DRV in combination with low-dose RTV, with or without coadministration of CBZ, was generally safe and well tolerated in HIV-negative, healthy volunteers. If DRV/r and CBZ are combined, patients should be monitored for potential CBZ-related AEs, CBZ concentrations should be monitored and the dose titrated for adequate response.
Darunavir/Ritonavir versus Carbamazepine
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Study Design
This study (TMC114-TiDP3-C172) was a Phase I, open-label, randomized, two-panel, crossover trial to investigate the PK interaction between DRV/r and CBZ. Thirty-two HIV-negative, healthy male and female volunteers, aged 1855 years were recruited. Written, informed consent was provided by all volunteers. Two panels of 16 patients received drug treatments as follows - Panel 1: DRV/r alone 600/100mg bid on Days 17, then in combination with CBZ (200mg qd on Days 810, 200mg bid on Days 1129) with an additional morning dose of all three drugs on Day 30. Panel 2: CBZ 200mg alone Days 13 (qd) and Days 423 (bid). On Days 2429: CBZ. 200mg bid with DRV/r 600/100mg bid, with an additional morning dose of all three drugs on Day 30. DRV, RTV, and CBZ were taken with water within 10 minutes after a meal. During the coadministration phase, CBZ was taken first followed by RTV (within 5 minutes) then DRV within 5 minutes). Total treatment duration was 30 days, with a further follow-up period of up to 32 days
Study Results
Administration of DRV/r alone or in combination with CBZ resulted in comparable DRV plasma concentration-time profiles. PK parameters of DRV at steady-state when given as DRV/r or as DRV/r plus CBZ. In mean values of Cmin, Cmax, and AUC12h of DRV were comparable between treatments. The 90% CIs of the LS means ratios for Cmax and AUC12h were within the limits of 80125%; the ratios of the LS means were close to 100%. Individual plots of predose plasma concentrations of CBZ and CBZE demonstrated that steady-state conditions for both compounds were achieved prior to full PK blood sampling Compared with CBZ alone, the mean plasma concentration-time curves showed that at steady-state, coadministration of DRV/r resulted in higher mean plasma concentrations of CBZ over the entire dose interval lower mean plasma concentrations of CBZE. After combined administration with DRV/r, mean values for CBZ of C0h, Cmin, Cmax and AUC12h were higher than those after CBZ administration alone. Cmin, Cmax and AUC12h of CBZ were increased by 54%, 43% and 45%, respectively, in the presence of DRV/r compared with CBZ alone (LS means). At steady state, mean values of CBZE of C0h, Cmin, Cmax and AUC12h were lower following DRV/r + CBZ administration compared with CBZ alone. The AUC12h ratio metabolite/parent drug (AUC12h met/par) was markedly reduced postadministration of DRV/r + CBZ versus CBZ. Cmin, Cmax and AUC12h of CBZE were reduced by 52%, 54% and 54%, respectively, in the presence of DRV/r compared with CBZ alone
Study Conclusions
Systemic exposure to DRV, coadministered with low-dose RTV, was largely unchanged in the presence of CBZ. The CBZ-induced reduction (approximately 50%) in RTV exposure had no clinically relevant effect on DRV PK in this study. Exposure to CBZ was increased by 45% in the presence of DRV/r; consequently, exposure to the active metabolite, CBZE, was reduced. DRV in combination with low-dose RTV, with or without coadministration of CBZ, was generally safe and well tolerated in HIV-negative, healthy volunteers. If DRV/r and CBZ are combined, patients should be monitored for potential CBZ-related AEs, CBZ concentrations should be monitored and the dose titrated for adequate response.
References
Sekar V, Tomaka F, Lavreys L, Meyvisch P, Bleys C, Da Pawn M. Pharmacokinetic interaction between darunavir in combination with low-dose ritonavir and carbamazepine. 17th International Aids Conference. Mexico City. 17; August 2008.
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