Pain relief model for a COX-2 inhibitor in patients with postoperative dental pain.

AIM: To develop a pain relief model for a cyclooxygenase (COX)-2 inhibitor, CS-706, that permits prediction of doses for acute pain relief in Japanese and Western populations. METHODS: A categorical response model was developed to describe the probability of pain relief (PR) over time for a Phase 2a study. Models were also developed to describe patient's use of rescue medication and onset of pain relief. RESULTS: The placebo response was described by a first-order increase in PR that achieved a stable response after 4 h. The effect of CS-706 on PR was described using an E(max) model; the plasma concentration of CS-706 producing 50% of the maximum response was estimated to be 87 ng ml(-1), the median peak plasma concentration achieved after a 50-mg oral dose. The probability of rescue medication (REMD) decreased over time and was a function of the last observed PR score. This probability was < 16% for patients with a PR score > or =2. The probability of experiencing meaningful PR was 98% in patients who did not require REMD and 47% in those who required REMD. For patients who did not require REMD, the median onset time of meaningful pain relief (TMPR) decreased with increasing doses. In patients who required REMD, there was a saturable decline in TMPR, with the greatest improvement occurring from placebo to 50-mg doses. CONCLUSIONS: The set of models developed permitted compilation of multiple dose-response curves for dose selection of CS-706 in Westerners and facilitated scaling of doses to a Japanese population.

Stereoselective pharmacokinetics of RS-8359, a selective and reversible MAO-A inhibitor, by species-dependent drug-metabolizing enzymes.

RS-8359, (+/-)-4-(4-cyanoanilino)-5,6-dihydro-7-hydroxy-7H-cyclopenta[d]pyrimidine selectively and reversibly inhibits monoamine oxidase A (MAO-A). After oral administration of rac-RS-8359 to rats, mice, dogs, monkeys, and humans, plasma concentrations of the (R)-enantiomer were greatly higher than were those of the (S)-enantiomer in all species studied. The AUC((R)) to AUC((S)) ratios were 2.6 in rats, 3.8 in mice, 31 in dogs, and 238 in monkeys, and the (S)-enantiomer was almost negligible in human plasma. After intravenous administration of RS-8359 enantiomers to rats, the pharmacokinetic parameters showed that the (S)-enantiomer had a 2.7-fold greater total clearance (CL(t)) and a 70% shorter half-life (t(1/2)) than those for the (R)-enantiomer but had no difference in distribution volume (V(d)). No significant difference in the intestinal absorption rate was observed. The principal metabolites were the 2-keto form, possibly produced by aldehyde oxidase, the cis-diol form, and the 2-keto-cis-diol form produced by cytochrome P450 in rats, the cis-diol form in mice, RS-8359 glucuronide in dogs, and the 2-keto form in monkeys and humans. Thus, the rapid disappearance of the (S)-enantiomer from the plasma was thought to be due to the rapid metabolism of the (S)-enantiomer by different drug-metabolizing enzymes, depending on species.