Study to Assess Pharmacokinetic Drug-Drug Interaction Between Avatrombopag When Co-Administered With Fluconazole, Itraconazole, or Rifampin in Healthy Subjects

Healthy Participants Clinical Trial

Official title:

A 3-Part, Open-Label Study to Assess Pharmacokinetic Drug-Drug Interaction Between Avatrombopag When Co-Administered With Fluconazole (Moderate Inhibitor of CYP2C9 and CYP3A), Itraconazole (Strong CYP3A Inhibitor), or Rifampin (Strong CYP3A and Moderate CYP2C9 Inducer) in Healthy Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02809768
• Other study ID #: E5501-A001-019
• Status: Completed
• Phase: Phase 1
• First received: June 20, 2016
• Last updated: March 7, 2017
• Start date: April 2016
• Est. completion date: September 2016

Study information

• Verified date: March 2017
• Source: Eisai Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine the effects of concomitant administration with fluconazole, itraconazole, and rifampin on the pharmacokinetics (PK) of a single 20-mg dose of avatrombopag in healthy participants.

Description:

This study will be a single center, open-label, drug-drug interaction study in healthy participants. The study will consist of 3 parts: In Part A, the effects of steady-state dosing of a moderate inhibitor of CYP2C9 and CYP3A (fluconazole) on the single-dose PK of avatrombopag will be assessed. In Part B, the effects of steady-state dosing of a strong CYP3A inhibitor (itraconazole) on the single-dose PK of avatrombopag will be assessed. In Part C, the effects of steady-state dosing of a strong CYP3A and moderate CYP2C9 inducer (rifampin) on the single-dose PK of avatrombopag will be assessed.

Each Part of the study will consist of 2 phases: Pretreatment and Treatment. The Pretreatment Phase will consist of 2 periods: Screening and Baseline Period 1.The Treatment Phase will consist of 2 treatment periods: Treatment Period 1 (administration of a single oral dose of avatrombopag 20 mg alone under fed conditions); and Treatment Period 2 (administration of oral doses of each inhibitor or inducer alone and concomitant administration of a single oral dose of avatrombopag 20 mg with each inhibitor or inducer [fluconazole in Part A, itraconazole in Part B, or rifampin in Part C] under fed conditions).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 48
• Est. completion date: September 2016
• Est. primary completion date: August 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

Inclusion Criteria:

1. Platelet count between the lower limit of normal and 300 × 10^9/L, inclusive, at Screening and each Baseline.

2. Non-smoking, male or female, age =18 years and =55 years old.

3. Body mass index (BMI) >18 and =32 kg/m^2 at Screening.

4. Females must not be pregnant at Screening as documented by a negative serum beta human chorionic gonadotropin (ß-hCG) test with a minimum sensitivity 25 IU/L or equivalent units of ß-hCG or at Baseline as documented by a negative urine pregnancy test result.

Exclusion Criteria:

1. Failure to discontinue use of agents associated with higher risk of thrombosis (including estrogen containing oral contraceptives) within at least 30 days before dosing.

2. Evidence of organ dysfunction or any clinically significant deviation from normal in their medical history (e.g., history of splenectomy); history of arterial or venous thrombosis, including partial or complete thromboses (e.g., stroke, transient ischemic attack, myocardial infarction, deep vein thrombosis, pulmonary embolism); known family history of hereditary thrombophilic disorders (e.g., Factor V Leiden, antithrombin III deficiency).

3. Hemoglobin less than lower limit of normal at Screening and Baseline Period 1.

4. Liver functions tests (alanine transaminase [ALT], aspartate transaminase [AST], or total bilirubin) greater than the upper limit of normal Screening and Baseline Period 1.

5. Any history of gastrointestinal surgery that may affect the pharmacokinetics (PK) profiles of avatrombopag (e.g., hepatectomy, nephrectomy, cholecystectomy or digestive organ resection) at Screening.

Related Conditions & MeSH terms

• Healthy Participants

Intervention

Drug:
• Avatrombopag

• Fluconazole

• Itraconazole

• Rifampin

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Eisai Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mean maximum observed concentration (Cmax)		Predose of Day 1 (Treatment Period 1), Predose of Day 7 (Treatment Period 2), and 1, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 144, and 216 hours postdose of avatromobag for Treatment period 1 and 2
Primary	Median time at which the highest drug concentration occurs (tmax)		Predose of Day 1 (Treatment Period 1), Predose of Day 7 (Treatment Period 2), and 1, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 144, and 216 hours postdose of avatromobag for Treatment period 1 and 2
Primary	Mean area under the concentration-time curve from zero time to time of last quantifiable concentration AUC(0-t)		Predose of Day 1 (Treatment Period 1), Predose of Day 7 (Treatment Period 2), and 1, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 144, and 216 hours postdose of avatromobag for Treatment period 1 and 2
Primary	Mean area under the concentration-time curve from zero time to 72 hours postdose AUC(0-72h)		Predose of Day 1 (Treatment Period 1), Predose of Day 7 (Treatment Period 2), and 1, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 144, and 216 hours postdose of avatromobag for Treatment period 1 and 2
Primary	Mean terminal elimination phase half-life (t1/2)		Predose of Day 1 (Treatment Period 1), Predose of Day 7 (Treatment Period 2), and 1, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 144, and 216 hours postdose of avatromobag for Treatment period 1 and 2
Primary	Mean apparent total clearance following oral administration (CL/F)		Predose of Day 1 (Treatment Period 1), Predose of Day 7 (Treatment Period 2), and 1, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 144, and 216 hours postdose of avatromobag for Treatment period 1 and 2
Primary	Mean apparent volume of distribution at terminal phase (Vz/F)		Predose of Day 1 (Treatment Period 1), Predose of Day 7 (Treatment Period 2), and 1, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 144, and 216 hours postdose of avatromobag for Treatment period 1 and 2
Primary	Mean area under the concentration-time curve from zero time extrapolated to infinite time AUC(0-inf)		Predose of Day 1 (Treatment Period 1), Predose of Day 7 (Treatment Period 2), and 1, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, 72, 96, 144, and 216 hours postdose of avatromobag for Treatment period 1 and 2
Secondary	Mean maximum platelet counts following avatrombopag dosing observed in each treatment period (Emax)		Predose of Day 1, Days 3, 4, 5, 7, 10, 12, 14, 21, and 28 of Treatment Period 1. Predose of Day 7, Days 9, 10, 11, 13, 16, 18, 20, 27, and 34 of Treatment Period 2
Secondary	Median observed time of maximum increase in platelet counts following avatrombopag dosing in each treatment period (TEmax)		Predose of Day 1, Days 3, 4, 5, 7, 10, 12, 14, 21, and 28 of Treatment Period 1. Predose of Day 7, Days 9, 10, 11, 13, 16, 18, 20, 27, and 34 of Treatment Period 2
Secondary	Mean area under the effect curve for platelet count following avatrombopag dosing through 28 days after dosing (AUEC(0-28d))		Predose of Day 1, Days 3, 4, 5, 7, 10, 12, 14, 21, and 28 of Treatment Period 1. Predose of Day 7, Days 9, 10, 11, 13, 16, 18, 20, 27, and 34 of Treatment Period 2
Secondary	Maximum change from baseline in platelet count (?Emax = Emax - baseline platelet count at predose on Treatment Period 1 Day 1) (?Emax)		Predose of Day 1, Days 3, 4, 5, 7, 10, 12, 14, 21, and 28 of Treatment Period 1. Predose of Day 7, Days 9, 10, 11, 13, 16, 18, 20, 27, and 34 of Treatment Period 2
Secondary	Maximum percent change from baseline in platelet count (%?Emax = ?Emax / baseline platelet count at predose on Period 1 Day 1 x 100) (%?Emax)		Predose of Day 1, Days 3, 4, 5, 7, 10, 12, 14, 21, and 28 of Treatment Period 1. Predose of Day 7, Days 9, 10, 11, 13, 16, 18, 20, 27, and 34 of Treatment Period 2
Secondary	Percentage of participants with treatment emergent adverse events and serious adverse events		Up to approximately 3 months