Clinical pharmacology of CFTR modulators

Abstract

With the development of cystic fibrosis transmembrane receptor (CFTR) modulating drugs, the landscape in cystic fibrosis (CF) care has changed dramatically. These drugs enable the treatment of the underlying cause of the disease. Although CFTR modulators show an impressive clincal effect at group level in people with CF (pwCF) with specific mutations, the individual effect is variable. In daily practice, more side effects of these drugs are observed than expected. The variability of clinical outcome between patients stresses the need to better understand the pharmacology of these drugs. In this thesis we studied several aspects of the clincal pharmacology of CFTR modulators, with a focus on pharmacokinetic aspects, variability between pwCF with different clinical phenotypes and drug-drug interactions. More than 1700 CFTR mutations lead to cystis fibrosis. CFTR modulators have been developed to revert the effects of the disease-causing mutations. Predicting the clinical response of a certain CFTR modulator (combination) in pwCF with a certain CFTR mutation is dfficult, especially for rare mutations. Rectal organoids, in vitro primary cell cultures, are developed and help in predicting drug response. The value of the use of organoid models in predicting treatment response is highlighted in one of our studies. The hypothesis of this study was based on in vitro data showing swelling of F508del/A455E organoids after incubation with lumacaftor/ivacaftor. Although the sample size was small and the study duration relatively short, the results suggest a clinical benefit from lumacaftor/ivacaftor in pwCF and a A455E mutation. Different features of CF disease may influence pharmacokinetic properties of drugs which may contribute to variation in drug exposure. In this thesis we included our review article in which features of CF disease are described that may change pharmacokinetic properties by changing the absorption, distribution, metabolism or elimination of CFTR modulating drugs. An important feature of many pwCF is pancreatic insufficiency and thereby fatmalabsorption. We hypothesized that the presence of fatmalabsorption may change the absorption and thereby exposure to CFTR modulators. We compared pharmacokinetic parameters of ivacaftor (one of the four currently available CFTR modulators) in a group of pancreas sufficient pwCF with a group of pancreas insufficient pwCF. Fatmalabsorption due to pancreatic insufficiency did not change the absorption or exposure to ivacaftor. As CFTR modulators are substrates of cytrochrome P450 3A4 (CYP3A4) and cytochrome P450 3A5 (CYP3A5), drug-drug interactions (DDI’s) with inhibitors or inducers of these enzymes may occur and thereby change drug exposure. In two of our studies drug-drug interactions between CFTR modulators and other drugs that are important in CF treatment were investigated. With these studies we obtained insight in how to manage these interactions in clinical practice. This opens doors for treatment with CFTR modulators for more pwCF. An important finding observed in our studies is the high variability of CFTR modulator exposure in pwCF using the same dosage. Future studies are needed to evaluate the usefulness of therapeutic drug monitorin of CFTR modulators to determine the optimal dosing regimen for each patient.