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Session 107 Poster Abstracts
Generic Antiretroviral Therapy
Wednesday, 1:30 - 3:30 pm
Hall A


631    
Pharmacokinetic Comparison of Generic and Trade Formulations of Lamivudine, Stavudine, and Nevirapine in 12 HIV-infected Malawian Subjects
Mina Hosseinipour*1, A Corbett2, C Kanyama1, I Mshali1, S Chinyama1, S Phakati1, N Rezk2, S White2, I Hoffman2, C Van der Horst2, and A Kashuba2
1Univ of North Carolina Project, Lilongwe, Malawi and 2Univ of North Carolina at Chapel Hill, USA

Background:  Recently, several generic antiretroviral (ARV) formulations were removed from the WHO medication list for inadequate bioequivalence. Malawi has introduced an ARV program using fixed dose Triomune (containing stavudine [d4T], lamivudine [3TC], nevirapine [NVP]). This study determined the pharmacokinetic properties of both generic and trade formulations of d4T, 3TC, and NVP in HIV-infected Malawians.

Methods:  We randomized 12 patients (6 male, 6 female) currently receiving Triomune to receive generic or trade formulations of d4T, 3TC, and NVP for 28 days. Subjects then crossed-over to the other formulation for 28 days. Pharmacokinetic visits occurred after day 21 of therapy, and 6 blood samples were collected over 8 hours post-observed dose. Areas under the concentration-time curve over 8 hours (AUC0-8h) were calculated using noncompartmental methods (WinNonLin 4.0.1). C12h and AUC0-12h were derived using lz extrapolations. Geometric mean ratios (R) and 90% confidence intervals (CI) were calculated (Stata 8.2) to determine bioequivalence (Cmax and AUC 90% CI = 0.8 to 1.25). Data are reported as mean±SD and R (90% CI).

Results:  These subjects’ age, weight and height were 38.4 ± 7.7 years, 71.2 ± 7.0 kg, and 164.8 ± 6.3 cm, respectively. Pharmacokinetic parameters are below (concentrations in mg/L, AUC in mg*h/L). Results were similar with AUC0-12h and C12h. d4T Cmax was significantly higher with Triomune. Malawians had significantly higher NVP exposures with both formulations compared to what has previously been reported for mixed populations of Western HIV-infected patients of similar age and body size; 33% of patients with grade 1 neuropathy reported fewer symptoms on the trade formulation.

 

Drug

Cmax

 

AUC0-8h

C0h

 

Trade

Generic

R (90% CI)

Trade

Generic

R (90% CI)

Trade

Generic

3TC

1.2±0.5

1.4±1.1

1.1 (0.8-1.6)

6.5±3.6

6.3±2.8

1.0 (0.7-1.3)

0.3±0.3

0.2±0.2

d4T

0.6±0.2

0.9±0.3

1.4 (1.2-1.7)

1.8±0.5

2.1±0.6

1.1 (1.0-1.2)

0.03±0.02

0.02±0.03

NVP

9.3±4.0

8.3±2.8

0.9 (0.7-1.2)

66.1±28.7

57.5±19.3

0.9 (0.7-1.1)

7.7±3.3

6.0±1.9

.

Conclusions:  In this pilot study, although exposures were generally similar between the formulations, Triomune did not meet the standard definition of bioequivalence. d4T peak concentrations were significantly higher with Triomune, which may be related to neuropathic toxicity. Since genetic and environmental factors may influence the pharmacokinetics of ARV, careful evaluation of drug exposure should be performed as part of the decision-making process before widely introducing these medications to new populations.

Keywords: Pharmacokinetics; Generic Antiretrovirals; Africa