The Bioequivalence of Atripla in an Oral Liquid Formulation Compared With the Tablet Formulation in Healthy Volunteers

The Stability and Bioequivalence of Tenofovir, Emtricitabine and Efavirenz (Atripla) in an Extemporaneously Prepared Oral Liquid Formulation Compared With the Commercially Available Tablet Formulation

The primary objective of this study is to determine the average bioequivalence of tenofovir, emtricitabine and efavirenz in an extemporaneously prepared oral liquid formulation (test formulation) compared with the commercially available tablet formulation (reference formulation). The study is designed as an open-label, randomized, 2-period, 2-treatment, 2-sequence, single-dose intensive pharmacokinetic study conducted in healthy volunteers. Subjects will be randomized to receive the Atripla tablet (reference formulation) or the Atripla tablet crushed and mixed in OraSweet solution (test formulation) on Study Day 1. Subjects will undergo a 12-hour intensive pharmacokinetic evaluation after ingesting a single dose of either the test or reference formulation. On days 2 and 3, subjects will provide an additional pharmacokinetic sample 24 and 48 hours post dose, respectively. Subjects will complete a washout period from day 2 to day 14 during which no study drugs will be ingested. On day 14, subjects will ingest either the reference or test formulation (opposite of the formulation received on Study Day 1). All subjects will undergo another 12-hour intensive pharmacokinetic evaluation. On days 16 and 17 subjects will provide an additional pharmacokinetic sample 24 and 48 hours post dose, respectively. Adverse events and concomitant medications will be documented throughout the study.

The sample size is 16 and is based upon a 10% drop-out rate (i.e. due to lost to follow-up, treatment discontinuation, etc.). Since the investigators are expecting two subjects not to complete the study, the investigators expect 14 evaluable subjects. If the discontinuation rate is greater than 10%, the investigators will continue to enroll until the investigators get 14 evaluable subjects. The primary endpoint is to determine average bioequivalence for test and reference formulations of tenofovir, emtricitabine and efavirenz according to the FDA guidance on bioequivalence testing. The ratio of the test to reference formulation mean Cmax and AUC24 for each drug and the 90% confidence interval around each mean ratio will be determined. Average bioequivalence will be met if 90% confidence intervals around the Cmax, and AUC24 mean ratios for each drug falls within the FDA's predefined limits of 0.80 to 1.25.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: tenofovir, emtricitabine and efavirenz fixed dose tablet; Drug: tenofovir, emtricitabine and efavirenz tablet added to solution

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age ≥19 and ≤65, HIV-1 negative, Able to give consent, Non-smoking,Screening EKG within normal limits, Females of childbearing potential must have a negative pregnancy test at screening and agree to use a double-barrier method of contraception throughout the study period.

Exclusion Criteria:

• Subjects receiving any prescription or over-the-counter products will be excluded from the study. Subjects using any form of recreational drugs will be excluded. Subjects who have any of the following laboratory abnormalities within 30 days of study entry will be excluded:

  • SGOT (AST)/SGPT (ALT) > 3 x upper limits of normal (ULN) (Subjects with liver disease are allowed to enroll unless their AST/ALT levels are greater than three times ULN)
  • Bilirubin > 2.5 x ULN
  • Amylase > 2 x ULN
  • Absolute Neutrophil Count < 1000 x 103/L
  • Hgb < 9.0 g/dl
  • Platelets <50,000 cells/mm3
  • Serum Creatinine > 2.5 mg/dl

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Atripla Tablet; Drug exposure after administration of Atripla Tablet	Drug: tenofovir, emtricitabine and efavirenz fixed dose tablet; Atripla contains 300mg of tenofovir, 200mg of emtricitabine and 600mg of efavirenz
Experimental: Atripla Liquid; Drug exposure after administration of an extemporaneously prepared liquid formulation of Atripla	Drug: tenofovir, emtricitabine and efavirenz tablet added to solution; Atripla contains 300mg of tenofovir, 200mg of emtricitabine and 600mg of efavirenz

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Concentration Time Curve for Tenofovir, Emtricitabine and Efavirenz	The area under the concentration time curve for tenofovir, emtricitabine and efavirenz	17 days
Maximum Concentration for Tenofovir, Emtricitabine and Efavirenz	The maximum concentration for tenofovir, emtricitabine and efavirenz	17 days

Collaborators and Investigators

• Sponsor: University of Alabama at Birmingham
• Collaborators: Bristol-Myers Squibb
• Investigators: Principal Investigator: Jennifer R King, PharmD, University of Alabama at Birmingham

Publications and helpful links

General Publications

• King J, McCall M, Cannella A, Markiewicz MA, James A, Hood CB, Acosta EP. A randomized crossover study to determine relative bioequivalence of tenofovir, emtricitabine, and efavirenz (Atripla) fixed-dose combination tablet compared with a compounded oral liquid formulation derived from the tablet. J Acquir Immune Defic Syndr. 2011 Apr 15;56(5):e130-2. doi: 10.1097/qai.0b013e31820eefbe. No abstract available.

Study record dates

Study Major Dates

• Study Start: February 1, 2009
• Primary Completion (Actual): February 1, 2010
• Study Completion (Actual): May 1, 2010

Study Registration Dates

• First Submitted: March 13, 2009
• First Submitted That Met QC Criteria: March 16, 2009
• First Posted (Estimate): March 17, 2009

Study Record Updates

• Last Update Posted (Estimate): September 14, 2012
• Last Update Submitted That Met QC Criteria: August 16, 2012
• Last Verified: June 1, 2012

More Information

Terms related to this study

• Keywords: Healthy Volunteers
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Tenofovir; Emtricitabine; Efavirenz
• Other Study ID Numbers: F081030003