CFTR Modulators: Does One Dose Fit All?

Meer, Renske van der; Wilms, Erik B; Heijerman, H.G.M.

doi:10.3390/jpm11060458

Cited by 14 publications

(4 citation statements)

References 53 publications

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“…Other non-genetic factors affecting metabolism may result from inhibition or induction of metabolizing enzymes by drugs. Among the CFTR modulators, it is known that lumacaftor is an inducer of CyP450 3A enzymes, and that steady-state exposure of ivacaftor is reduced when administered in combination with lumacaftor [ 32 , 33 ]. In clinical settings, such an event can be assessed by Therapeutic Drug Monitoring (TDM), but unfortunately the measurement of plasma levels of modulators and their metabolites is far from being standard practice and is available only in very few laboratories.…”

Section: Discussionmentioning

confidence: 99%

The L467F-F508del Complex Allele Hampers Pharmacological Rescue of Mutant CFTR by Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis Patients: The Value of the Ex Vivo Nasal Epithelial Model to Address Non-Responders to CFTR-Modulating Drugs

Sondo

Cresta

Pastorino

et al. 2022

IJMS

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Loss-of-function mutations of the CFTR gene cause cystic fibrosis (CF) through a variety of molecular mechanisms involving altered expression, trafficking, and/or activity of the CFTR chloride channel. The most frequent mutation among CF patients, F508del, causes multiple defects that can be, however, overcome by a combination of three pharmacological agents that improve CFTR channel trafficking and gating, namely, elexacaftor, tezacaftor, and ivacaftor. This study was prompted by the evidence of two CF patients, compound heterozygous for F508del and a minimal function variant, who failed to obtain any beneficial effects following treatment with the triple drug combination. Functional studies on nasal epithelia generated in vitro from these patients confirmed the lack of response to pharmacological treatment. Molecular characterization highlighted the presence of an additional amino acid substitution, L467F, in cis with the F508del variant, demonstrating that both patients were carriers of a complex allele. Functional and biochemical assays in heterologous expression systems demonstrated that the double mutant L467F-F508del has a severely reduced activity, with negligible rescue by CFTR modulators. While further studies are needed to investigate the actual prevalence of the L467F-F508del allele, our results suggest that this complex allele should be taken into consideration as plausible cause in CF patients not responding to CFTR modulators.

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Section: Discussionmentioning

confidence: 99%

The L467F-F508del Complex Allele Hampers Pharmacological Rescue of Mutant CFTR by Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis Patients: The Value of the Ex Vivo Nasal Epithelial Model to Address Non-Responders to CFTR-Modulating Drugs

Sondo

Cresta

Pastorino

et al. 2022

IJMS

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“…According to the Italian legislative directives, in January 2022 TEZ-IVA, ELX/TEZ/IVA, and LUM/IVA therapies were prescribed to patients 1, 2, and 3, respectively, without modifying the physiotherapy program or the remaining therapies to which the patients were already subjected. The drugs were taken with fat-containing food to increase their bioavailability [36].…”

Section: Clinical Characteristics Of the Enrolled Patientsmentioning

confidence: 99%

Modulator Therapy in Cystic Fibrosis Patients with cis Variants in F508del Complex Allele: A Short-Term Observational Case Series

Terlizzi

Centrone

Ferrari

et al. 2022

JPM

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Previous studies reported the influence of cis variants in F508del cystic fibrosis (CF) patients in their responses to CFTR modulators. The current study is a prospective, observational study involving three patients with CF and pancreatic insufficiency, carrying a complex allele including F508del with A238V, I1027T, or L467F. We report clinical data before and after 4 weeks of treatment with tezacaftor (TEZ)/ivacaftor (IVA), elexacaftor (ELX)/TEZ/IVA, and lumacaftor (LUM)/IVA for patients with complex alleles A238V, I1027T, and L467F, respectively. The 50-year-old patient bearing F508del;A238V/D1152H showed a normal sweat test (13 mEq/L) and improvements in forced expiratory volume in the first second (FEV1) (+7 points), body mass index (BMI) (+0.85), and respiratory CF Questionnaire-Revised (CFQ-R) domain (+22.2 points). The 12-year-old patient bearing F508del;I1027T/R709X showed an improvement in a sweat test (−40 mEq/l), FEV1 (+9 points) and the respiratory CFQ-R domain (+16.7 points). No changes in outcomes were observed for the 6-year-old patient F508del;L467F/F508del. Our data highlight that the reported variants do not modify the phenotypic expression of F508del. Searching L467F is crucial in CF patients with F508del nonresponsive to ELX/TEZ/IVA. Further data are needed to evaluate the clinical effect of these variants after a longer follow up.

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“…High variability in treatment response has been found in patients with the same CFTR genotype and dosage regimen [29][30][31], suggesting that interindividual differences in pharmacokinetics per se are likely incriminated to explain, at least in part, such inconstancy in drug response.…”

Section: Pharmacokinetics-pharmacodynamics Of Cftr Modulator Drugsmentioning

confidence: 99%

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

et al. 2022

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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.

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CFTR Modulators: Does One Dose Fit All?

Cited by 14 publications

References 53 publications

The L467F-F508del Complex Allele Hampers Pharmacological Rescue of Mutant CFTR by Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis Patients: The Value of the Ex Vivo Nasal Epithelial Model to Address Non-Responders to CFTR-Modulating Drugs

The L467F-F508del Complex Allele Hampers Pharmacological Rescue of Mutant CFTR by Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis Patients: The Value of the Ex Vivo Nasal Epithelial Model to Address Non-Responders to CFTR-Modulating Drugs

Modulator Therapy in Cystic Fibrosis Patients with cis Variants in F508del Complex Allele: A Short-Term Observational Case Series

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

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