Kalydeco(ivacaftor)的药物相互作用是什么？

(ivacaftor) has drug interactions with CYP3A inhibitors, CYP3A inducers, ciprofloxacin, CYP2C9 substrates, CYP3A and/or P-gp substrates. Drug interactions may reduce or enhance the efficacy of the drug. Understanding interactions can help ensure that the drug works optimally.

About Kalydeco(ivacaftor)

Kalydeco is the first oral preparation launched by Vertex Pharmaceuticals to treat CFTR gene mutations, and its generic name is ivacaftor. (ivacaftor, also known as VX-770) is mainly suitable for cystic fibrosis (CF) patients 4 months or older with gated mutations (Class III mutations, accounting for about 5% of the total). Its mutation sites include G551D, G1244E, G1349D, G178R, G551s, S1251N, S1255P, S549N, and S549R. In addition, it also has a certain therapeutic effect on cystic fibrosis (CF) caused by R117H mutation (a class IV mutation).

The possibility of other drugs affecting Kalydeco (ivacaftor)

1. CYP3A inhibitors

Ivacaftor is a sensitive CYP3A substrate. Coadministration with ketoconazole, a potent CYP3A inhibitor, significantly increased ivacaftor exposure by 8.5-fold. Based on modeling of these results, a dose reduction of KALYDECO is recommended for patients 6 months and older who are receiving concomitant strong CYP3A inhibitors (such as ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin). KALYDECO is not recommended for patients younger than 6 months of age who are taking strong CYP3A inhibitors.

Coadministration with fluconazole, a moderate inhibitor of CYP3A, increased ivacaftor exposure by 3-fold. Therefore, a reduced KALYDECO dose is recommended for patients 6 months and older who are receiving concomitant moderate inhibitors of CYP3A (such as fluconazole and erythromycin). KALYDECO is not recommended for patients younger than 6 months of age who are taking moderate inhibitors of CYP3A.

Coadministration of KALYDECO with grapefruit juice (which contains one or more components that moderately inhibit CYP3A) may increase ivacaftor exposure. Therefore, avoid foods or drinks containing grapefruit during treatment with KALYDECO.

2. CYP3A inducers

Coadministration with rifampicin, a strong CYP3A inducer, significantly decreased ivacaftor exposure (AUC) by approximately 9-fold. Therefore, coadministration with strong CYP3A inducers such as rifampicin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John's wort is not recommended.

3. Ciprofloxacin

Coadministration of KALYDECO with ciprofloxacin had no effect on ivacaftor exposure. Therefore, no dose adjustment is required during coadministration of KALYDECO with ciprofloxacin.

The possibility of Kalydeco(ivacaftor) affecting other medicines

1. CYP2C9 substrate

Ivacaftor may inhibit CYP2C9; therefore, monitoring of the international normalized ratio (INR) is recommended during coadministration of KALYDECO with warfarin. Other therapeutic products that may increase exposure to KALYDECO include glimepiride and glipizide; these therapeutic products should be used with caution.

2. CYP3A and/or P-gp substrate

Ivacaftor and its M1 metabolite may inhibit CYP3A and P-gp. Coadministration with oral midazolam, a sensitive CYP3A substrate, increased midazolam exposure by 1.5-fold, consistent with ivacaftor's weak inhibitory effect on CYP3A.

Coadministration with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold, consistent with the weak inhibitory effect of ivacaftor on P-gp. Administration of KALYDECO may increase the systemic exposure of drugs that are CYP3A and/or P-gp substrates, thereby increasing or prolonging their therapeutic effects and adverse events. Therefore, caution and appropriate monitoring are recommended when KALYDECO is coadministered with sensitive CYP3A and/or P-gp substrates such as digoxin, cyclosporine, and tacrolimus.

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