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

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

Detailed Description
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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.

Official Title
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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

Conditions
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Healthy Subjects, Drug-drug Interaction, Pharmacokinetics, Quizartinib

Intervention / Treatment
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* Drug: Dabigatran Etexilate Mesylate
* Drug: Quizartinib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dabigatran + Quizartinib<br>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<br>* Single oral 150 mg capsule dose<br>* Other names: Pradaxa;Drug: Quizartinib<br>* Single oral 60 mg dose of quizartinib administered as two 30 mg tablets (26.5 mg free base per tablet)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) of Total Dabigatran and of Free Dabigatran Following a Single Dose in Participants Without and With Concomitant Quizartinib | Maximum Plasma Concentration (Cmax) is defined as the maximum observed plasma concentration and was calculated using non-compartmental analysis. | 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) of Total Dabigatran and of Free Dabigatran Following a Single Dose in Participants Without and With Concomitant Quizartinib | 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. | 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) of Total Dabigatran and of Free Dabigatran Following a Single Dose in Participants Without and With Concomitant Quizartinib | 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. | 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) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time of Maximum Plasma Concentration (Tmax) of Total Dabigatran and of Free Dabigatran Following a Single Dose in Participants Without and With Concomitant Quizartinib | Time of Maximum Plasma Concentration (Tmax) is defined as time of maximum observed plasma concentration and was calculated using non-compartmental analysis. | 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) of Total Dabigatran and of Free Dabigatran Following a Single Dose in Participants Without and With Concomitant Quizartinib | Terminal Elimination Half-Life (T1/2) is defined as terminal elimination half-life and was calculated using non-compartmental analysis. | 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) of Quizartinib and the Metabolite ACC886 Following Single Dose of Dabigatran With Quizartinib in Participants | 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. | 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) of Quizartinib and the Metabolite ACC886 Following Single Dose of Dabigatran With Quizartinib in Participants | 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. | 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) of Quizartinib and the Metabolite ACC886 Following Single Dose of Dabigatran With Quizartinib in Participants | 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. | 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) | 
| Number of Participants Reporting Treatment-Emergent Adverse Events (TEAE) Relatedness to Study Medication Following Single Dose of Dabigatran Without and With Quizartinib in Participants | 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. | Up to 2 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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P-gp, Healthy subjects, Drug-drug Interaction, Pharmacokinetics, Quizartinib, Dabigatran Etexilate