Chemistry Reference
In-Depth Information
PF-184298 exhibited linear pharmacokinetics in human subjects over the
dose range studied (1-20mg), with a mean terminal elimination half-life of 30 h.
The specific CYP contribution to the clearance of PF-184298 could not be
determined from in vitro data due to the very low turnover of the compound.
However, CYP2D6 genotyping of healthy volunteers in Study 1 demonstrated
that this polymorphic CYP is unlikely to play a major role in the clearance of
PF-184298, since an ultra-rapid metaboliser and poor metabolisers had similar
exposures compared to extensive metabolisers. This was a significant obser-
vation since CYP2D6 metabolism was a key issue in the research programme
that led to the discovery of PF-184298 and demonstrated a successful outcome
of the efforts to reduce CYP2D6 contribution in the series which were described
earlier in this chapter.
Further insight into the contribution of individual CYPs came from studies
in healthy volunteers with the CYP3A4 inhibitor ketoconazole, which resulted
in a modest increase in exposures of PF-184298, demonstrating a role of this
enzyme in the clearance of the compound.
12.4 Summary and Conclusions
This drug discovery program successfully delivered a development candidate
with the potential to be a ''best in class'' agent for the treatment of SUI and
other SNRI-mediated diseases. Key elements for the successful advancement of
PF-184298 to the clinic were (i) high confidence in rationale for the drug target,
(ii) a high-quality in vivo model which could also serve as a translatable bio-
marker to the clinic, (iii) a package of data from preclinical species provided
evidence that Phase 1 (cytochrome P450) mediated metabolism was a sig-
nificant mechanism in the clearance of PF-184298 and that this compound had
very low turnover in human in vitro metabolic systems and (iv) use of a bulk-
sparing pre-clinical toxicology package which allowed a rapid readout of
human pharmacokinetics. This project also highlighted to us the complex
nature of working in dual pharmacology and CNS target space. The interplay
of many activities, for example potency, selectivity, off-target pharmacology,
routes of metabolism and blood-brain barrier penetration proved to be
extremely challenging to optimise into a single molecule.
Acknowledgements
The authors would like to thank the following Pfizer colleagues for their
valuable contributions to this project:
IanGurre,GlAlan,LynnPurkins, Jonathan Fray, Gerwyn Bish, Alan
Stobie, Stephen Phillips, Donald Newgreen, Miles Tackett, Arnaud Lemaitre,
Julian Blagg, Liz Hopkins, David Winpenny, Alison Bridgeland, Debbie Lovering,
Carol Bains, Kerry Paradowski, Iain Gardner, Peter Bungay, Jackie Kendal, Edel
Evrard, Nicola Lindsay, Edward Pegden,PaulBlackwell,TimBuxton,Russell
Cave, Yann Lecouturier, Malcolm Mackenny, Melanie Skerten, Hans Rollema,
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