Impact of benzodiazepines on posaconazole serum concentrations. A population-based pharmacokinetic study on drug interaction

Abstract

Objectives:

Posaconazole is broadly used for antifungal prophylaxis and therapy. Current data suggest a concentration-dependent effect. Unlike other triazoles, cytochrome P450 is not a relevant route of biotransformation for posaconazole but glucuronidation, which might lead to a different spectrum of drug interactions. For benzodiazepines, the major metabolic pathway involves oxidation, but some, including lorazepam and temazepam, undergo conjugation to glucuronic acid.

Research design and methods:

Since 2006 serum levels of posaconazole are determined regularly in all hospitalized patients with intake of this triazole. Here we investigate posaconazole concentration at steady state in relation to the concomitant medication of benzodiazepines.

Results:

While similar posaconazole concentrations were determined in samples obtained from patients receiving temazepam when compared to samples without any benzodiazepine, a relevant reduction of posaconazole concentration could be observed in patients with concomitant intake of lorazepam. This difference in posaconazole concentration with or without concomittant intake of lorazepam, was consistently significant for analyses of all samples (median 336 ng/ml vs. 585 ng/ml, p 0.001), for the average concentrations (569 ng/ml vs. 276 ng/ml, p 0.039), and for patients receiving a total daily dose of 800 mg posaconazole (292 ng/ml vs. 537 ng/ml, p 0.003). There was also a similar, but not significant trend for patients with a prophylactic dosage of 200 mg posaconazole three times daily (689 ng/ml vs. 512 ng/ml, p 0.186).

Conclusions:

In this retrospective study, analyzing blood samples from daily clinical practice of patients in various clinical settings and with different indications for antifungal therapy, concomitant medication of lorazepam was associated with decreased posaconazole concentrations. Therefore, lorazepam but not temazepam might induce posaconazole clearance by glucuronidation.

Keywords::

• Benzodiazepine
• Interaction
• Lorazepam
• Posaconazole
• Temazepam

Transparency

Declaration of funding

The authors have received no payment in preparation of this manuscript.

Declaration of financial/other relationships

W.J.H. has received research support from Astellas, Basilea, Gilead, MSD/Merck and Pfizer, and compensation as a member of the scientific advisory board to Merck, and Pfizer, and served has as speaker for Gilead, MSD/Merck, and Pfizer. H.E. has worked at speaker’s bureau for Gilead; A.G., A.U., AH.-B., J.Z., D.S., U.L. and H.K. declare no conflict of interest.

Acknowledgments

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed any relevant financial relationships.