publié le 2 mars 2006
Significant Decrease in TMC125 Exposures when Co-administered with Tipranavir Boosted with Ritonavir in Healthy Subjects Monika Schöller*1, M Kraft2, R Hoetelmans1, V Vyncke1, K Vandermeulen1, M Peeters1, L Bastiaanse1, C Debroye1, B Woodfall1, and B Baeten1 1Tibotec, Mechelen, Belgium and 2Boehringer Ingelheim, Ingelheim, Germany
Background : TMC125 is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with potent activity against both wild type HIV and viruses resistant to currently approved NNRTI. Tipranavir (TPV), co-administered with low-dose ritonavir (RTV), is indicated for combination ART of HIV-1-infected patients who are protease inhibitor (PI)-experienced. The objective of this study was to evaluate in healthy subjects the pharmacokinetic interaction between TMC125 (formulation TF035) and ritonavir-boosted tipranavir (TPV/r) at steady state.
Methods : TMC125-C161 was an open-label, 2-period crossover, randomized trial in 24 healthy subjects. In session I, 800 mg TMC125 was administered twice daily for 7 days followed by a single morning dose on day 8. After a washout period of at least 14 days, session II consisted of a multiple-dose regimen of TPV/r 500/200 mg twice daily from day 1 to day 16. TMC125 800 mg was co-administered twice daily from days 9 to 16 in 12 subjects randomized to group 1 and from day 1 to 8 in 12 subjects randomized to group 2. TMC125 and TPV/r were both administered after food intake. The pharmacokinetics of TMC125, TPV, and RTV were assessed in steady state over 12 hours. Pharmacokinetic parameters were analyzed using a linear mixed-effect model for a crossover design.
Results : This study included 24 subjects (19 males, 5 females ; mean age 37 years). When combined with TPV/r, TMC125 AUC12h was 24% (90%CI 18 to 33% ; p <0.05) compared to administration of TMC125 alone. TMC125 Cmax and Cmin were 29% (90%CI 22 to 40%) and 18% (90%CI 13 to 25%), respectively (both p <0.05). AUC12h, Cmax, and Cmin of TPV were 118% (90%CI 103 to 136%), 114% (90%CI 102 to 127%), and 124% (90%CI 96 to 159), respectively, when combined with TMC125 compared to administration of TPV/r alone. RTV AUC12h, Cmax, and Cmin were 123% (90%CI 105 to 145 ; p <0.05), 119% (90%CI 104 to 137 ; p <0.05), and 134% (90%CI 87 to 208), respectively, when given in combination with TMC125. The concomitant administration of TMC125 and TPV/r was generally safe.
Conclusions : Because of the significant and clinically relevant decrease of exposure to TMC125 observed when TMC125 and TPV/r were co-administered in healthy subjects, the combination of these drugs is not recommended.