Open AccessPharmacokinetic and Drug–Drug Interaction Profiles of the Combination of Tezacaftor/Ivacaftor
Author(s) -
Garg Varun,
Shen Jinshan,
Li Chonghua,
Agarwal Sagar,
Gebre Asfiha,
Robertson Sarah,
Huang Jiayin,
Han Linda,
Jiang Licong,
Stephan Kristin,
Wang Linda T.,
LekstromHimes Julie
Publication year - 2019
Publication title -
clinical and translational science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.303
H-Index - 44
eISSN - 1752-8062
pISSN - 1752-8054
DOI - 10.1111/cts.12610
Subject(s) - ivacaftor , pharmacology , medicine , norethisterone , pharmacokinetics , combination therapy , nonmem , cystic fibrosis , cystic fibrosis transmembrane conductance regulator , population , environmental health , research methodology
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, CYP 3A inhibitors, and a permeability glycoprotein (P‐gp) substrate. The effects of steady‐state tezacaftor/ivacaftor on the pharmacokinetics ( PK s) of digoxin (a P‐gp substrate), midazolam, and ethinyl estradiol/norethindrone ( CYP 3A substrates) were evaluated. Effects of strong (itraconazole) and moderate (ciprofloxacin) CYP 3A inhibitors on tezacaftor/ivacaftor PK s 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 CYP 3A, including hormonal contraceptives. Strong CYP 3A inhibitors significantly increase the exposures of tezacaftor and ivacaftor.