Effect of Steady-State Faldaprevir on Pharmacokinetics of Atorvastatin or Rosuvastatin in Healthy Volunteers: A Prospective Open-Label, Fixed-Sequence Crossover Study.
J Clin Pharmacol
; 57(10): 1305-1314, 2017 10.
Article
em En
| MEDLINE
| ID: mdl-28513969
ABSTRACT
Faldaprevir (FDV) is a potent, orally administered inhibitor of hepatitis C virus protease. It inhibits multiple cytochrome P-450 enzymes and multiple membrane transporters. The objective of this study was to evaluate the effect of steady-state faldaprevir on the pharmacokinetics (PK) of a single dose of atorvastatin or rosuvastatin. In this single-center, open-label, fixed-sequence crossover study, 33 healthy adult male and female volunteers were given either atorvastatin 10 mg (n = 16) or rosuvastatin 10 mg (n = 17) on day 1. Subjects subsequently received 240 mg twice daily of faldaprevir (loading dose) on day 5, followed by 240 mg faldaprevir once daily from day 6 to day 10, with an additional single dose of atorvastatin (10 mg) or rosuvastatin (10 mg) given on day 10. PK samples for the statins were collected on days 1-3 and days 10-12. Concomitant administration with faldaprevir led to approximately 9-fold and 34-fold increases in AUC0-∞ and Cmax , respectively, of atorvastatin and approximately 15-fold and 33-fold increases in AUC0-∞ and Cmax , respectively, of rosuvastatin, compared with the statins given alone. Exposure to the major metabolites (ortho-hydroxyatorvastatin and N-desmethylrosuvastatin) was increased to a similar magnitude as that of the parent compounds. The marked drug-drug interaction observed is most likely related to the inhibitory effects of faldaprevir on transporters, particularly hepatic uptake transporters such as OTAP1B1 and OATP1B3. Given the significant increase in exposure to statins in healthy volunteers, coadministration of faldaprevir with statins should be avoided.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Antivirais
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Oligopeptídeos
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Tiazóis
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Inibidores de Serina Proteinase
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Inibidores de Hidroximetilglutaril-CoA Redutases
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Rosuvastatina Cálcica
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Atorvastatina
Tipo de estudo:
Clinical_trials
Limite:
Adult
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
J Clin Pharmacol
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Estados Unidos