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Abstract
The pharmacokinetic (PK) interaction between famotidine and TMC278, a next generation non-nucleoside reverse transcriptase inhibitor (NNRTI), in HIV-negative volunteers
Van Heeswijk R.1, Hoetelmans R.1, Kestens D.1, Stevens M.1, Peeters M.1, Williams P.1, Woodfall B.1, Boven K.2
Objectives: TMC278 is a next generation NNRTI with potent and sustained efficacy in ARV-naïve patients [CROI-2007]. As TMC278 showed pH-dependent solubility in vitro the current study evaluated the interaction between TMC278 and the H2-antagonist famotidine, as well as dosing strategies to circumvent the anticipated interaction.
Methods: This was a single-dose, open-label, randomized, 4-way crossover trial in 24 HIV-negative volunteers. On four occasions, each separated by a 14-day washout, volunteers received TMC278 150 mg alone (A), TMC278 2h after famotidine 40 mg (B), TMC278 4h before famotidine (C), and TMC278 12h after famotidine (D). Intragastric pH was measured over 24h during Treatments A and B. PK of TMC278 and famotidine was assessed up to 168h and 24h postdose, respectively. TMC278 was administered with food.
Results: When TMC278 was administered 2h after famotidine, the TMC278 Cmax and AUCinf were reduced by 85% (LSMratio 0.15, 90% CI 0.12-0.19) and 76% (LSMratio 0.24, 90%CI 0.20-0.28), respectively. The TMC278 AUCinf was increased by 13% (LSMratio 1.13, 90%CI 1.01-1.27) when TMC278 was administered 4h before famotidine, and was not affected when TMC278 was administered 12h after famotidine (LSMratio 0.91, 90%CI 0.78-1.07). A negative correlation was observed between intragastric pH and exposure to TMC278. The PK parameters of famotidine were not influenced by TMC278. All treatments were generally well tolerated. Three subjects (12.5%) experienced AEs, all grade 1 or 2. One subject was withdrawn with grade 2 mouth ulceration during Treatment C, without rash or other skin events.
Conclusions: TMC278 should not be administered shortly after famotidine. However, no clinically relevant effects on TMC278 exposure were observed when TMC278 was administered either 4h before, or 12h after famotidine. These results confirm the pH-dependent bioavailability of TMC278 and suggest that separate intake of TMC278 and famotidine 40 mg prevents reduced absorption and thus allows coadministration without dose modification.
4th IAS Conference on HIV Pathogenesis, Treatment and Prevention
Abstract no.
TUPDB01
Suggested Citation
"VanHeeswijkR., et al.
The pharmacokinetic (PK) interaction between famotidine and TMC278, a next generation non-nucleoside reverse transcriptase inhibitor (NNRTI), in HIV-negative volunteers.
Poster discussion:
4th IAS Conference on HIV Pathogenesis, Treatment and Prevention:
Abstract no.
TUPDB01"
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