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

NCT02809768 | Completed Phase 1

• 1 other identifier: E5501-A001-019
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Healthy Participants

Keywords

Healthy participants; Pharmacokinetic Drug-Drug Interaction; Avatrombopag

Outcome Measures

Primary Outcomes (8)

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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 Outcomes (6)

• 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

• 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

• 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

• Maximum change from baseline in platelet count (ΔEmax = Emax - baseline platelet count at predose on Treatment Period 1 Day 1) (ΔEmax)

  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

• Maximum percent change from baseline in platelet count (%ΔEmax = ΔEmax / baseline platelet count at predose on Period 1 Day 1 x 100) (%ΔEmax)

  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

Study Arms (3)

Avatrombopag plus fluconazole

EXPERIMENTAL

Part A: Participants will be administered a single oral dose of avatrombopag (20-mg) on Day 1 of Treatment Period 1. In Treatment Period 2, fluconazole (400-mg) will be administered once daily on Days 1 to 16, and a single dose of avatrombopag (20-mg) on Day 7 in Treatment Period 2. Each dose of avatrombopag will be administered under fed conditions 30 minutes after the start of a meal.

Drug: Avatrombopag; Drug: Fluconazole

Avatrombopag plus itraconazole

EXPERIMENTAL

Part B: Participants will be administered a single oral dose of avatrombopag (20-mg) on Day 1 of Treatment Period 1. In Treatment Period 2, itraconazole (200-mg) will be administered twice daily on Day 1 and 200-mg once daily on Days 2 to 16. A single dose of avatrombopag (20-mg) will be administered on Day 7 of Treatment Period 2. Each dose of avatrombopag will be administered under fed conditions 30 minutes after the start of a meal.

Drug: Avatrombopag; Drug: Itraconazole

Avatrombopag plus rifampin

EXPERIMENTAL

Part C: Participants will be administered a single oral dose of avatrombopag (20-mg) on Day 1 of Treatment Period 1. In Treatment Period 2, rifampin (600-mg) will be administered once daily on Days 1 to 16. In order to avoid a food-effect on rifampin absorption, each dose will be administered 1 hour before participants consume a meal. On Day 7 of Treatment Period 2, rifampin (600-mg) and avatrombopag (20-mg) will be administered 1 hour before meal and 30 minutes after starting meal consumption.

Drug: Avatrombopag; Drug: Rifampin

Interventions

Avatrombopag DRUG

Also known as: E5501

Avatrombopag plus fluconazole; Avatrombopag plus itraconazole; Avatrombopag plus rifampin

Fluconazole DRUG

Avatrombopag plus fluconazole

Itraconazole DRUG

Avatrombopag plus itraconazole

Rifampin DRUG

Avatrombopag plus rifampin

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Platelet count between the lower limit of normal and 300 × 10\^9/L, inclusive, at Screening and each Baseline.
• Non-smoking, male or female, age ≥18 years and ≤55 years old.
• Body mass index (BMI) \>18 and ≤32 kg/m\^2 at Screening.
• Females must not be pregnant at Screening as documented by a negative serum beta human chorionic gonadotropin (β-hCG) test with a minimum sensitivity 25 IU/L or equivalent units of β-hCG or at Baseline as documented by a negative urine pregnancy test result.

You may not qualify if:

• Failure to discontinue use of agents associated with higher risk of thrombosis (including estrogen containing oral contraceptives) within at least 30 days before dosing.
• 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).
• Hemoglobin less than lower limit of normal at Screening and Baseline Period 1.
• Liver functions tests (alanine transaminase \[ALT\], aspartate transaminase \[AST\], or total bilirubin) greater than the upper limit of normal Screening and Baseline Period 1.
• 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.

Sponsors & Collaborators

• Eisai Inc.: lead

Study Sites (1)

Unknown Facility

San Antonio, Texas, United States

Location

MeSH Terms

Interventions

avatrombopag; Fluconazole; Itraconazole; Rifampin

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Piperazines; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds

Study Officials

• Eisai Medical Information

  Eisai Inc.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 20, 2016
• First Posted: June 22, 2016
• Study Start: April 1, 2016
• Primary Completion: August 1, 2016
• Study Completion: September 1, 2016
• Last Updated: March 9, 2017

Record last verified: 2017-03

Locations

US (1)