Predictability of intranasal pharmacokinetics in man using pre-clinical pharmacokinetic data with a dopamine 3 receptor agonist, PF-219061

Abstract

1. (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.

2. 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.

3. 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.

4. 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%.

5. 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.

Keywords::

• Intranasal
• pharmacokinetics
• bioavailability
• conjugation

Acknowledgements

We gratefully acknowledge many Pfizer colleagues for their scientific and practical input into the D3 agonist drug discovery program that is described in this article. In particular we thank, Susan Cole, Rob Webster, Katherine Fenner, Jill Segelbacher and Russell Jones from the Department of Pharmacokinetics, Dynamics and Metabolism. Andrew Cook from Discovery Chemistry, Ben Gardener from Discovery Biology, Val Gillon from Material Sciences, Stefan Sultana from Clinical Development and colleagues at the Pfizer Clinical Research Unit, Brussels.

Declaration of interest: The authors report no conflicts of interest.