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The pharmacokinetics, safety, and tolerability of ACP-103, a selective serotonin 5-HT(2A) receptor inverse agonist, were evaluated in 2 double-blind, placebo-controlled, dose escalation studies in healthy male volunteers. Pharmacokinetic sampling was measured up to 216 hours after single oral/nasogastric doses of ACP-103 and after the last dose of once-daily oral administration of ACP-103 for 14 days. Single doses of ACP-103 (20-300 mg) resulted in dose-proportionate mean C(max) values (9-152 ng/mL) and AUC(0-infinity) (706-10 798 h x ng/mL), and multiple doses (50-150 mg) resulted in dose-proportionate mean C(max,ss) (93-248 ng/mL) and AUC(0-infinity,ss) (1839-4680 h x ng/mL). The half-life of ACP-103 was approximately 55 hours, with a t(max) at 6 hours. ACP-103 was well tolerated at single doses up to and including 300 mg and multiple doses up to 100 mg once daily for 14 days.

The once-daily formulation of diltiazem hydrochloride (Cardizem CD) is marketed for the treatment of essential hypertension and stable angina pectoris. The steady-state pharmacokinetics of once-daily diltiazem and its metabolites, desacetyldiltiazem (DAD) and N-desmethyldiltiazem (MA), were examined in two groups of eight healthy subjects each. The first group (group A) received 240, 480, and 720 mg diltiazem once daily for 7 days in a single-blind, stair-step, dose-escalation design. The second group (group B) received 180, 360, and 720 mg diltiazem in a similar manner. At each dose level, serial blood samples were collected for up to 24 hours after the last (seventh) dose. Plasma samples were analyzed for diltiazem and the metabolites by high-performance liquid chromatography. The disposition of diltiazem, DAD, and MA was nonlinear over the 240- to 720-mg (group A) and 180- to 720-mg (group B) diltiazem dose ranges studied. In group A, mean diltiazem area under the plasma concentration-time curve (AUC) at the 240-mg dose level was 2410 h.ng/mL compared with 10,167 h.ng/mL at the 720-mg dose level. In group B, mean diltiazem AUC at the 180-mg dose level was 1092 h.ng/mL compared with 8398 h.ng/mL at the 720-mg dose level. The apparent oral clearance decreased 35% over a threefold dose range (group A) and 51% over a fourfold dose range (group B). Mean ratios of AUCDAD/AUC(DILT) were similar at all dose levels. Mean AUCMA/AUC(DILT) ratios, however, decreased with increasing diltiazem dose, suggesting that the nonlinear disposition of MA may be less pronounced than that of parent drug.