medication Following Single Dose of Dabigatran Without and With Quizartinib in Participants [Up to 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 million international (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)

• 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 hours prior to check-in and during confinement

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

• 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: NCT04459585
• Other Study ID Numbers: AC220-A-U104
• First Posted: Jul 7, 2020
• Last Update Posted: Jul 9, 2021
• Last Verified: Jun 1, 2021

• 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; P-gp; Dabigatran Etexilate
• Additional relevant MeSH terms: Dabigatran

Study Results

Participant Flow

Recruitment Details	A total of 20 participants who met all inclusion criteria and no exclusion criteria were enrolled from 28 Aug 2020 to 20 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 received only dabigatran etexilate (Reference Treatment) on Day 1 of Period 1 followed by quizartinib and dabigatran etexilate administration (Test Treatment) on Day 5 of Period 2.

Arm/Group Title	Dabigatran Etexilate/Dabigatran Etexilate + Quizartinib
Arm/Group Description	Participants who received a single oral dose of 150mg dabigatran etexilate on Day 1 of Period 1 and then received a single oral dose of 60mg quizartinib 2 hours prior to the administration of a single oral dose of 150mg dabigatran etexilate on the morning of Day 5 of Period 2.
Period Title: Period 1 (Day 1 to Day 5)
STARTED	20
COMPLETED	20
NOT COMPLETED	0
Period Title: Period 1 (Day 1 to Day 5)
STARTED	20
COMPLETED	20
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Dabigatran Etexilate/Dabigatran Etexilate + Quizartinib
Arm/Group Description	Participants who received a single oral dose of 150mg dabigatran etexilate on Day 1 of Period 1 and then received a single oral dose of 60mg quizartinib 2 hours prior to the administration of a single oral dose of 150mg dabigatran etexilate on the morning of Day 5 of Period 2.
Overall Participants	20
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	20 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	39.0 (10.37)
Sex: Female, Male (Count of Participants)
Female	9 45%
Male	11 55%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	12 60%
White	8 40%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Maximum Plasma Concentration (Cmax) of Total Dabigatran and of Free Dabigatran Following a Single Dose in Participants Without and With Concomitant Quizartinib
Description	Maximum Plasma Concentration (Cmax) is defined as the maximum observed plasma concentration and was calculated using non-compartmental analysis.
Time Frame	Period 1 Day 1 (Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60 and 72 hours post-dose) and Period 2 Day 5 (pre-dose and 1, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 14, 26, 38, 50, 62, and 74 hours post-dose)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set.

Arm/Group Title	Period 1: Dabigatran Etexilate	Period 2: Dabigatran Etexilate + Quizartinib
Arm/Group Description	Participants who received a single oral dose of 150mg dabigatran etexilate on Day 1 of Period 1.	Participants who received a single oral dose of 60mg quizartinib 2 hours prior to the administration of a single oral dose of 150mg dabigatran etexilate on Day 5 of Period 2.
Measure Participants	20	20
Total Dabigatran	192 (94.5)	239 (141)
Free Dabigatran	159 (82.2)	201 (127)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Period 1: Dabigatran Etexilate, Period 2: Dabigatran Etexilate + Quizartinib
	Comments	Statistical comparison was analyzed for Total Dabigatran.
	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	111.88
	Confidence Interval	(2-Sided) 90%; 77.57 to 161.35
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the comparison, the Dabigatran Etexilate + Quizartinib (Period 2) represents the numerator and Dabigatran Etexilate (Period 1) represents the denominator.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Period 1: Dabigatran Etexilate, Period 2: Dabigatran Etexilate + Quizartinib
	Comments	Statistical comparison was analyzed for Free Dabigatran.
	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% 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	112.98
	Confidence Interval	(2-Sided) 90%; 77.20 to 165.34
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the comparison, the Dabigatran Etexilate + Quizartinib (Period 2) represents the numerator and Dabigatran Etexilate (Period 1) represents the denominator.

2. Primary Outcome

Title	Area Under the Plasma Concentration-Time Curve up to the Last Quantifiable Concentration Post-Dose (AUClast) of Total Dabigatran and of Free Dabigatran Following a Single Dose in Participants Without and With Concomitant Quizartinib
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.
Time Frame	Period 1 Day 1 (Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60 and 72 hours post-dose) and Period 2 Day 5 (pre-dose and 1, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 14, 26, 38, 50, 62, and 74 hours post-dose)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set.

Arm/Group Title	Period 1: Dabigatran Etexilate	Period 2: Dabigatran Etexilate + Quizartinib
Arm/Group Description	Participants who received a single oral dose of 150mg dabigatran etexilate on Day 1 of Period 1.	Participants who received a single oral dose of 60mg quizartinib 2 hours prior to the administration of a single oral dose of 150mg dabigatran etexilate on Day 5 of Period 2.
Measure Participants	20	20
Total Dabigatran	1720 (870)	2100 (1280)
Free Dabigatran	1390 (736)	1710 (1100)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Period 1: Dabigatran Etexilate, Period 2: Dabigatran Etexilate + Quizartinib
	Comments	Statistical comparison was analyzed for Total Dabigatran.
	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% 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	111.37
	Confidence Interval	(2-Sided) 90%; 78.51 to 157.97
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the comparison, the Dabigatran Etexilate + Quizartinib (Period 2) represents the numerator and Dabigatran Etexilate (Period 1) represents the denominator.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Period 1: Dabigatran Etexilate, Period 2: Dabigatran Etexilate + Quizartinib
	Comments	Statistical comparison was analyzed for Free Dabigatran.
	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% 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	111.08
	Confidence Interval	(2-Sided) 90%; 77.35 to 159.51
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the comparison, the Dabigatran Etexilate + Quizartinib (Period 2) represents the numerator and Dabigatran Etexilate (Period 1) represents the denominator.

3. Primary Outcome

Title	Area Under the Plasma Concentration-Time Curve up to Infinity (AUCinf) of Total Dabigatran and of Free Dabigatran Following a Single Dose in Participants Without and With Concomitant Quizartinib
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.
Time Frame	Period 1 Day 1 (Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60 and 72 hours post-dose) and Period 2 Day 5 (pre-dose and 1, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 14, 26, 38, 50, 62, and 74 hours post-dose)

Outcome Measure Data

Analysis Population Description

The pharmacokinetic parameter of Area Under the Plasma Concentration-Time Curve up to Infinity was assessed using the Pharmacokinetic Analysis Set except for 1 participant that did not meet the protocol inclusion criteria for this analysis.

Arm/Group Title	Period 1: Dabigatran Etexilate	Period 2: Dabigatran Etexilate + Quizartinib
Arm/Group Description	Participants who received a single oral dose of 150mg dabigatran etexilate on Day 1 of Period 1.	Participants who received a single oral dose of 60mg quizartinib 2 hours prior to the administration of a single oral dose of 150mg dabigatran etexilate on Day 5 of Period 2.
Measure Participants	20	20
Total Dabigatran	1740 (902)	2140 (1280)
Free Dabigatran	1420 (760)	1730 (1100)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Period 1: Dabigatran Etexilate, Period 2: Dabigatran Etexilate + Quizartinib
	Comments	Statistical comparison was analyzed for Total Dabigatran.
	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% 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	112.97
	Confidence Interval	(2-Sided) 90%; 79.38 to 160.79
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the comparison, the Dabigatran Etexilate + Quizartinib (Period 2) represents the numerator and Dabigatran Etexilate (Period 1) represents the denominator.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Period 1: Dabigatran Etexilate, Period 2: Dabigatran Etexilate + Quizartinib
	Comments	Statistical comparison was analyzed for Free Dabigatran.
	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% 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	110.72
	Confidence Interval	(2-Sided) 90%; 76.77 to 159.68
	Parameter Dispersion	Type: Value:
	Estimation Comments	For the comparison, the Dabigatran Etexilate + Quizartinib (Period 2) represents the numerator and Dabigatran Etexilate (Period 1) represents the denominator.

4. Secondary Outcome

Title	Time of Maximum Plasma Concentration (Tmax) of Total Dabigatran and of Free Dabigatran Following a Single Dose in Participants Without and With Concomitant Quizartinib
Description	Time of Maximum Plasma Concentration (Tmax) is defined as time of maximum observed plasma concentration and was calculated using non-compartmental analysis.
Time Frame	Period 1 Day 1 (Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60 and 72 hours post-dose) and Period 2 Day 5 (pre-dose and 1, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 14, 26, 38, 50, 62, and 74 hours post-dose)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set.

Arm/Group Title	Period 1: Dabigatran Etexilate	Period 2: Dabigatran Etexilate + Quizartinib
Arm/Group Description	Participants who received a single oral dose of 150mg dabigatran etexilate on Day 1 of Period 1.	Participants who received a single oral dose of 60mg quizartinib 2 hours prior to the administration of a single oral dose of 150mg dabigatran etexilate on Day 5 of Period 2.
Measure Participants	20	20
Total Dabigatran	2.0	2.0
Free Dabigatran	2.0	2.0

5. Secondary Outcome

Title	Terminal Elimination Half-Life (T1/2) of Total Dabigatran and of Free Dabigatran Following a Single Dose in Participants Without and With Concomitant Quizartinib
Description	Terminal Elimination Half-Life (T1/2) is defined as terminal elimination half-life and was calculated using non-compartmental analysis.
Time Frame	Period 1 Day 1 (Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60 and 72 hours post-dose) and Period 2 Day 5 (pre-dose and 1, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 14, 26, 38, 50, 62, and 74 hours post-dose)

Outcome Measure Data

Analysis Population Description

The pharmacokinetic parameter of Terminal Elimination Half-Life was assessed using the Pharmacokinetic Analysis Set except for 1 participant that did not meet the protocol inclusion criteria for this analysis.

Arm/Group Title	Period 1: Dabigatran Etexilate	Period 2: Dabigatran Etexilate + Quizartinib
Arm/Group Description	Participants who received a single oral dose of 150mg dabigatran etexilate on Day 1 of Period 1.	Participants who received a single oral dose of 60mg quizartinib 2 hours prior to the administration of a single oral dose of 150mg dabigatran etexilate on Day 5 of Period 2.
Measure Participants	20	20
Total Dabigatran	15.4 (4.4)	18.1 (17.0)
Free Dabigatran	14.2 (4.2)	14.1 (6.6)

6. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) of Quizartinib and the Metabolite ACC886 Following Single Dose of Dabigatran With Quizartinib in Participants
Description	Maximum Plasma Concentration (Cmax) is defined as the maximum observed plasma concentration and was calculated using non-compartmental analysis. Cmax was assessed for Quizartinib and Metabolite AC886.
Time Frame	Period 2 Day 5 (Pre-dose and 1, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 14, 26, 38, 50, 62, and 74 hours post-dose)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set.

Arm/Group Title	Period 2: Dabigatran Etexilate + Quizartinib
Arm/Group Description	Participants who received a single oral dose of 60mg quizartinib 2 hours prior to the administration of a single oral dose of 150mg dabigatran etexilate on Day 5 of Period 2.
Measure Participants	20
Quizartinib	250 (50.8)
AC886	25.7 (8.71)

7. Secondary Outcome

Title	Time of Maximum Plasma Concentration (Tmax) of Quizartinib and the Metabolite ACC886 Following Single Dose of Dabigatran With Quizartinib in Participants
Description	Time of Maximum Plasma Concentration (Tmax) is defined as time of maximum observed plasma concentration and was calculated using non-compartmental analysis. Tmax was assessed for Quizartinib and Metabolite AC886.
Time Frame	Period 2 Day 5 (Pre-dose and 1, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 14, 26, 38, 50, 62, and 74 hours post-dose)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set.

Arm/Group Title	Period 2: Dabigatran Etexilate + Quizartinib
Arm/Group Description	Participants who received a single oral dose of 60mg quizartinib 2 hours prior to the administration of a single oral dose of 150mg dabigatran etexilate on Day 5 of Period 2.
Measure Participants	20
Quizartinib	3.0
AC886	8.0

8. Secondary Outcome

Title	Area Under the Plasma Concentration-Time Curve From Time 0 to 74 Hours (AUClast,74) of Quizartinib and the Metabolite ACC886 Following Single Dose of Dabigatran With Quizartinib in Participants
Description	Area Under the Plasma Concentration-Time Curve From Time 0 to 74 Hours (AUClast,74) is defined as area under the plasma concentration-time curve to the last quantifiable concentration post dose at 74 hours and was calculated using non-compartmental analysis. AUClast,74 was assessed for Quizartinib and Metabolite AC886.
Time Frame	Period 2 Day 5 (Pre-dose and 1, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 14, 26, 38, 50, 62, and 74 hours post-dose)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set.

Arm/Group Title	Period 2: Dabigatran Etexilate + Quizartinib
Arm/Group Description	Participants who received a single oral dose of 60mg quizartinib 2 hours prior to the administration of a single oral dose of 150mg dabigatran etexilate on Day 5 of Period 2.
Measure Participants	20
Quizartinib	9390 (1660)
AC886	1350 (495)

9. Secondary Outcome

Title	Number of Participants Reporting Treatment-Emergent Adverse Events (TEAE) Relatedness to Study Medication Following Single Dose of Dabigatran Without and With Quizartinib in Participants
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	Up to 2 months

Outcome Measure Data

Analysis Population Description

TEAEs were assessed using the Safety Analysis Set.

Arm/Group Title	Period 1: Dabigatran Etexilate	Period 2: Dabigatran Etexilate + Quizartinib
Arm/Group Description	Participants who received a single oral dose of 150mg dabigatran etexilate on Day 1 of Period 1.	Participants who received a single oral dose of 60mg quizartinib 2 hours prior to the administration of a single oral dose of 150mg dabigatran etexilate on Day 5 of Period 2.
Measure Participants	20	20
Related	0 0%	2 NaN
Unrelated	0 0%	1 NaN

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	Period 1: Dabigatran Etexilate		Period 2: Dabigatran Etexilate + Quizartinib
Arm/Group Description	Participants who received a single oral dose of 150mg dabigatran etexilate on Day 1 of Period 1.		Participants who received a single oral dose of 60mg quizartinib 2 hours prior to the administration of a single oral dose of 150mg dabigatran etexilate on Day 5 of Period 2.
All Cause Mortality
	Period 1: Dabigatran Etexilate		Period 2: Dabigatran Etexilate + Quizartinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)
Serious Adverse Events
	Period 1: Dabigatran Etexilate		Period 2: Dabigatran Etexilate + Quizartinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Period 1: Dabigatran Etexilate		Period 2: Dabigatran Etexilate + Quizartinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		3/20 (15%)
Nervous system disorders
Dizziness	0/20 (0%)		1/20 (5%)
Headache	0/20 (0%)		1/20 (5%)
Paraesthesia	0/20 (0%)		1/20 (5%)

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.