Abstract
For many people with cystic fibrosis (pwCF), CFTR modulators will be the cornerstone of their treatment. These modulators show robust treatment effects at group level in pwCF with specific mutations. The individual effect however, is variable. In this review we will explain reasons for reconsideration of dosing regimens of CFTR modulating therapy in order to improve treatment response and prevent side effects. Since the effect of a drug depends on pharmacodynamics and pharmacokinetics, pharmacodynamics and pharmacokinetic properties of CFTR modulators will be discussed. Pharmacokinetic-pharmacodynamic relationships will be used to gain insight in dosage response and exposure response relationships. To understand the cause of variation in drug exposure, pharmacokinetic properties that may change due to CF disease will be explained. We show that with current insight, there are conceivable situations that give reason for reconsideration of dosing regimens, however many questions need to be unravelled.
Highlights
Elexacaftor/tezacaftor/ivacaftor was shown to be efficacious in people with cystic fibrosis (pwCF) with phe508del-minimal function (MF) genotypes, in whom previous CFTR modulator regimens were ineffective
Dosing regimens of approved CFTR modulators are based on pharmacodynamic effects in vitro, serum pharmacokinetic studies, and early dose ranging studies
Plasma and Cellular Drug Concentrations. For drugs such as CFTR modulators that act within cells, intra cellular concentrations would ideally be obtained to be related to treatment effect
Summary
Cystic fibrosis (CF) is a chronic, hereditary, multi-organ disease caused by absence or dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein [1]. CFTR function either through potentiation of the abnormal protein channel at the cell surface (ivacaftor), or through correction of protein transport to the cell surface (lumacaftor, tezacaftor, elexacaftor) These treatments have been approved by the European. Elexacaftor/tezacaftor/ivacaftor was shown to be efficacious in pwCF with phe508del-minimal function (MF) genotypes, in whom previous CFTR modulator regimens were ineffective. For this genotype, Middleton et al showed a 13.8 points higher ppFEV1 at 4 weeks and 13.4 points through week 24 compared to placebo [3]. Heijerman et al, showed the individual repsonse to elexacaftor/tezacaftor/ivacaftor treatment in the supplementary figures, with a change in ppFEV1 ranging from −2.5% to >+20% [2]. In the final part of this review we will discuss remaining questions which need to be resolved in order to determine if current dosing strategies can be applied to all patients or need reconsideration in certain patient groups
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