The Effects of Weak and Strong CYP3A Induction by Rifampicin on the Pharmacokinetics of Five Progestins and Ethinylestradiol Compared to Midazolam.
Clin Pharmacol Ther
; 108(4): 798-807, 2020 10.
Article
em En
| MEDLINE
| ID: mdl-32275771
ABSTRACT
It is known that co-administration of CYP3A inducers may decrease the effectiveness of oral contraceptives containing progestins as mono-preparations or combined with ethinylestradiol. In a randomized clinical drug-drug interaction study, we investigated the effects of CYP3A induction on the pharmacokinetics of commonly used progestins and ethinylestradiol. Rifampicin was used to induce CYP3A. The progestins chosen as victim drugs were levonorgestrel, norethindrone, desogestrel, and dienogest as mono-products, and drospirenone combined with ethinylestradiol. Postmenopausal women (n = 12-14 per treatment group) received, in fixed sequence, a single dose of the victim drug plus midazolam without rifampicin, with rifampicin 10 mg/day (weak induction), and with rifampicin 600 mg/day (strong induction). The effects on progestin exposure were compared with the effects on midazolam exposure (as a benchmark). Unbound concentrations were evaluated for drugs binding to sex hormone binding globulin. Weak CYP3A induction, as confirmed by a mean decrease in midazolam exposure by 46%, resulted in minor changes in progestin exposure (mean decreases 15-37%). Strong CYP3A induction, in contrast, resulted in mean decreases by 57-90% (mean decrease in midazolam exposure 86%). Namely, the magnitude of the observed induction effects varied from weak to strong. Our data might provide an impetus to revisit the currently applied clinical recommendations for oral contraceptives, especially for levonorgestrel and norethindrone-containing products, and they might give an indication as to which progestin could be used, if requested, by women taking weak CYP3A inducers-although it is acknowledged that the exact exposure-response relationship for contraceptive efficacy is currently unclear for most progestins.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Progestinas
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Rifampina
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Midazolam
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Anticoncepcionais Orais Hormonais
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Citocromo P-450 CYP3A
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Etinilestradiol
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Indutores do Citocromo P-450 CYP3A
Tipo de estudo:
Clinical_trials
/
Etiology_studies
/
Guideline
/
Risk_factors_studies
Limite:
Aged
/
Female
/
Humans
/
Middle aged
País/Região como assunto:
Europa
Idioma:
En
Revista:
Clin Pharmacol Ther
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Alemanha