Effects of Fostamatinib on the Pharmacokinetics of the CYP2C8 Substrate Pioglitazone: Results From In Vitro and Phase 1 Clinical Studies

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• 作者：Paul Martin ; Michael Gillen ; David Millson ; Stuart Oliver ; Clive Brealey ; Dominic Surry ; David Sweeny ; David Lau and Philip Leese
• 刊名：Clinical Pharmacology in Drug Development
• 出版年：2016
• 出版时间：May/June 2016
• 年：2016
• 卷：5
• 期：3
• 页码：170-179
• 全文大小：257K
• ISSN：2160-7648

文摘

Fostamatinib is a prodrug that undergoes gastrointestinal tract dephosphorylation to form the active metabolite, R406. Here we report its cytochrome P450–inducing potential. In vitro, R406 3 and 10 μM induced CYP2C8 to levels representing 53% and 75%, respectively, of the level achieved by the positive control, rifampicin. Induction of other enzymes was minor. The effect of fostamatinib (100 mg twice daily) on the pharmacokinetics of a single oral 30-mg dose of the CYP2C8 substrate pioglitazone and its metabolite, hydroxy pioglitazone, was then investigated (open-label, nonrandomized, 2-period phase I study [n = 15]). Coadministration of fostamatinib and pioglitazone (vs pioglitazone alone) was associated with lower mean maximum plasma concentration values for pioglitazone (geometric least-squares mean ratio, 82.8; 90% confidence interval, 64.2–106.8) and hydroxy pioglitazone (90.9; 78.6–105.1), an increase in pioglitazone AUC (117.8; 108.4–128.0), a decrease in hydroxy pioglitazone AUC_(0–t) (89.7; 78.9–101.9), and an increase in pioglitazone geometric mean t_1/2λz (9.4–12.8 hours). No tolerability concerns were identified upon coadministration. These data suggest that although clinical significance has not been formally evaluated, fostamatinib is unlikely to have a clinically significant effect on the pharmacokinetics of pioglitazone (which may be extrapolated to other CYP2C8 substrates). However, vigilance is advised should these agents be prescribed together.