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


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.
Department of Internal Medicine II, University of Würzburg Medical Center, Oberdürrbacher Str. 6, 97080 Würzburg, Germany. Heinz_W@klinik.uni-wuerzburg.de
Werner J
WJ
Heinz
Anna
A
Grau
Anne
A
Ulrich
Annegret
A
Helle-Beyersdorf
Janina
J
Zirkel
Diana
D
Schirmer
Ulrike
U
Lenker
Hermann
H
Einsele
Hartwig
H
Klinker
D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001569:Benzodiazepines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D008140:Lorazepam / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D012189:Retrospective Studies; D044967:Serum / Q000378:metabolism; D013693:Temazepam / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*
D014151:Anti-Anxiety Agents; D000935:Antifungal Agents; D014230:Triazoles; D001569:Benzodiazepines; C101425:posaconazole; D013693:Temazepam; D008140:Lorazepam