Absence of Pharmacokinetic Interaction between the NNRTI Rilpivirine (TMC278) and the Integrase Inhibitor Raltegravir
H Crauwels1, M Stevens1, Guy De La Rosa*2, and K Boven3
1Tibotec BVBA, Beerse, Belgium; 2Tibotec Therapeutics, Titusville, NJ, US; and 3Tibotec Inc, Titusville, NJ, US
Background: The NNRTI rilpivirine (RPV) demonstrated high virologic response rates and non-inferiority vs efavirenz (EFV), in 2 large international double-blind phase III trials in ARV-naļve HIV-1-infected adults, through 96 weeks. The current trial evaluated the pharmacokinetic interaction between RPV and raltegravir (RAL), in view of potential concomitant use of these ARV.
Methods: This was a phase I, open-label, randomized, cross-over trial in 24 HIV volunteers. Participants received in 1 session RPV 25 mg once daily alone for 11 days, and in another session RAL 400 mg twice daily for 4 days immediately followed by co-administration of RPV 25 mg once daily and RAL 400 mg twice for 11 days. All study drugs were taken with a meal. Steady-state 24-hour pharmacokinetic profiles were assessed at the end of each treatment, for RPV, RAL and its main metabolite RAL-glucuronide, as applicable. Plasma samples were analyzed using validated LC-MS/MS methods. Pharmacokinetic parameters were calculated with non-compartmental analysis. The least square (LS) means and associated 90%CI of treatment ratios were calculated based on log-transformed pharmacokinetic parameters (Cmin, Cmax, AUCtau).
Results: RPV pharmacokinetics were unaffected by co-administration of RAL (see the table). Also, RPV did not affect the pharmacokinetics of RAL and RAL-glucuronide to a clinically relevant extent. Furthermore, the RAL-glucuronide/RAL pharmacokinetic parameter ratios were similar in the absence or presence of RPV (mean [SD] AUC12h ratio 75%  vs 70% , respectively). RPV and RAL pharmacokinetic parameters in this trial were in line with previously reported data. Co-administration of RPV and RALwas generally safe and well tolerated.
Conclusions: RPV 25 mg once daily and RAL 400 mg twice daily can be co-administered without dose modifications.