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Session 115 Poster Abstracts
Pharmacology: Drug Stability and Bioequivalence
Friday, 1:30 - 3:30 pm
Hall A


669    
An International Bioequivalence Study of Generic and Brand Formulations of Nevirapine, Zidovudine, and Lamivudine
Heather E Wynn Vezina*1, K Henry2,4, G Ravindran3, A Kurpad5, T Raj5, K Fox1, D Weller1, R Brundage1, R Bromander1, W Cavert1, and H Balfour, Jr1
1Univ of Minnesota, Minneapolis, USA; 2Univ of Minnesota, Minneapolis, USA; 3St John's Med Coll, Bangalore, Karnataka, India; 4Hennepin County Med Ctr, Minneapolis, MN, USA; and 5Inst of Population Hlth and Clin Res, St John's Natl Academy of Hlth Sci, Bangalore, Karnataka, India

Background:  Generic antiretrovirals are often used in developing countries without bioequivalence data of generic versus brand products. Drug exposure may differ between products and ethnic differences in pharmacokinetics may exist. Careful bioequivalence studies are needed for the specific population in which generics are used.

Methods:  This was a prospective, randomized, 2-period crossover bioequivalence study of the test (T) formulation Duovir-N (nevirapine [NVP]/zidovudine [AZT]/lamivudine[3TC]) 200/300/150 mg (Cipla, India) and the reference (R) formulations Viramune (NVP) 200 mg (Boehringer Ingelheim, USA) co-administered with Combivir (AZT/3TC) 300/150 mg (GlaxoSmithKline, USA) in 15 HIV-negative Indian women. FDA standards for determining average bioequivalence were used. Subjects took a single-dose of test or reference with 240 mL of water after fasting overnight. NVP, AZT and 3TC plasma concentrations were determined over 96 hours using HPLC. After a 14-day washout, subjects took the other formulation and sampling was repeated. Noncompartmental methods were used to calculate AUC0-t and AUC0-¥ for all drugs. Average bioequivalence was determined using log-transformed Cmax, AUC0-t, and AUC0-¥ mean ratios (T/R) and 90% confidence interval (CI) limits of 0.80 to 1.25 (WinNonLin). Period and treatment effects were tested by analysis of variance.

Results:  NVP, AZT, and 3TC pharmacokinetics were similar for test and reference drugs:  90% CI for NVP Cmax, AUC0-t, and AUC0-¥ mean ratios were within the 0.80 to 1.25 limits and met average bioequivalence; 90% CI for AZT Cmax mean ratio and 3TC Cmax, AUC0-t, and AUC0-¥ mean ratios were outside the 0.80 to 1.25 limits and did not meet average bioequivalence. There were no period or treatment effects.

 

 

 

Pharmacokinetic Results—mean (±SD), n = 15

 

Cmax (ng/mL)

Tmax (h)

AUC0-t (h·ng/ml)

AUC0-¥ (h·ng/ml)

NVP

T

R

2862±568

2697±482

3.6±5.8

4.1±5.8

152,323±23,545

148,696±28,914

233,039±52,888

219,677±58,897

AZT

T

R

2728±1078

2756±1243

0.6±0.2

0.7±0.4

4272±868

3971±868

4339±862

4045±865

3TC

T

R

1762±711

1678±601

1.1±0.6

1.7±1.5

7454±2573

7013±2157

8350±2558

7994±2138

 

 

Bioequivalence Results—mean Ratio (90% CI)

Cmax

AUC0-t

AUC0-¥

NVP

AZT

3TC

1.06

1.01

1.03

0.94–1.21

0.77–1.34

0.80–1.34

1.04

1.08

1.05

0.93–1.17

0.94–1.23

0.85–1.31

1.08

1.07

1.04

0.94–1.24

0.94–1.23

0.86–1.26

 

Conclusions:  Using FDA average bioequivalence standards, NVP in Duovir-N is bioequivalent to Viramune, but AZT and 3TC are not bioequivalent to Combivir. Lack of bioequivalence does not mean lack of clinical efficacy, only that a difference in rate and extent of absorption exists. Drug dissolution testing was not conducted but could explain these findings.

Keywords: bioequivalence; generic; nevirapine