Discussion
Our multicenter study revealed that combination therapy of Phe508del homozygous individuals with CF with lumacaftor/ivacaftor leads to highly variable serum concentrations of the two drugs that are not correlated with each other. Ivacaftor and lumacaftor have half-lives of 12 and 23 hours, respectively [8]. Since our study participants administered the morning dose according to protocol and blood was subsequently collected after a defined time lag with low inter-patient variability, different time points of blood sampling after dosage can hardly explain the large patient-to-patient variation of drug concentrations. We therefore speculate that the individual genetic repertoire of the polymorphic cytochrome P450 superfamily, drug-drug interactions and a variable body composition, particularly of the fat compartment, may give rise to a broad distribution of absorption, residence time, metabolism and excretion of these hydrophobic drugs.
According to our knowledge three groups have published protocols to determine the concentration of lumacaftor or ivacaftor by LC-MS in primary cells [6], sputum [4] and serum [4 -7] from in total 13 CF patients [4-7]. Our data on samples from 51 Phe508del homozygotes CF patients corroborate the previous reports that serum concentrations of ivacaftor during concomitant medication with lumacaftor are substantially lower than during ivacaftor monotherapy confirming the manufacturer’s report [8] that lumacaftor is a CYP3A4 inducer that leads to a more rapid turnover of the CYP3A4 substrate ivacaftor.
With the exception of the correlation between ivacaftor levels and the change in sweat chloride, the absolute drug levels of lumacaftor or ivacaftor did not correlate with any improvement in anthropometry, lung function or CFTR activity in sweat gland, respiratory or intestinal epithelium. The remaining ivacaftor levels in presence of lumacaftor might therefore be of importance. However, our data indicate that the absolute blood levels of lumacaftor or ivacaftor seem to be no informative biomarkers to predict clinical improvement or the attenuation of the CF basic defect by combination therapy with these CFTR modulators. These findings are consistent with previous reports containing smaller numbers of ICM and NPD [12].
Nevertheless, drug monitoring of lumacaftor/ivacaftor may still be helpful to assess the patient’s adherence to the prescribed treatment. Further studies are required to assess whether the CFTR correctors elexacaftor and tezacaftor [13-17] exert a similar pharmacokinetic behavior as observed for ivacaftor and lumacaftor.