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.