Therapeutic Drug Monitoring of Ivacaftor, Lumacaftor, Tezacaftor, and Elexacaftor in Cystic Fibrosis: Where Are We Now?

Abstract

Drugs modulating the cystic fibrosis transmembrane conductance regulator (CFTR) protein, namely ivacaftor, lumacaftor, tezacaftor, and elexacaftor, are currently revolutionizing the management of patients with cystic fibrosis (CF), particularly those with at least one F508del variant (up to 85% of patients). These “caftor” drugs are mainly metabolized by cytochromes P450 3A, whose enzymatic activity is influenced by environmental factors, and are sensitive to inhibition and induction. Hence, CFTR modulators are characterized by an important interindividual pharmacokinetic variability and are also prone to drug–drug interactions. However, these CFTR modulators are given at standardized dosages, while they meet all criteria for a formal therapeutic drug monitoring (TDM) program that should be considered in cases of clinical toxicity, less-than-expected clinical response, drug or food interactions, distinct patient subgroups (i.e., pediatrics), and for monitoring short-term adherence. While the information on CFTR drug exposure–clinical response relationships is still limited, we review the current evidence of the potential interest in the TDM of caftor drugs in real-life settings.

Real-life impact of highly effective CFTR modulator therapy in children with cystic fibrosis

“…All CFTR modulators are metabolized by the CYP3A4 und CYP3A5 pathway, for which extensive pharmacogenetic heterogeneity exists. At this time, there is scarce information on drug plasma levels and their potential role in explaining side effects ( Choong et al, 2022 ). In our study, only three patients needed to reduce the ETI dose because of hepatic toxicity.…”

Therapeutic Drug Monitoring and Pharmacokinetics-Based Individualization of Drug Therapy

“…In another article, an overview is provided of current knowledge regarding the therapeutic monitoring of these substances in peripheral fluid spaces (contribution 21). Comprehensive updates are presented on the monitoring of cystic fibrosis transmembrane conductance regulators (CFTCRs) as well as of biological therapy substances applicable against non-infectious uveitis in contributions (22) and (23). Finally, a review of the most recent literature of TDM in psychiatry, starting with the publication of the latest update of the widely accepted guidelines of the Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie, is delivered [2].…”

Cystic fibrosis: comorbidity with other serious diseases

“…Муковисцидоз (МВ) (CF, Cystic fibrosis; OMIM: 219700) -частое наследственное моногенное заболевание (1:2500 новорожденных в Европе и 1:9-10 000 в РФ), обусловленное мутациями в гене CFTR [1][2][3][4][5]. Для РФ характерно самое высокое разнообразие генетических вариантов CFTR, наличие генетических вариантов, редко встречающихся в мире и высокая частота мутаций, встречающихся однократно, из которых преобладают мутации, не входящие в международные базы данных [1].…”