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

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.

Figure 1

VX14‐661‐006 study design. Coadministration of TEZ/IVA With itraconazole, midazolam, and digoxin. TEZ/IVA was administered within 30 minutes of starting a breakfast (morning dose). Itraconazole was administered in the fasting state. Digoxin was administered 1 hour after midazolam dosing. Samples were collected before the morning dose unless otherwise noted. ^aAn additional dose of itraconazole 200 mg was administered on day 15. *Denotes the day of intensive PK sampling; PK samples were drawn after TEZ/IVA administration at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours; after itraconazole administration at 2 hours; after midazolam administration at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours; and after digoxin administration at 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12, 24, 48, 72, 96, and 120 hours. ^†Time increments for urine collection were 0–6, 6–12, 12–24, 24–48, 48–72, 72–96, and 96–120 hours. IVA, ivacaftor; PK, pharmacokinetic; TEZ, tezacaftor.

Figure 2

VX15‐661‐008 study design. Coadministration of TEZ/IVA with ethinyl estradiol/norethindrone. Samples were collected before the morning dose unless otherwise noted. ^aCOC was administered for the first 21 days of the cycle, and an inert tablet was administered for the subsequent 7 days, consistent with prescribing information. *Denotes the day of intensive PK sampling; PK samples were drawn after TEZ/IVA administration at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours and after COC administration at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours. On days of intensive PK sampling, subjects abstained from all food and drink (except water) for at least 8 hours before the start of the morning meal (except as permitted for dosing). TEZ/IVA was administered as a fixed‐dose combination tablet containing TEZ 100 mg/IVA 150 mg in the morning and an IVA 150 mg tablet in the evening. Study drugs (EE/NE, TEZ, and IVA) were administered within 30 minutes after starting a standard meal except on days of intensive PK sampling. On days of intensive PK sampling (days 21, 29, 49, and 56), subjects abstained from all food and drink (except water) for at least 8 hours before the start of the morning meal (to be consumed within 30 minutes). COC, combined oral contraceptive; EE, ethinyl estradiol; IVA, ivacaftor; NE, norethindrone; PK, pharmacokinetics; TEZ, tezacaftor.

Figure 3

VX12‐770‐017 study design. Coadministration of TEZ/IVA with ciprofloxacin. Study drug was administered within 30 minutes after a standard meal. Samples were collected before the morning dose unless otherwise noted. *Denotes the day of intensive PK sampling; PK samples were drawn after TEZ/IVA administration at 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 hours. IVA, ivacaftor; PK, pharmacokinetics; TEZ, tezacaftor.

Figure 4

Mean (SD) plasma concentration‐vs.‐time profiles of tezacaftor, ivacaftor, and their metabolites at steady‐state dosing in the absence or presence of itraconazole. Representative data are from study 006 cohort 1. PK profiles are presented for administration of TEZ 25 mg q.d./IVA 50 mg q.d. in the absence (open circles) or presence (closed circles) of itraconazole. For the closed circles, days 12–14 correspond to period 2, days 26–28 (coadministration of itraconazole). IVA, ivacaftor; PK, pharmacokinetic; TEZ, tezacaftor.