CI-1007

The disposition of CI-1007 (I), an antipsychotic dopamine agonist, was studied after iv or po administration to rats, monkeys, and dogs and po administration to human cytochrome P450 2D6 extensive metabolizers (EMs). I was extensively metabolized after po administration, with high hepatic clearance (CL) values and negligible urinary excretion. Values for systemic plasma CL (28-40 ml/min/kg) suggested hepatic plasma flow-limited CL. The oral CL of I was similar among the species. Strong correlation was achieved in interspecies scaling for CL. After oral administration of [14C]I, the major route of 14C elimination in rats was in the bile (64%), followed by feces (29%) and urine (3.2%). Fecal excretion (64%) was the major route of 14C elimination in monkeys, followed by urine (14%). Three hydroxy metabolites, i.e. PD 147693 (II), PD 149394 (III), and PD 155144 (IV), and two sulfates, i.e. PD 163637 (VI) and PD 163639 (VIII), were identified in monkey plasma, urine, or feces. VIII was the major metabolite excreted in monkey urine, and VI was the major component in feces. Trace amounts of II, VI, and VIII were detected in the plasma and urine of human EMs but not in rats or dogs. II is an active metabolite that was present in all species. After oral administration, observed maximal plasma concentration and AUC values for II were higher than the corresponding values for I in dog plasma, approximately 20-40% of the values for I in monkeys and human EMs, and <5% of the values for I in rat plasma. Although the metabolic profiles differ among species, strong correlation was achieved in allometric scaling because the elimination of I from the body is mainly limited by hepatic blood flow.

CI-1007 is a novel dopamine autoreceptor agonist and partial dopamine D2/D3 agonist that is currently under development for the treatment of schizophrenia. This single-blind, rising, multiple-dose, inpatient bridging study was designed to evaluate the safety and tolerability of CI-1007 in consecutive panels of patients with schizophrenia. Following a 4-day placebo washout period, 16 patients (4 per panel) were assigned to receive one of four fixed-dosage regimens of CI-1007 (5, 10, 15, or 20 mg q12h for 9 doses). CI-1007 was generally well tolerated over the dose range evaluated. Adverse events, including mild to moderate sporadic orthostatic hypotension and/or nausea and vomiting, were most commonly observed after the initial drug dose and decreased after repeated dosing. Serum concentrations of growth hormone (GH) increased following the administration of CI-1007, confirming its central dopamine agonist activity. Changes in serum prolactin were not related to dose. The pharmacokinetics of CI-1007 and its active metabolite appear linearly related to dose. The results of this study suggest that patients with schizophrenia tolerate slightly higher initial doses of CI-1007 than do healthy subjects.