Efavirenz Comparative Bioavailability

Study Overview
=================
Brief Summary
-----------------
The primary objective of this study is to determine the average bioequivalence of a generic efavirenz 600 mg tablet (test formulation)compared with Stocrin(R) 600 mg tablets (Reference formulation).The study is designed as an open label, randomized, crossover, 2-treatments, 2-period, 2-sequence, single dose pharmacokinetic study conducted in healthy volunteers. Subjects will be randomized to receive generic efavirenz 600 (Test formulation) or Stocrin(R) 600 tablets (Reference formulation)on study day 1 (period 1). Subjects will undergo a 24 hour intensive pharmacokinetic evaluation after ingesting a single dose of either the Test or Reference formulation. Subjects will provide additional pharmacokinetic samples 36, 48, 72, 120 and 192 hours postdose, respectively. Subjects will complete a wash out period from day 8 to day 28 during wich no study drug will be ingested. On day 29 subjects will ingest either the Test or the Reference formulation (opposite to the formulation received on period 1). All subjects undergo another 24 hour intensive pharmacokinetic evaluation and pharmacokinetics samples on days 36, 48, 72, 120, 192 pos dose, respectively. Adverse events and and concomitant medication will be documented throughout the study.

Detailed Description
-----------------
The primary objective of this study is to determine the average bioequivalence of generic efavirenz 600 mg tablet (test formulation)compared with Stocrin(R) 600 mg tablets (Reference formulation).The study is designed as an open label, randomized, crossover, 2-treatments, 2-period, 2-sequence, single dose pharmacokinetic study conducted in healthy volunteers. Subjects will be randomized to receive generic efavirenz 600 (Test formulation) or Stocrin(R) 600 tablets (Reference formulation)on study day 1 (period 1), then they will undergo a 24 hour intensive pharmacokinetic evaluation after ingesting a single dose of either the Test or Reference formulation. Additional pharmacokinetic samples 36, 48, 72, 120 and 192 hours postdose will be drawn. Subjects will complete a wash out period form day 8 to day 28 during which no study drug will be ingested. On day 29 (period 2) they will ingest either the Test or the Reference formulation (opposite to the formulation received on period 1). All subjects undergo another 24 hour intensive pharmacokinetic evaluation and pharmacokinetics samples on days 36, 48, 72, 120, 192 pos-dose, respectively, will be drawn. Adverse events and concomitant medication will be documented throughout the study. The sample size is 28 and is based on a 15% dropout rate (due to lost to follow-up, treatment discontinuation, etc.) Since the investigators are expecting four subjects not to complete the study,24 evaluable subjects are finally expected. If the discontinuation rate is greater than 15%, the investigators will continue to enroll until they get 24 evaluable subjects. The primary endpoint is to determine average bioequivalence for Test and Reference formulation of efavirenz according to the FDA guidance on bioequivalence testing. The ratio of the Test to Reference formulation mean for efavirenz AUC0-192, AUC0-inf and Cmax and the 90% confidence interval around each mean ratio will be determined. Average bioequivalence will be met if 90% confidence interval around de AUC and Cmax mean ratios for efavirenz falls within the FDA's predefined limits of 0.80 to 1.25. Safety will be evaluated by administering a questionnaire to the subjects during the study . This questionnaire will list the most frequent adverse effects already described for the innovator (Stocrin(R)). Safety will also be evaluated from vital signs recordings, lab tests out of the limits fixed in the study protocol and Psychiatric Evaluations during screening, in the wash out period and 15 days after the last administration of the study medication.

Official Title
-----------------
Comparative Bioavailability Study of Two Efavirenz 600 mg Formulations in Healthy Volunteers.

Conditions
-----------------
Healthy

Intervention / Treatment
-----------------
* Drug: Efavirenz 600 Test-Stocrin 600 Reference
* Drug: Stocrin 600 Reference-Efavirenz 600 Test


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male, Caucasians Age >=18 and <=50, BMI>18 and BMI<30 kg/m2 HIV-1 negative, B Hepatitis negative, C Hepatitis negative. Able to give consent, Non/light-smoking, Lab screening and EKG within the limits stipulated in the protocol. Healthy as determine by medical examination. Exclusion Criteria: Subjects with any current or past history of psychiatric disorder. Subjects receiving any prescription or over-the-counter product. Subjects using any form of recreational drug. Subjects who has eaten grapefruit or drunk grapefruit juice during the last 15 days before administration of study drug. Subjects who had had xanthine containing beverages (mate, coffee, tea, chocolate, etc.) during 48 ours previous to study drug administration. Subjects with history of hepatic disease, renal disease, GI diseases, chronic infectious disease, heart disease, lung disease, neurologic disease, endocrine disease, etc. Subjects suffering any acute disease at screening or check-in. Alanine S. Transaminase(AST)/Alanine L. Transaminase(ALT) > 3 times upper limit of normal (ULN). Bilirubin > 2.5 times ULN. Amylase > 2 times ULN. Absolute Neutrophil Count <1000/mL. Hgb < 9.0 g/dl. Platelets > 50.000 cell/mm3, Serum Creatinine > 2.5 mg/dl

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Efavirenz 600 Test-Stocrin 600 Reference<br>Efavirenz 600 mg will be randomly assigned. | Drug: Efavirenz 600 Test-Stocrin 600 Reference<br> <br> |
| Other: Stocrin 600 Reference-Efavirenz 600 Test<br>Stocrin 600 mg will be randomly assigned. | Drug: Stocrin 600 Reference-Efavirenz 600 Test<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve for efavirenz (AUC0-192) | The area under the concentration-time curve (AUC0-192) for efavirenz in a time frame of 8 days. | 0 to 192 h | 
| Maximum Concentration for efavirenz (Cmax) | The maximum concentration taken form the curve concentration vs. time for efavirenz. | 0 to 192 h | 
| Area Under the Curve 0 to infinity for efavirenz (AUC0-inf) | Area under the concentration-time curve from time 0 to infinity for efavirenz. | 0 to infinity | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to the Cmax for efavirenz (tmax) | It is the time elapsed from 0 time to the Cmax time for efavirenz | 0 to 192 h | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
efavirenz, bioequivalence, fasting, healthy volunteers