RT Journal Article
SR Electronic
T1 Application of Physiologically Based Pharmacokinetic Modeling to Understanding the Clinical Pharmacokinetics of UK-369,003
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1203
OP 1213
DO 10.1124/dmd.111.038224
VO 39
IS 7
A1 Kenny J. Watson
A1 John Davis
A1 Hannah M. Jones
YR 2011
UL http://dmd.aspetjournals.org/content/39/7/1203.abstract
AB 5-[2-Ethoxy-5-(4-ethyl-piperazine-1-sulfonyl)-pyridin-3-yl]-3-ethyl-2-(2-methoxy-ethyl)-2,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one (UK-369,003) is a phosphodiesterase-5 inhibitor in clinical development at Pfizer. UK-369,003 is predominantly metabolized by cytochrome P450 3A4 and is also a substrate for the efflux transporter P-glycoprotein. The pharmacokinetics of UK-369,003 has been profiled after oral administration of 1 to 800 mg of an immediate release formulation to healthy volunteers. Nonlinearity was observed in the systemic exposure at doses of 100 mg and greater. In addition, the pharmacokinetics of UK-369,003 has also been investigated after oral administration of the more therapeutically attractive modified release formulation. Systemic exposure was prolonged with the modified release formulation, but bioavailability was reduced in comparison with that of the immediate release formulation. Physiologically based pharmacokinetic modeling strategies are commonly used in drug discovery and development. This work describes application of the physiologically based pharmacokinetic software GastroPlus to understand the pharmacokinetics of UK-369,003. The impact of gut wall and hepatically mediated CYP3A4 metabolism, in addition to the actions of P-glycoprotein, in causing the nonlinear pharmacokinetics of the immediate release formulation and the reduced bioavailability of the modified release form, was investigated. The model accurately described the systemic exposure of UK-369,003 after intravenous and both immediate and modified release oral administration and suggested that CYP3A4 is responsible for the majority of the nonlinearity in systemic exposure observed after administration of the immediate release form. Conversely, the reduced bioavailability of the modified release formulation is believed to be caused by incomplete release from the device, incomplete absorption of released drug, and, to a lesser extent, CYP3A4 metabolism.