Pharmacokinetics and pharmacodynamics of CI-992 following intravenous and oral administration to cynomolgus monkeys

The purpose of this study was to characterize CI-992 pharmacokinetics and pharmacokinetics/pharmacodynamics (PK/PD) in sodium deplete monkeys. Panels of monkeys were administered CI-992 as a 1 h intravenous infusions (0.1 and 1 mg kg(-1)) or as single oral doses (0, 10, 50, and 100 mg kg(-1)). Mean arterial blood pressure (MABP) was monitored and serial blood samples were collected up to 24 h postdose. Plasma CI-992 concentrations were quantitated by radioimmunoassay. Pharmacokinetic parameters were calculated by noncompartmental methods. PK/PD relationships were assessed by standard methods. Oral bioavailability of CI-992 in the monkeys was <2%; steady-state volume of distribution was 0.67 L kg(-1); clearance was 10.4 mL min(-1) kg(-1). Following oral administration, t(max) generally occurred 6-9 h postadministration; plasma CI-992 concentrations increased with increasing dose between 10 and 50 mg kg(-1), but did not change appreciably from 50 to 100 mg kg(-1). After intravenous administration, change in MABP was correlated with plasma CI-992 concentration through an effect compartment model in which the maximum achievable effect was a 22 mm Hg decrease in MABP; the steady-state concentration which produced half the maximum effect was 11 ng mL(-1). Following the 10 mg kg(-1) oral dose the maximum decrease in MABP was 19.1 mm Hg; higher doses did not produce greater maximum response but increased the duration of action. In contrast to observations following intravenous administration, a trend for decreasing MABP with increasing plasma CI-992 was not apparent following oral CI-992 administration. (C) 1998 John Wiley & Sons, Ltd.