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Case Reports
. 2018;12(1):71-74.
doi: 10.2174/1872312812666180328105259.

Cytochrome P450 3A4 Induction: Lumacaftor versus Ivacaftor Potentially Resulting in Significantly Reduced Plasma Concentration of Ivacaftor

Elena K Schneider  1   2
Affiliations
Case Reports

Cytochrome P450 3A4 Induction: Lumacaftor versus Ivacaftor Potentially Resulting in Significantly Reduced Plasma Concentration of Ivacaftor

Elena K Schneider. Drug Metab Lett. 2018.

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 µg/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.

Keywords: CFTR modulator; Cystic fibrosis; cytochrome; drug interactions; ivacaftor; lumacaftor..

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Figures

Fig. (1)
Fig. (1)
Effect of ivacaftor, ivacaftor-M1, ivacaftor-M6, lumacaftor and tezacaftor on the activity of CYP3A4 (right hand side: CYP1A2, CYP2B6 and CYP2C9) in a cell-free luminescence assay. The P450-Glo assay was performed using chloramphenicol (CYP3A4), omeprazole (CYP1A2), rifampin (CYP2B6) and rifampicin (CYP2C9) at 10 µM as a positive control (cytochrome induction). Data is the mean of three independent measurements. Luminescence ratio units are corrected for the enzyme + vehicle background. Data are presented as relative luminescence units and are expressed as the mean ± SD (n=3).
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