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

• Published in: Clinical pharmacology in drug development Vol. 5; no. 3; pp. 170 - 179
• Main Authors: Martin, Paul, Gillen, Michael, Millson, David, Oliver, Stuart, Brealey, Clive, Surry, Dominic, Sweeny, David, Lau, David, Leese, Philip
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.05.2016; Wiley Subscription Services, Inc
• Subjects: Adult; Area Under Curve; Confidence intervals; CYP2C8; Cytochrome P-450 CYP2C8 - drug effects; Cytochrome P-450 CYP2C8 - metabolism; Cytochrome P-450 Enzyme Inducers - pharmacology; Drug Interactions; drug-to-drug interaction; enzyme induction; Enzyme Induction - drug effects; fostamatinib; Half-Life; Humans; Male; Middle Aged; Oxazines - pharmacology; pharmacokinetics; pioglitazone; Pyridines - pharmacology; Thiazolidinediones - pharmacokinetics; Young Adult; pharmacokinetics; CYP2C8; pioglitazone; enzyme induction; fostamatinib; drug-to-drug interaction
• ISSN: 2160-763X; 2160-7648
• DOI: 10.1002/cpdd.243

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 t1/2λz (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.