Healthy
Conditions
Keywords
Healthy Volunteers
Brief summary
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.
Interventions
DRUGtenofovir, emtricitabine and efavirenz fixed dose tablet
Atripla contains 300mg of tenofovir, 200mg of emtricitabine and 600mg of efavirenz
DRUGtenofovir, emtricitabine and efavirenz tablet added to solution
Atripla contains 300mg of tenofovir, 200mg of emtricitabine and 600mg of efavirenz
Sponsors
Bristol-Myers Squibb
University of Alabama at Birmingham
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
19 Years to 65 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration Time Curve for Tenofovir, Emtricitabine and Efavirenz | 17 days | The area under the concentration time curve for tenofovir, emtricitabine and efavirenz |
| Maximum Concentration for Tenofovir, Emtricitabine and Efavirenz | 17 days | The maximum concentration for tenofovir, emtricitabine and efavirenz |
Countries
United States
Participant flow
Recruitment details
Healthy volunteers recruited in Birmingham, AL from March 2009 and August 2009
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Includes groups randomized to receive tablet first and liquid first | 16 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants |
| Age Continuous | 33.3 years STANDARD_DEVIATION 10.9 |
| Region of Enrollment United States | 16 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 16 |
| serious Total, serious adverse events | 0 / 16 |
Outcome results
Primary
Area Under the Concentration Time Curve for Tenofovir, Emtricitabine and Efavirenz
The area under the concentration time curve for tenofovir, emtricitabine and efavirenz
Time frame: 17 days
Population: US Food and Drug Administration. Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug ProductsdGeneral Considerations. Rockville, MD: United States Food and Drug Administration Center for Drug Evaluation and Research.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Atripla Tablet | Area Under the Concentration Time Curve for Tenofovir, Emtricitabine and Efavirenz | Tenofovir AUC | 1.8 mg*hr/mL | Geometric Coefficient of Variation 29.2 |
| Atripla Tablet | Area Under the Concentration Time Curve for Tenofovir, Emtricitabine and Efavirenz | Efavirenz AUC | 58.7 mg*hr/mL | Geometric Coefficient of Variation 57.5 |
| Atripla Tablet | Area Under the Concentration Time Curve for Tenofovir, Emtricitabine and Efavirenz | Emtricitabine AUC | 10.9 mg*hr/mL | Geometric Coefficient of Variation 24.7 |
| Atripla Liquid | Area Under the Concentration Time Curve for Tenofovir, Emtricitabine and Efavirenz | Efavirenz AUC | 56.7 mg*hr/mL | Geometric Coefficient of Variation 80 |
| Atripla Liquid | Area Under the Concentration Time Curve for Tenofovir, Emtricitabine and Efavirenz | Emtricitabine AUC | 10.8 mg*hr/mL | Geometric Coefficient of Variation 15.9 |
| Atripla Liquid | Area Under the Concentration Time Curve for Tenofovir, Emtricitabine and Efavirenz | Tenofovir AUC | 2.2 mg*hr/mL | Geometric Coefficient of Variation 36.3 |
p-value: <0.05log transformation
Primary
Maximum Concentration for Tenofovir, Emtricitabine and Efavirenz
The maximum concentration for tenofovir, emtricitabine and efavirenz
Time frame: 17 days
Population: US Food and Drug Administration. Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug ProductsdGeneral Considerations. Rockville, MD: United States Food and Drug Administration Center for Drug Evaluation and Research.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Atripla Tablet | Maximum Concentration for Tenofovir, Emtricitabine and Efavirenz | Efavirenz Cmax | 1.5 mg/L | Geometric Coefficient of Variation 39 |
| Atripla Tablet | Maximum Concentration for Tenofovir, Emtricitabine and Efavirenz | Emtricitabine Cmax | 1.8 mg/L | Geometric Coefficient of Variation 32.3 |
| Atripla Tablet | Maximum Concentration for Tenofovir, Emtricitabine and Efavirenz | Tenofovir Cmax | 0.3 mg/L | Geometric Coefficient of Variation 27.7 |
| Atripla Liquid | Maximum Concentration for Tenofovir, Emtricitabine and Efavirenz | Efavirenz Cmax | 1.3 mg/L | Geometric Coefficient of Variation 28.8 |
| Atripla Liquid | Maximum Concentration for Tenofovir, Emtricitabine and Efavirenz | Emtricitabine Cmax | 2.1 mg/L | Geometric Coefficient of Variation 21 |
| Atripla Liquid | Maximum Concentration for Tenofovir, Emtricitabine and Efavirenz | Tenofovir Cmax | 0.2 mg/L | Geometric Coefficient of Variation 47.8 |