PMID- 36866442 OWN - NLM STAT- MEDLINE DCOM- 20230421 LR - 20230503 IS - 1875-9114 (Electronic) IS - 0277-0008 (Linking) VI - 43 IP - 4 DP - 2023 Apr TI - Safety of elexacaftor/tezacaftor/ivacaftor dose reduction: Mechanistic exploration through physiologically based pharmacokinetic modeling and a clinical case series. PG - 291-299 LID - 10.1002/phar.2786 [doi] AB - INTRODUCTION: Elexacaftor/tezacaftor/ivacaftor (ETI) treatment is associated with significant improvement in lung function in people with cystic fibrosis (pwCF); however, some patients experience adverse effects (AEs) including hepatotoxicity. One potential strategy is dose reduction in ETI with the goal of maintaining therapeutic efficacy while resolving AEs. We report our experience of dose reduction in individuals who experienced AEs following ETI therapy. We provide mechanistic support for ETI dose reduction by exploring predicted lung exposures and underlying pharmacokinetics-pharmacodynamics (PK-PD) relationships. METHOD: Adults prescribed ETI who underwent dose reduction due to the AEs were included in this case series, and their percent predicted forced expiratory volume in 1 s (ppFEV(1) ) and self-reported respiratory symptoms were collected. The full physiologically based pharmacokinetic (PBPK) models of ETI were developed incorporating physiological information and drug-dependent parameters. The models were validated against available pharmacokinetic and dose-response relationship data. The models were then used to predict lung concentrations of ETI at steady-state. RESULTS: Fifteen patients underwent dose reduction in ETI due to AEs. Clinical stability without significant changes in ppFEV(1) after dose reduction was observed in all patients. Resolution or improvement of AEs occurred in 13 of the 15 cases. The model-predicted lung concentrations of reduced dose ETI exceeded the reported half maximal effective concentration (EC(50) ) from measurement of in vitro chloride transport, providing a hypothesis as to why therapeutic efficacy was maintained. CONCLUSION: Albeit in a small number of patients, this study provides evidence that reduced ETI doses in pwCF who have experienced AEs may be effective. The PBPK models enable exploration of a mechanistic basis for this finding by simulating target tissue concentrations of ETI that can be compared with drug efficacy in vitro. CI - (c) 2023 The Authors. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy published by Wiley Periodicals LLC on behalf of Pharmacotherapy Publications, Inc. FAU - Hong, Eunjin AU - Hong E AUID- ORCID: 0000-0002-6696-3948 AD - Department of Clinical Pharmacy, USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, California, Los Angeles, USA. FAU - Li, Regina AU - Li R AD - Department of Clinical Pharmacy, USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, California, Los Angeles, USA. FAU - Shi, Alan AU - Shi A AD - Department of Clinical Pharmacy, USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, California, Los Angeles, USA. FAU - Almond, Lisa M AU - Almond LM AD - Simcyp Division, Certara UK Ltd, Sheffield, UK. FAU - Wang, Joshua AU - Wang J AD - Division of Pulmonary and Critical Care Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. AD - USC Anton Yelchin CF Clinic, Los Angeles, California, USA. FAU - Khudari, Amin Z AU - Khudari AZ AD - Department of Clinical Pharmacy, USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, California, Los Angeles, USA. FAU - Haddad, Soumar AU - Haddad S AD - Department of Clinical Pharmacy, USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, California, Los Angeles, USA. FAU - Sislyan, Sarkis AU - Sislyan S AD - Department of Clinical Pharmacy, USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, California, Los Angeles, USA. FAU - Angelich, Marissa AU - Angelich M AD - Department of Clinical Pharmacy, USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, California, Los Angeles, USA. FAU - Chung, Peter S AU - Chung PS AD - Division of Pulmonary and Critical Care Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. AD - USC Anton Yelchin CF Clinic, Los Angeles, California, USA. FAU - Rao, Adupa P AU - Rao AP AD - Division of Pulmonary and Critical Care Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. AD - USC Anton Yelchin CF Clinic, Los Angeles, California, USA. FAU - Beringer, Paul M AU - Beringer PM AUID- ORCID: 0000-0002-3744-3310 AD - Department of Clinical Pharmacy, USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, California, Los Angeles, USA. AD - USC Anton Yelchin CF Clinic, Los Angeles, California, USA. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230312 PL - United States TA - Pharmacotherapy JT - Pharmacotherapy JID - 8111305 RN - RRN67GMB0V (elexacaftor) RN - 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator) RN - 1Y740ILL1Z (ivacaftor) RN - 0 (tezacaftor) SB - IM MH - Adult MH - Humans MH - *Cystic Fibrosis Transmembrane Conductance Regulator/genetics/therapeutic use MH - Drug Tapering MH - *Cystic Fibrosis/drug therapy MH - Mutation OTO - NOTNLM OT - adverse events OT - cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy OT - dose reduction OT - pharmacology OT - physiologically based pharmacokinetic (PBPK) EDAT- 2023/03/04 06:00 MHDA- 2023/04/21 06:41 CRDT- 2023/03/03 03:03 PHST- 2023/02/09 00:00 [revised] PHST- 2023/01/10 00:00 [received] PHST- 2023/02/11 00:00 [accepted] PHST- 2023/04/21 06:41 [medline] PHST- 2023/03/04 06:00 [pubmed] PHST- 2023/03/03 03:03 [entrez] AID - 10.1002/phar.2786 [doi] PST - ppublish SO - Pharmacotherapy. 2023 Apr;43(4):291-299. doi: 10.1002/phar.2786. Epub 2023 Mar 12.