ECFS 2020 - Optimizing pharmaceutical care in cystic fibrosis

European Cystic Fibrosis Society   287  CHAPTER 17 Interactions in patients on CFTR modulators, a case study Author Anna Connolly Introduction The development and introduction of cystic fibrosis transmembrane conduct- ance regulator (CFTR) modulator therapies has been described as the dawn of a new therapeutic era within cystic fibrosis (CF) patient care. These medications target the basic molecular defect in specific CF muta- tions. Currently, the European Medicines Agency (EMA) has licensed three CFTR modulator therapies: ivacaftor monotherapy (Kalydeco), lumacaftor/ivacaftor (Orkambi), and tezacaftor/ivacaftor (Symkevi) taken in combination with ivacaftor. In October 2019, the U.S. Food and Drug Administra- tion (FDA) approved Trikafta (elexacaftor/ ivacaftor/tezacaftor), the first triple combi- nation CFTR modulator therapy. As these agents are used chronically and regular CF treatments continue concurrently, it is important that clinicians and pharmacists are aware of the potential impact of drug- drug interactions [1]. 1 CFTR modulators 1.1. Ivacaftor Ivacaftor is a sensitive CYP3A substrate. Co-administration of ivacaftor with strong CYP3A inducers (e.g. rifampicin) is not recommended due to decreased ivacaftor exposure. Co-administration with strong CYP3A inhibitors (e.g. voriconazole) and moderate CYP3A inhibitors (e.g. flucona- zole) increases ivacaftor exposure, and a dose adjustment is recommended. Grape- fruit juice and Seville oranges should be avoided during treatment with ivacaftor. They may increase exposure to ivacaftor due to moderate inhibition of CYP3A. Ivacaftor may inhibit CYP2C9. Therefore, monitoring of the international normalized ratio (INR) is recommended during co-administration of warfarin with ivacaftor. Ivacaftor is a weak inhibitor of P-glycoprotein (P-gp), therefore concomitant use with P-gp substrates (e.g. digoxin) may alter the exposure of these substrates [2]. 1.2. Lumacaftor/ ivacaftor Lumacaftor is a strong inducer of CYP3A and ivacaftor is a weak inhibitor of CYP3A when given as monotherapy. No dose adjustment is necessary when CYP3A