Effects of Fostamatinib on the Pharmacokinetics of the CYP2C8 Substrate Pioglitazone: Results From In Vitro and Phase 1 Clinical Studies.
Clin Pharmacol Drug Dev
; 5(3): 170-9, 2016 May.
Article
en En
| MEDLINE
| ID: mdl-27163495
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Oxazinas
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Piridinas
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Tiazolidinedionas
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Citocromo P-450 CYP2C8
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Inductores de las Enzimas del Citocromo P-450
Tipo de estudio:
Prognostic_studies
Límite:
Adult
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Humans
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Male
/
Middle aged
Idioma:
En
Revista:
Clin Pharmacol Drug Dev
Año:
2016
Tipo del documento:
Article
Pais de publicación:
Estados Unidos