Pharmacokinetics, Safety, and Pharmacologic Effects of OPC‐21268, a Nonpeptide Orally Active Vasopressin V1 Receptor Antagonist, in Humans

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Abstract
The pharmacokinetics, safety, and pharmacologic effects of OPC‐21268, a nonpeptide orally active vasopressin V1 receptor antagonist, have been investigated in 33 healthy subjects. First, 24 subjects were randomly divided into 3 groups of 8, 6 of whom were given 2 ascending single oral doses out of 6 (10, 50, 150, 300, 450, and 600 mg) of OPC‐21268 after an overnight fast. The remaining two subjects in each group received placebo as control at each dosing. Additionally, after this procedure, the 6 subjects who received 50‐mg single doses were given the same dose in a nonfasting condition. After the single‐dose study was completed and the safety and tolerability were ascertained, the remaining 9 subjects, including 3 controls, were given 300 mg of the drug 3 times daily for 7 days (days 3–9) and were given single 100‐mg oral doses before (day 1) and after (day 10) this repeated‐dose study. OPC‐21268 plasma concentrations declined in a monoexponential or biexponential pattern after reaching the maximum plasma concentrations (Cmax). The mean (± standard error of the mean) plasma half‐life (t1/2) of the α phase ranged from 1.31 ± 0.11 to 1.78 ± 0.15 hours, and the mean t1/2 of the β phase ranged from 4.31 ± 0.28 to 6.28 ± 0.59 hours. The area under the concentration (AUC0‐∞) and Cmax were proportional to the dose (P < .001). The mean apparent oral clearance ranged from 6.24 ± 0.62 to 10.22 ± 0.79 L/h, and the mean percentage fraction of administered dose excreted unchanged in the urine up to 48 hours ranged from 0.39 ± 0.03 to 1.02 ± 0.09%. The mean tmax (the time taken to reach Cmax) was 1.03 ± 0.23 hours. The nonfasting condition lengthened the mean tmax significantly from 0.5 to 1.75 ± 0.10 hours, but did not alter the other kinetic parameters. The simulation curve for repeated dosing predicted from the plasma concentration‐time relationship after the single dosing on day 1 corresponded well with that obtained from the actual data. There were no significant differences in pharmacokinetic parameters between the first (day 1) and final (day 10) administrations, and the parameters were also compatible with those obtained in the single‐dose study. In the single‐ and repeated‐dose studies, the drug did not alter the blood pressure or the heart rate throughout the study period. Further plasma vasopressin levels were not changed and remained within the normal range throughout the two study periods. No increase in urine volume occurred after single or repeated OPC‐21268 administration. The results suggest that the plasma concentration of OPC‐21268 increases in proportion to the dose. Its elimination is dose independent and is not changed on repeated administration. The drug is not likely to influence hemodynamics, plasma vasopressin, or urine output. Oral doses up to 600 mg for single administration and 100 mg three times daily for repeated dosing for the period of 7 days, are on the basis of the current study considered to be safe and tolerable.