Pharmacokinetic and Drug-Drug Interaction Profiles of the Combination of Tezacaftor/Ivacaftor.

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Garg V, Shen J, Li C, Agarwal S, Gebre A, Robertson S, Huang J, Han L, Jiang L, Stephan K, Wang LT, Lekstrom-Himes J

Pharmacokinetic and Drug-Drug Interaction Profiles of the Combination of Tezacaftor/Ivacaftor.

Clin Transl Sci. 2019 May;12(3):267-275. doi: 10.1111/cts.12610. Epub 2019 Jan 29.

PubMed ID

30694595 [ View in PubMed

]

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.

DrugBank Data that Cites this Article

Drugs

Tezacaftor

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Tezacaftor	Cytochrome P450 3A4	Protein	Humans	No	Substrate Inhibitor Inducer	Details
Tezacaftor	Cytochrome P450 3A5	Protein	Humans	No	Substrate Inducer	Details

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Tezacaftor	P-glycoprotein 1	Protein	Humans	No	Substrate Inhibitor	Details

Drug Reactions

Reaction
Tezacaftor DB11712 Cytochrome P450 3A5 Cytochrome P450 3A4 M1 Metabolite, Tezacaftor DBMET02579 M2 Metabolite, Tezacaftor DBMET02580 M5 metabolite, Tezacaftor DBMET02581	Details

Drug Interactions

Drugs	Interaction
Integrate drug-drug interactions in your software
Digoxin Tezacaftor	The serum concentration of Digoxin can be increased when it is combined with Tezacaftor.
Tezacaftor Ritonavir	The metabolism of Tezacaftor can be decreased when combined with Ritonavir.
Tezacaftor Ketoconazole	The metabolism of Tezacaftor can be decreased when combined with Ketoconazole.
Tezacaftor Nefazodone	The metabolism of Tezacaftor can be decreased when combined with Nefazodone.
Tezacaftor Itraconazole	The metabolism of Tezacaftor can be decreased when combined with Itraconazole.