Introduction
Combination therapy with the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) corrector lumacaftor and the CFTR potentiator ivacaftor has demonstrated reduction of pulmonary exacerbations and a gain of body weight and lung function in Phe508del homozygous people with CF [1, 2]. We could previously show that lumacaftor-ivacaftor improves CFTR function determined by nasal potential difference (NPD) and intestinal current measurement (ICM) to 10 to 20% of normal CFTR activity. This effect on CFTR function was observed even in the absence of short term effects on lung function [9] Whilst the effects of lumacaftor/ivacaftor therapy on numerous facets of basic defect and clinical disease have been reported [3], published information about the pharmacokinetics of the drugs, the association of drug concentration in tissues and body fluids with clinical outcome and the relationship between serum concentrations and the effect on CFTR function remain scarce [ 4- 7, 12].
Lumacaftor and ivacaftor are subject to clinically relevant drug-drug interactions between the CFTR modulators themselves and other concomitant medications used by people with CF. Lumacaftor is a CYP3A4/2C8/2C9/2C19 inducer and thus influences the turnover of ivacaftor, a CYP3A4 substrate [8]. Moreover, the two CFTR modulators are highly hydrophobic compounds. Consequently the tissue distribution of the drugs will depend on the body composition of fat, muscles and water which is highly variable among CF patients depending on the extent of malabsorption and its nutritional management and physical activity.
In a prospective observational study we have examined clinical outcomes and biomarkers of CFTR function in Phe508del homozygous CF patients before and 8-16 weeks after initiation of lumacaftor-ivacaftor therapy [9]. Here we report on the association of serum concentrations of lumacaftor and ivacaftor with biomarkers of CFTR function and clinical outcomes obtained on the same day.Here we report on the association of serum concentrations of lumacaftor and ivacaftor with biomarkers of CFTR function and clinical outcomes obtained on the same day.