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Single Oral Dose Safety, Tolerability, and Pharmacokinetics of PNU-96391 in Healthy Volunteers

From the Clinical Pharmacology (Dr. Rodríguez, Dr. Azie, Mr. Adams), Drug Metabolism (Mr. Staton, Mr. Bombardt), and Clinical Support Biostatistics (Dr. Francom) Units, Pharmacia Corporation, Kalamazoo, Michigan, and the BIOS Clinical Pharmacology Unit (Dr. Donaldson), Basingstoke, England. Dr. Rodríguez's current affiliation is Chiron Corporation, Emeryville, California.

The safety, tolerability, and pharmacokinetics of PNU-96391, an orally active weak dopamine D2 receptor antagonist with modulatory properties of central dopaminergic function, was characterized. Fifty-three healthy normal volunteers were enrolled in this randomized, double-blinded, placebo-controlled, single-dose study. Subjects were assigned to single oral doses of placebo and 1, 3, 10, 30, 100, 150, and 200 mg PNU-96391. Safety and tolerability were assessed using telemetry, Holter monitoring, surface ECG, vital signs, safety laboratories, and adverse event reports. Pharmacokinetic parameters were determined by model-independent techniques. Adverse events were infrequent, of mild to moderate intensity, and in the dose range of 1 to 150 mg. Dose escalation was stopped at 200 mg because of severe nausea, dizziness, lightheadedness, and tachycardia. Besides the increase in heart rate, no other drug-related effects on vital signs were observed. Safety laboratory measurements were not significantly changed. Evidence of drug activity was demonstrated by a dose-dependent elevation in serum prolactin. PNU-96391 was rapidly absorbed, with maximum concentrations achieved between 0.5 and 4 hours in all subjects. The half-life of the drug was short (2 to 6 h). The main metabolite, PNU-100014, was rapidly formed, with a t_max ranging from 1 to 6 hours. Peak levels of the metabolite are approximately half of the parent drug, and the half-life is slightly longer (4 to 10 h). Increases in dose resulted in linear increases in exposure for both PNU-96391 and PNU-100014. Hence, PNU-96391 was well tolerated at doses ranging from 1 to 150 mg.

Key Words: PNU-96391 • safety • tolerability • pharmacokinetics • movement disorders

Address for reprints: Nkechi Azie, MD, 7215-24-205, Clinical Pharmacology, Pharmacia Corporation, Kalamazoo, MI 49007.

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