Pharmacokinetics and Pharmacodynamics of an Investigational Antipsychotic Agent, CI-1007, in Rats and Monkeys

Abstract

Purpose. To study the pharmacokinetics (PK) and pharmacodynamics (PD) of an investigational antipsychotic agent, CI-1007, in rats and monkeys.

Methods. CI-1007 and a pharmacologically active metabolite, PD 147693 (Ml), were evaluated in animal antipsychotic tests (inhibition of dopamine neuron firing and spontaneous locomotor activity in rats, and inhibition of continuous avoidance in monkeys). Plasma concentrations of CI-1007 and Ml were determined using validated HPLC assays. Log-linear and link models were used for PK/PD analysis.

Results. CI-1007 and Ml have shown similar effects on dopamine neuron firing (2.5 mg/kg i.p.), and produced dose-related effects on spontaneous locomotor activity in rats (0.3−30 mg/kg, p.o.) and on continuous avoidance in monkeys (0.6−1.2 mg/kg p.o.). After pharmacologically active CI-1007 doses, mean plasma CI-1007 C_max increased from 19 to 200 ng/ml in Sprague-Dawley rats at doses of 3−30 mg/ kg, and from 8.1 to 34 ng/ml in squirrel monkeys at doses of 0.6−1.2 mg/kg, but corresponding plasma M1 C_max values were near or below the limit of quantitation (5 ng/ml). CI-1007 EC50 was 31.1 ng/ml in rats, calculated from a log-linear regression. In monkeys, CI-1007 EC_e50, γ, and K_eo at 0.6 and 1.2 mg/kg were 4.8 and 4.5 ng/ml, 1.9 and 2.0, and 0.47 and 0.48 hr⁻¹, respectively, calculated by the link model.

Conclusions. CI-1007 has shown dose-related pharmacokinetics and pharmacodynamics in rats and monkeys. Although Ml produces anti-psychotic-like effects similar to CI-1007, the contribution of Ml to the activity of the parent drug may not be significant in rats and monkeys as based on plasma levels. CI-1007 plasma concentration correlates log-linearly with inhibition effect from the rat locomotor study. The counter-clockwise hysteresis relationship of CI-1007 plasma concentration and inhibition effect from the monkey avoidance test was described by a link model, and the resulting C_e (concentration in effect compartment) versus effect profile exhibits a sigmoidal curve.