Evaluation of steady-state pharmacokinetic interactions between ritonavir-boosted BILR 355, a non-nucleoside reverse transcriptase inhibitor, and lamivudine/zidovudine in healthy subjects.

What Is Known And Objective: BILR 355 is a second generation non-nucleoside reverse transcriptase inhibitor. It has shown promising in vitro anti-HIV-1 activities and favourable human pharmacokinetic properties after co-administration with ritonavir (RTV). Lamivudine (3TC) is a nucleoside reverse transcriptase inhibitor. It is excreted predominantly in urine by a transporter-mediated pathway. These two drugs are likely to be given together to HIV-infected patients. The objective of this study was to investigate any steady-state pharmacokinetic interactions between RTV-boosted BILR 355 and 3TC/zidovudine (ZDV).

Methods: This was a randomized, open label, prospective study. In group A, 39 healthy subjects were given 3TC/ZDV (150 mg/300 mg) twice daily (b.i.d.) for 7 days, and then BILR 355 and RTV (BILR 355/r, 150 mg/100 mg) were co-administered with this regimen for an additional 7 days. Intensive blood samples were taken on days 7 and 14 for pharmacokinetic assessments. In group B, 12 healthy subjects were given BILR 355/r (150 mg/100 mg) b.i.d. for 7 days. The pharmacokinetic data from group B were pooled with data from group B subjects in other similar studies performed in parallel (BILR 355 alone group in BILR 355 drug-drug interaction studies with tipranavir, lopinavir/RTV, and emtricitabine/tenofovir DF; BILR 355 regimen was the same).

Results And Discussion: After co-administration with BILR 355/r, the AUC(12,ss) and C(max,ss) of 3TC increased by 45% and 24%, respectively; the elimination half-life (t(1/2) ,ss) of 3TC was significantly increased. However, the pharmacokinetics of ZDV was unchanged. Co-administration with 3TC/ZDV resulted in a 22% decrease in AUC(12,ss) and a 20% decrease in C(max,ss) for BILR 355. The observed increase in exposure and prolongation of t(1/2,ss) of 3TC is potentially related to inhibition of OCT-mediated urinary excretion of 3TC.

What Is New And Conclusion: Concomitant administration of BILR 355 with 3TC/ZDV resulted in a modest decrease in exposure to BILR 355 and a 45% increase in exposure to 3TC.