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
(TPV/r) at steady state.
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.
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.
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.