Pharmacokinetics and tolerability of a novel 5-HT1D agonist, PNU-142633F.
OBJECTIVE
The objectives of this study were to characterize the safety, tolerability and pharmacokinetics of a single, oral dose of PNU-142633F escalating 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 mg) having eight volunteers (six PNU-142633F and two placebo). Clinical laboratory tests, electrocardiogram, Holter monitoring, and assessment of adverse events were used to gauge the tolerability of PNU-142633. Serial blood samples and urine collections were obtained and plasma and urine PNU-142633 concentrations were determined by a validated HPLC fluorescence method.


RESULTS
PNU-142633 was well tolerated after oral administration. There were no reports of serious or unexpected adverse events. The most common adverse event that was possibly medication-related was transient dizziness. There were no clinically significant or dose-related effects of PNU-142633 on any vital sign parameters (aural temperature, systolic and diastolic blood pressure, pulse rate or respiratory rate), at any study time or dose. There were no clinically significant ECG changes. Only sporadic abnormalities in clinical 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 slightly above the lower limit of quantitation (2 ng/ml). At higher doses (30-100 mg) the terminal half-life was relatively constant at approximately 11 hours. Neither Cmax nor AUC(0-infinity) increased proportionally with the 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% after the 100 mg dose.


CONCLUSIONS
The clinical safety and pharmacokinetic data support the study of this agent as a potential treatment for migraine attacks.
Fleishaker
J C
JC
Clinical Pharmacology Unit, Pharmacia and Upjohn, Kalamazoo, MI 49007, USA.
Pearson
L K
LK
Knuth
D W
DW
Gomez-Mancilla
B
B
Francom
S F
SF
McIntosh
M J
MJ
Freestone
S
S
Azie
N E
NE
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D002839:Chromans / Q000097:blood / Q000276:immunology / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010919:Placebos; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000502:physiology*; D017366:Serotonin Receptor Agonists / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
D002839:Chromans; D010919:Placebos; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; C401885:PNU 142633F