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NATIONAL HIV/AIDS RESEARCH AND BEST PRACTICES CONFERENCE - page 56 / 103

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B8. Pharmacokinetic Comparison of Generic and Trade Formulations of Lamivudine, Stavudine and Nevirapine in HIV-Infected Malawian Subjects

Hosseinipour M1, Corbett A2, Kanyama C1, Mshali I1, Chinyama S1, Phakati S1, Rezk N2, van der Horst C2, Kashuba A2

1UNC Project, Lilongwe, Malawi; 2University of North Carolina, USA

Objectives:  Several generic antiretroviral (ARV) formulations were removed from the WHO medication list for inadequate bioequivalence.  Malawi has introduced an ARV program using fixed dose generic Triomune (d4T,3TC, NVP).  This study determined the pharmacokinetic (PK) properties of generic and trade formulations of d4T, 3TC, and NVP in HIV-infected Malawians.  

Methods:  12 patients (6M, 6F) currently on Triomune-40 were randomized to receive generic or trade formulations of d4T (40mg), 3TC and NVP for 28 days.  Subjects then crossed-over to the alternate formulation.  Blood samples were collected at 0, 0.5, 2, 4, 6, and 8 hours post-observed dose. Areas under the concentration-time curve over 8 hours (AUC0-8h) were calculated using non-compartmental methods.  C12h and AUC0-12h were derived using z extrapolations. Geometric mean ratios (R) and 90% confidence intervals (CI) were calculated to determine bioequivalence (Cmax and AUC 90% CI=0.8-1.25).

Results:  Age, weight and height were 38.47.7yr, 71.27.0kg, and 164.86.3 cm, respectively. PK parameters are below (conc. in mg/L, AUC in mg*h/L).

Drug

Cmax

AUC0-8h

C0h

Trade

Generic

R [90% CI]

Trade

Generic

R [90% CI]

Trade

Generic

3TC

1.20.5

1.41.1

1.1 [0.8-1.6]

6.53.6

6.32.8

1.0 [0.7-1.3]

0.30.3

0.20.2

d4T

0.60.2

0.90.3

1.4 [1.2-1.7]

1.80.5

2.10.6

1.1 [1.0-1.2]

0.030.02

0.020.03

NVP

9.34.0

8.32.8

0.9 [0.7-1.2]

66.128.7

57.519.3

0.9 [0.7-1.1]

7.73.3

6.01.9

d4T Cmax was higher with Triomune. Malawians had significantly higher NVP exposures with both formulations compared to reported results for Western HIV-infected patients of similar age and body size.  3/9 (33%) patients reported less neuropathy symptoms on the trade formulation.  

Conclusions:  Although exposures were 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 neuropathy.  

Recommendations: Since genetic and environmental factors may influence the PK of antiretrovirals, evaluation of drug exposure should be performed as these medications are introduced to new populations.

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