Title:Cytochrome P450 3A4 Induction: Lumacaftor versus Ivacaftor Potentially Resulting in Significantly Reduced Plasma Concentration of Ivacaftor
VOLUME: 12 ISSUE: 1
Author(s):Elena K. Schneider*
Affiliation:Department of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC 3010
Keywords:Cystic fibrosis, ivacaftor, lumacaftor, CFTR modulator, cytochrome, drug interactions.
Abstract:Background & Objective: Since the release of ivacaftor-lumacaftor, several red-flags have
been raised that highlight the clinical efficacy of this combination strategy that may be limited due to
antagonistic drug-drug interactions.
Method: The effect of ivacaftor, its major metabolites M1 and M6, lumacaftor and the novel cystic fibrosis
transmembrane conductance regulator (CFTR) modulator tezacaftor at 10 g/mL on the enzymatic
activity of the major xenobiotic metabolizing enzymes CYP1A2 and CYP3A4 as well as the
minor enzymes CYP2B6 and CYP2C9 was assayed.
Results: Lumacaftor (3.74 x 105 ± 3.11 x 104 RLU), and ivacaftor-M6 (3.43 x 105 ± 7.61 x 103 RLU)
markedly induced the activity of CYP3A4. Ivacaftor (2.22 x 105 ± 3.94 x 104 RLU) showed a lower
relative ratio of luminescence units compared to chloramphenicol (3.17 x 105 ± 1.55 x 104 RLU). Interestingly,
ivacaftor-M1 (6.74 x 104 ± 3.09 x 104 RLU) and the novel CFTR modulator tezacaftor
(2.40 x 104 ± 8.14 x 104 RLU) did not show CYP3A4 induction. In the CYP1A2 and CYP2C9 assay,
all metabolites showed a decrease in the ratio of luminescence units compared to the controls. Ivacaftor,
its major metabolites, lumacaftor and tezacaftor all showed a slight increase in the ratio of luminescence
units compared to the control rifampin with CYP2B6.
Conclusion: All in all, present findings would suggest that lumacaftor and ivacaftor-M6 are strong inducers
of CYP3A4, potentially reducing ivacaftor concentrations; ivacaftor itself induces CYP3A4 to
some extent.
