Insights Into Patient Variability During Ivacaftor-Lumacaftor Therapy in Cystic Fibrosis.

Patrick O Hanafin,John Wilson,Helmut Ellemunter,Tony Velkov,Carsten Schwarz,Matthias Griese,Marsha Tan,Matthias Kappler,Elena K Schneider-Futschik,Isabelle Sermet-Gaudelus,Gauri G Rao

doi:10.3389/fphar.2021.577263

Abstract

Background: The advent of cystic fibrosis transmembrane conductance regulator protein (CFTR) modulators like ivacaftor have revolutionised the treatment of cystic fibrosis (CF). However, due to the plethora of variances in disease manifestations in CF, there are inherent challenges in unified responses under CFTR modulator treatment arising from variability in patient outcomes. The pharmacokinetic (PK) data available for ivacaftor-lumacaftor cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator drug combination is limited.Methods: Secondary objectives were to identify (1) patient characteristics and (2) the interactions between ivacaftor-lumacaftor responsible for interindividual variability (IIV).Results: Peak plasma concentrations (Cmax) of ivacaftor - lumacaftor were >10 fold lower than expected compared to label information. The one-way ANOVA indicated that the patient site had an effect on Cmax values of ivacaftor metabolites ivacaftor-M1, ivacaftor-M6, and lumacaftor (p < 0.001, p < 0.001, and p < 0.001, respectively). The Spearman’s rho test indicated that patient weight and age have an effect on the Cmax of lumacaftor (p = 0.003 and p < 0.001, respectively) and ivacaftor metabolite M1 (p = 0.020 and p < 0.001, respectively). Age (p < 0.001) was found to effect on Cmax of ivacaftor M6 and on Tmax of ivacaftor M1 (p = 0.026). A large impact of patient characteristics on the IIV of PK parameters Cmax and Tmax, was observed among the CF patients.Conclusion: Understanding the many sources of variability can help reduce this individual patient variability and ensure consistent patient outcomes.

Highlights

Cystic fibrosis (CF) is an autosomal recessive genetic disorder that affects chloride transport throughout the epithelial cells of the body, resulting in abnormalities in the respiratory, endocrine, gastrointestinal, and reproductive systems (Condren and Bradshaw, 2013; Tan et al, 2020)
Drug action is the function of the net absorption, distribution, metabolism, excretion and interactions with target sites which are influenced by genetic factors (Dubovsky, 2015)
In CF care, screening for potential drug-drug interactions is of the paramount importance to identify and potentially substitute co-medications that alter drug bioavailability via cytochrome P450 (CYP450) induction or inhibition of CYP450

Summary

Introduction

Cystic fibrosis (CF) is an autosomal recessive genetic disorder that affects chloride transport throughout the epithelial cells of the body, resulting in abnormalities in the respiratory, endocrine, gastrointestinal, and reproductive systems (Condren and Bradshaw, 2013; Tan et al, 2020). The dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) channel causes dehydration of mucosal surfaces subsequently increasing viscous mucus that obstructs luminal compartments in lung, pancreas and intestine (Elborn, 2016; Schneider et al, 2017a). The discovery and development of CFTR modulators that directly influence the dysfunctional chloride channel has had a significant impact on CF treatment world-wide (Ghelani and Schneider-Futschik, 2019; Schneider-Futschik, 2019; Allobawi et al, 2020). The advent of cystic fibrosis transmembrane conductance regulator protein (CFTR) modulators like ivacaftor have revolutionised the treatment of cystic fibrosis (CF). The pharmacokinetic (PK) data available for ivacaftor-lumacaftor cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator drug combination is limited

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