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Background. A spirodiketopiperazine CCR5 antagonist, 873140 has been shown to be a CYP450 3A substrate in vitro. The objective of this study was to assess the in vivo effects of lopinavir/ritonavir (LPV/r), on the steady-state pharmacokinetics of 873140 in healthy adult subjects.

Methods:  In part 1, 873140 pharmacokinetics were determined in 8 subjects who received a single oral 50-mg  test dose of 873140 with or without a single 100-mg dose of ritonavir (RTV). Based on the pharmacokinetics and safety results, part 2 was conducted as an open-label, single-sequence, 3-period repeat dose study in 24 subjects. Subjects received 873140 at 400 mg twice a day for 7 days (period 1), LPV/r at 400/100 mg twice a day for 14 days (period 2), and 873140 at 400 mg + LPV/r at 400/100 mg twice a day for 7 days (period 3). All doses of 873140 and LPV/r were administered with a moderate fat meal. Serial pharmacokinetic sampling occurred on day 7 of periods 1 and 3 and day 14 of period 2. 

Results.  In part 1, a single RTV dose increased the 873140 AUC and C_max 2.1- and 2.3-fold. Pharmacokinetic parameters for part 2 are summarized below. Repeat dose co-administration of 873140 with LPV/r resulted in 7.7-, 6.2-, and 7.1-fold increase in the 873140 AUC, C_max, and C_min, respectively. No change in LPV AUC or C_max and a small increase in RTV AUC and C_max (28% and 32%) was observed. The combination of 873140 and LPV/r was well tolerated and all adverse effects were mild in severity. Two subjects discontinued for non-drug related reasons. Self-limiting gastrointestinal complaints were most commonly reported. No significant laboratory abnormalities were noted.

*Units for AUC and Cmax/Ct are ng.h/mL and ng/mL for 873140 & RTV; mg.h/mL and mg/mL for LPV

Conclusions:  Co-administration of 873140 and LPV/r was well tolerated and resulted in significantly increased 873140 plasma concentrations. These results support the further evaluation of 873140 with RTV-boosted PI regimens.

Keywords: CCR5; drug interaction; 873140