Treatment complexity in cystic fibrosis (CF): An increasing multifaceted challenge

Abstract

The study by Bruch et al 1 describes one center's experience with the potential therapeutic implications of a drug interaction between lumacaftor/ivacaftor and ibuprofen, based on concerns about in vitro data suggesting that lumacaftor acts as a strong inducer of CYP3A4 enzymes, potential inducer of CYP2B6, CYP2C8, CYP2C9, and CYP2C19 enzymes, and inhibitor of CYP2C8 and CYP2C9 enzymes. 2,3 Given the increasing availability and development of cystic fibrosis transmembrane regulator protein (CFTR) modulators and other therapeutic agents, this study is both timely and important. It demonstrates that with added treatment options also comes the need to consider possible, less known drug interactions-one of several potential consequences from increased treatment complexity.

Cystic fibrosis: novel therapies, remaining challenges

“…Despite this, UK, US and Australian guidelines for CF clinics state pharmacists remain ‘recommended’ as part of the multidisciplinary clinic as opposed to mandatory for some other allied health disciplines. The high cost, complex dosing and interactions and high patient expectations of the CFTR agents, plus concerns regarding treatment burden and adherence to other CF medicines, are all areas in which pharmacists can and should play a crucial role …”

“…The high cost, complex dosing and interactions and high patient expectations of the CFTR agents, plus concerns regarding treatment burden and adherence to other CF medicines, are all areas in which pharmacists can and should play a crucial role. 41 The accelerating development of novel therapies presents enormous opportunities and challenges for pharmacy. Pharmacy needs to demonstrate its role in optimising medication management in this setting before being recognised as a vital part of the CF clinic.…”

Multitarget CFTR Modulators Endowed with Multiple Beneficial Side Effects for Cystic Fibrosis Patients: Toward a Simplified Therapeutic Approach

“…This complex regimen, combined with patients' comorbidities, makes therapeutic burden and drug-drug interactions important issues in CF care. [8][9][10][11] Over the years, there has been an intensive effort to find drugs acting on the root cause of the disease: lumacaftor (VX-809) and tezacaftor (VX-661) are pharmacological chaperones that correct the folding defect and improve trafficking of the , while ivacaftor (VX-770) is a small molecule acting as a potentiator of the channel's conductance. [12][13][14] However, F508del-CFTR patients do not benefit from monotherapy with these agents, providing only ~4% improvement in lung function measured as improvement in FEV1 percentage predicted.…”

“…CF epithelial cell vulnerability and dysregulation of the local inflammatory responses lead to more severe viral infections and appear to render the airway even more prone to bacterial infection, leading to pulmonary exacerbations that accelerate disease progression, impair quality of life, and increase hospitalization and mortality rate. − To reduce symptoms and slow organ deterioration, patients receive multiple treatments (antibiotics, steroids, mucolytics, bronchodilators, pancreatic enzymes) and undergo a daily physical exercise regimen including physiotherapy to loosen and remove airway mucus. This complex regimen, combined with patients’ comorbidities, makes therapeutic burden and drug–drug interactions important issues in CF care. − Over the years, there has been an intensive effort to find drugs acting on the root cause of the disease: lumacaftor (VX-809) and tezacaftor (VX-661) are pharmacological chaperones that correct the folding defect and improve trafficking of the mutant, while ivacaftor (VX-770) is a small molecule acting as a potentiator of the channel’s conductance. − However, F508del-CFTR patients do not benefit from monotherapy with these agents, providing only ∼4% improvement in lung function measured as improvement in the FEV1 percentage predicted. On the other hand, the combination of a corrector (lumacaftor) with a potentiator (ivacaftor), marketed as Orkambi, has provided minimal health benefits for people aged 12 and older, who were homozygous for the F508del-CFTR mutation .…”