Pharmacokinetics of stavudine, lamivudine and nevirapine in a combined formulation GPO-VIR S30 compared to three single original brands and assessment of efficacy and safety of GPO-VIR S30 in human immunodeficiency virus (HIV)-infected patients

Abstract

The purposes were to study and compare the pharmacokinetic parameters of stavudine (d4T), lamivudine (3TC) and nevirapine (NVP) after administration as combined drugs formulation, GPO-vir S30, to those after giving three single drug tablets of the original brands in HIV-infected patients and also to determine short-term safety and efficacy of GPO-vir S30 in HIV-infected patients. The opened-label, randomized, 2-ways crossover trial was carried in twenty HIV-infected patients. They were divided into two groups, ten of them received the combined drugs tablet, and another group received the single drug tablets of the original brands for two weeks. Plasma samples were collected. The drug products were then switched, and the second period samples were collected after crossover for another two weeks. Plasma samples were analyzed by the HPLC validated method. Safety and efficacy of GPO-vir S30 were further followed for 12 weeks through viral load (VL) and CD4 counts. Pharmacokinetics of d4T, 3TC and NVP showed no statistically significant differences between GPO-vir S30 and the original brands products (P>0.05). Bioequivalence study based on 90% confidence interval limits indicated that the AUC[subscript 0-12hr] ratio of d4T, 3TC and NVP were all in the 0.8-1.25 equivalent limits. C[subscript max] ratio of NVP was also within the equivalent range; however, C[subscript max] ratio of d4T and 3TC were both met the lower limit but were slightly higher than 1.25 for the upper limit (1.31 and 1.30, respectively). These results indicated that the extent of absorption of d4T and 3TC were equivalent while the rates of absorption of these two drugs from GPO-vir S30 tablet might be slightly faster. Since all these drugs were used in chronic dosing which the extent of absorption were much more related to therapeutic effects than the rate of absorption, the two products could then be interpreted as bioequivalent. Short-term clinical monitoring for therapeutic effect of GPO-vir S30 for 12 more weeks revealed that VL of 15 from the total of 19 patients were decreased to undetectable level, the less 4 patients had VL with in the range of 50-157 copies/mL. Mean CD4 was increased from 108 to 206 cells/mm[superscript 3]. Majority adverse events were dermatological reaction. GPO-vir S30 and the original brands products could be interpreted as bioequivalence since both pharmacokinetic parameters of d4T, 3TC and NVP did not showed statistically significant differences and 90% confidence interval of AUC[subscript 0-12hr] ratio of all three drugs were within the 0.8-1.25 limits. Short-term monitoring for clinical effect of GPO-vir S30 revealed satisfactory results.