Predictability of intranasal pharmacokinetics in man using pre-clinical pharmacokinetic data with a dopamine 3 receptor agonist, PF-219061.
(R)-3-(4-propylmorpholin-2-yl) phenol (PF-219061) is a potent, selective agonist of the dopamine 3 receptor for the treatment of female sexual dysfunction. In vivo, PF-219061 exhibits liver blood flow clearance in both rat and dog. Oral bioavailability was 0.7% in dog and less than 5% in rat. Intranasal dosing was investigated to improve bioavailability. Pre-clinical assessments in rat and dog demonstrated intranasal bioavailabilities of 16-38% in rat and 54-61% in dog with very rapid absorption. It was predicted that an intranasal dose in man would give approximately 25-50% bioavailability. The clinical data verified the preclinical predictions demonstrating rapid absorption and approximately dose-proportional increases in exposure. The intranasal bioavailability in man was estimated to be 26-38%. These findings indicate the potential utility of intranasal dosing as a route that circumvents the first-pass effects for PF-219061 resulting in high exposures.
Attkins
N J
NJ
Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Sandwich, UK. neil.attkins@pzer.com
Heatherington
A C
AC
Phipps
J
J
Verrier
H
H
Huyghe
I
I
D000281:Administration, Intranasal; D000327:Adsorption; D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D004285:Dogs; D018492:Dopamine Antagonists / Q000493:pharmacokinetics* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D009025:Morpholines / Q000493:pharmacokinetics* / Q000494:pharmacology; D010636:Phenols / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012735:Sexual Dysfunction, Physiological / Q000188:drug therapy
C543941:(R)-3-(4-propylmorpholin-2-yl) phenol; D018492:Dopamine Antagonists; D009025:Morpholines; D010636:Phenols; D050637:Receptors, Dopamine D3