title: Effects of Fostamatinib on the Pharmacokinetics of the CYP2C8 Substrate Pioglitazone: Results From In Vitro and Phase 1 Clinical Studies.
abstract: 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.
authors.affiliation: AstraZeneca, Macclesfield, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Martin
authors.affiliation: AstraZeneca, Wilmington, DE, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Gillen
authors.affiliation: Former-AstraZeneca, Macclesfield, UK.
authors.forename: David
authors.initials: D
authors.lastname: Millson
authors.affiliation: AstraZeneca, Macclesfield, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Oliver
authors.affiliation: Former-AstraZeneca, Macclesfield, UK.
authors.forename: Clive
authors.initials: C
authors.lastname: Brealey
authors.affiliation: Former-AstraZeneca, Macclesfield, UK.
authors.forename: Dominic
authors.initials: D
authors.lastname: Surry
authors.affiliation: Rigel Pharmaceuticals, Inc, South San Francisco, CA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Sweeny
authors.affiliation: Rigel Pharmaceuticals, Inc, South San Francisco, CA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Lau
authors.affiliation: Quintiles Phase I Unit, Overland Park, KS, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Leese
mesh_terms: D000328:Adult; D000631:Aminopyridines; D019540:Area Under Curve; D065727:Cytochrome P-450 CYP2C8 / Q000187:drug effects / Q000378:metabolism*; D065693:Cytochrome P-450 Enzyme Inducers / Q000494:pharmacology*; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D009025:Morpholines; D010078:Oxazines / Q000494:pharmacology*; D000077205:Pioglitazone; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines; D045162:Thiazolidinediones / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000631:Aminopyridines; D065693:Cytochrome P-450 Enzyme Inducers; D009025:Morpholines; D010078:Oxazines; D011725:Pyridines; D011743:Pyrimidines; D045162:Thiazolidinediones; D065727:Cytochrome P-450 CYP2C8; C523665:fostamatinib; D000077205:Pioglitazone
keywords: CYP2C8; drug-to-drug interaction; enzyme induction; fostamatinib; pharmacokinetics; pioglitazone