Results
In total, 51 p.Phe508del homozygous CF patients took lumacaftor and
ivacaftor within this post-approval study. Eight to sixteen weeks after
the initiation of treatment with CFTR modulators blood was taken to
determine the serum concentrations of lumacaftor and ivacaftor
(Supplementary Table S1). The median serum levels were 0.5 µg/ml for
ivacaftor and 24 µg/ml for lumacaftor (Table 1), comparable to data from
the EMA assessment report [8]. The serum samples contained on
average 50-fold more lumacaftor than ivacaftor. Figure 1 shows the
ivacaftor and lumacaftor concentrations for the 49 samples with less
than 2 µg/ml ivacaftor, the remaining two samples contained high levels
of ivacaftor of 9 and close to 4 µg/ml, respectively (Supplementary
Table S1). The data in Figure 1 demonstrate the lack of any correlation
between ivacaftor and lumacaftor levels.
The serum levels of lumacaftor, ivacaftor and the lumacaftor/ivacaftor
ratio were tested for association with anthropometry, spirometry and
CFTR activity determined within 0.1 – 2.5 hours past blood sampling. In
14 of 15 tests no significant correlations between drug serum levels and
clinical parametrs. Neither body mass index, FEV1, sweat chloride
concentration, Sermet score [10] of the NPD and the chloride
secretory response [9] in the ICM (Table 2) correlated. One
exceptions from this general finding was noted, i.e. the serum level of
ivacaftor correlated with the decrease of sweat chloride concentration
(P = 0.02). The correlation of the ratio of lumacaftor to
ivacaftor levels with the increase of the Sermet score towards the
normal range in the NPD showed a trend (P = 0.06).