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Pharmacokinetic and Drug-Drug Interaction Profiles of the Combination of Tezacaftor/Ivacaftor.
- Source :
-
Clinical and translational science [Clin Transl Sci] 2019 May; Vol. 12 (3), pp. 267-275. Date of Electronic Publication: 2019 Jan 29. - Publication Year :
- 2019
-
Abstract
- Drug-drug interaction (DDI) studies are described for tezacaftor/ivacaftor, a new cystic fibrosis transmembrane conductance regulator modulator therapy for the treatment of cystic fibrosis. Three phase I DDI studies were conducted in healthy subjects to characterize the DDI profile of tezacaftor/ivacaftor with cytochrome P450 (CYP)3A substrates, CYP3A inhibitors, and a permeability glycoprotein (P-gp) substrate. The effects of steady-state tezacaftor/ivacaftor on the pharmacokinetics (PKs) of digoxin (a P-gp substrate), midazolam, and ethinyl estradiol/norethindrone (CYP3A substrates) were evaluated. Effects of strong (itraconazole) and moderate (ciprofloxacin) CYP3A inhibitors on tezacaftor/ivacaftor PKs were also determined. Tezacaftor/ivacaftor increased digoxin area under the curve (AUC) by 30% but did not affect midazolam, ethinyl estradiol, or norethindrone exposures. Itraconazole increased the AUC of tezacaftor 4-fold and ivacaftor 15.6-fold. Ciprofloxacin had no significant effect on tezacaftor or ivacaftor exposure. Coadministration of tezacaftor/ivacaftor may increase exposure of sensitive P-gp substrates. Tezacaftor/ivacaftor is unlikely to impact exposure of drugs metabolized by CYP3A, including hormonal contraceptives. Strong CYP3A inhibitors significantly increase the exposures of tezacaftor and ivacaftor.<br /> (© 2019 Vertex Pharmaceuticals, Incorporated. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)
- Subjects :
- ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism
Adolescent
Adult
Aminophenols blood
Benzodioxoles blood
Ciprofloxacin pharmacology
Cytochrome P-450 CYP3A Inhibitors pharmacology
Drug Interactions
Drug Therapy, Combination
Ethinyl Estradiol
Female
Humans
Indoles blood
Male
Middle Aged
Quinolones blood
Young Adult
Aminophenols pharmacokinetics
Benzodioxoles pharmacokinetics
Indoles pharmacokinetics
Quinolones pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1752-8062
- Volume :
- 12
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Clinical and translational science
- Publication Type :
- Academic Journal
- Accession number :
- 30694595
- Full Text :
- https://doi.org/10.1111/cts.12610