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Optimized LC-MS/MS Method for the High-throughput Analysis of Clinical Samples of Ivacaftor, Its Major Metabolites, and Lumacaftor in Biological Fluids of Cystic Fibrosis Patients
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Concomitant use of isavuconazole and CYP3A4/5 inducers: Where pharmacogenetics meets pharmacokinetics

Ruth Van Daele1, Yves Debaveye2, Robin Vos3

  • 1Department of Pharmaceutical and Pharmacological Sciences, KU Leuven and Pharmacy Department, University Hospitals Leuven, Leuven, Belgium.

Mycoses
|May 8, 2021
PubMed
Abstract

Insights

Isavuconazole can be safely combined with less potent CYP450 inducers in patients with specific CYP3A5 genetic profiles. Therapeutic drug monitoring is advised, especially for extensive metabolizers, to ensure optimal isavuconazole exposure.

Area of Science:

  • Pharmacology
  • Clinical Pharmacy
  • Genetics

Background:

  • Isavuconazole is a triazole antifungal used for invasive aspergillosis and mucormycosis.
  • It is metabolized by CYP3A4/5; potent CYP3A inducers like rifampin reduce its exposure.
  • Concomitant use with moderate/strong CYP450 inducers is contraindicated, but less potent inducers warrant investigation.

Purpose of the Study:

  • To document isavuconazole exposure in patients using less potent CYP450 inducers.
  • To investigate the influence of CYP3A genotype on this drug-drug interaction.

Main Methods:

  • Case series of three patients treated with isavuconazole and a less potent CYP3A inducer (rifabutin or phenobarbital).
  • Isavuconazole concentrations were determined.
  • CYP3A4/5 genotype was analyzed.

Main Results:

  • CYP3A4/5 genotype significantly impacts isavuconazole exposure.
  • Genotype may influence the interaction with CYP450 inducers.
  • Low isavuconazole exposure occurred in an extensive metabolizer (CYP3A4*1/*1, CYP3A5*1/*3).

Conclusions:

  • Less potent CYP3A inducers may be combined with isavuconazole in patients with CYP3A5 loss-of-function (CYP3A5*3/*3).
  • Therapeutic drug monitoring is recommended for this combination.
  • Caution is advised for extensive metabolizers due to potential low drug exposure.
Keywords:
CYP450 inductionexposuregenotypingisavuconazolephenobarbitalrifabutin

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