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.