Concomitant Administration of BILR 355⁄r with Emtricitabine⁄ Tenofovir Disoproxil Fumarate Increases Exposure to Emtricitabine and Tenofovir: A Randomized, Open-Label, Prospective Study

The objective of this study was to evaluate the pharmacokinetic interaction of ritonavir-boosted BILR 355 (BILR 355 ⁄ r) with emtricitabine (FTC) ⁄ tenofovir disoproxil fumarate (TDF). This was an open-label, prospective study. For Group A, 26 healthy subjects were given FTC ⁄ TDF (200 ⁄ 300 mg) once daily (QD) for 7 days and then co-administered with BILR 355 ⁄ r( 150⁄ 100 mg) twice daily (bid) for an additional 7 days. Pharmacokinetics assessments were performed at days 7 and 14. For Group B, eight subjects were given BILR 355 ⁄ r( 150⁄ 100 mg) bid for 7 days. The pharmacokinetic data from Group B were also pooled with Group B subjects from other similar studies performed in parallel to this study. After co-administra- tion with BILR 355 ⁄ r, the geometric mean ratio (GMR, %) and 90% confidence interval (CI, %) of combined versus alone treatment for FTC AUC0-24,ss, Cmax,ss and C0-12,ss were 160 (154-166), 128 (121-136) and 223 (206-241), respectively; and for tenofovir AUC0-24,ss, Cmax,ss and C24,ss were 126 (121-132), 131 (117-146) and 132 (124-140), respectively. Co-administration with FTC ⁄ TDF resulted in an 18% increase in AUC0-12,ss, 14% increase in Cmax,ss and 19% increase in C12,ss for BILR 355. BILR 355 was well tolerated in this study. There was no evidence of increased risk of TFV or FTC toxicity upon co-adminis- tration of FTC ⁄ TDF with BILR 355 ⁄ r. Highly active antiretroviral therapy (HAART), antiretroviral therapy that combines three or more anti-human immunode- ficiency virus (HIV)-1 agents, has proven to be effective in reducing viral load and HIV-1-related mortality and morbid- ity (1,2). The recommended HAART often includes a dual nucleoside reverse-transcriptase inhibitors (NRTI) 'back- bone' with the addition of a protease inhibitor or non- nucleoside reverse transcriptase inhibitor. TRUVADA � (Gilead, Foster City, CA, USA) tablets are fixed-dose combination tablets containing emtricitabine (FTC) (200 mg) and tenofovir disoproxil fumarate (TDF) (300 mg). FTC is a synthetic nucleoside analogue of cyti- dine. Tenofovir DF or TDF, a prodrug of tenofovir, is converted in vivo to tenofovir, an acyclic nucleoside phos- phonate (nucleotide) analogue of adenosine 5¢-monophos- phate (3). Both FTC and tenofovir exhibit inhibitory activity against HIV-1 reverse transcriptase and show good efficacy in combating HIV-1 infection. In addition, the FTC ⁄ TDF fixed-dose combination displays a superior safety profile compared with thymidine analogues. After oral administration, FTC is rapidly and nearly completely absorbed, and the systemic FTC is preliminarily eliminated by renal excretion, with 60-70 %o f an oral dose excreted in urine as unchanged drug. After oral administration, TDF is rapidly absorbed and converted to the active form, tenofovir. Urinary excretion is the predominant elimination pathway, with approximately 70-80% of the intravenous dose recov- ered as unchanged drug in the urine. The renal excretion of both FTC and tenofovir is through a combination of glo-