Pharmacokinetics and tolerability of a novel 5-HT1D agonist, PNU-142633F

Objectives: The objectives of this study were to characterize the safety, t olerability and pharmacokinetics of a single, oral dose of PNU-142633F esca lating over the range of 1.0 mg to 100 mg (free base equivalents). Methods: This was a randomized, double-blind, single-dose, placebo-controlled, dose -escalation trial, with each dose group (1.0, 3.0, 10, 30, 50, 75 and 100 m g) having eight volunteers (six PNU-142633F and two placebo). Clinical labo ratory tests, electrocardiogram, Holter monitoring, and assessment of adver se events were used to gauge the tolerability of PNU-142633. Serial blood s amples and urine collections were obtained and plasma and urine PNU-142633 concentrations were determined by a validated HPLC fluorescence method. Res ults: PNU-142633 was well tolerated after oral administration. There were n o reports of serious or unexpected adverse events. The most common adverse event that was possibly medication-related was transient dizziness. There w ere no clinically significant or dose-related effects of PNU-142633 on any vital sign parameters (aural temperature, systolic and diastolic blood pres sure, pulse rate or respiratory rate), at any study time or dose. There wer e no clinically significant ECG changes. Only sporadic abnormalities in cli nical chemistry values and hematology were noted. After the 1.0 mg and 3.0 mg doses, plasma concentrations of PNU-142633 were either below or only sli ghtly above the lower limit of quantitation (2 ng/ml). At higher doses (30 - 100 mg) the terminal half-life was relatively constant at approximately 1 1 hours. Neither C-max nor AUC(0-infinity) increased proportionally with th e administered dose. The mean percentage of the dose excreted in the urine as intact PNU-142633 increased from 14.3% after the 1 mg dose to 49.3% afte r the 100 mg dose. Conclusions: The clinical safety and pharmacokinetic dat a support the study of this agent as a potential treatment for migraine att acks.