Implications for IV posaconazole dosing in the era of obesity

Roeland E. Wasmann, Cornelis Smit, Marieke H. Van Donselaar, Eric P.A. Van Dongen, René M.J. Wiezer, Paul E. Verweij, David M. Burger, Catherijne A.J. Knibbe, Roger J.M. Brüggemann

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

Background: The prevalence of obesity has shown a dramatic increase over recent decades. Obesity is associated with underdosing of antimicrobial drugs for prophylaxis and treatment. Posaconazole is a broad-spectrum triazole antifungal drug licensed for prophylaxis and treatment of invasive fungal infections. It is unclear how posaconazole should be dosed in obese patients. Methods: We performed a prospective study investigating the pharmacokinetics of posaconazole in morbidly obese (n = 16) and normal-weight (n = 8) subjects, with a weight ranging between 61.4 and 190 kg, after a 300 or 400 mg IV dose. Population pharmacokinetic modelling was used to assess the effect of body size on posaconazole pharmacokinetics. ClinicalTrials.gov Identifier: NCT03246386. Results: Total body weight best predicted changes in CL and V. Model-based simulations demonstrated that, for treatment of fungal infections, a daily IV dose of 300 mg will result in a PTA of ≥90% in individuals up to 140 kg, after which both twice daily loading and the daily maintenance dose should be increased to 400 mg. For prophylaxis, a 300 mg IV dose is adequate in patients up to 190 kg. Conclusions: Body size has a significant impact on posaconazole CL and V, resulting in a lower exposure in obese subjects compared with normal-weight subjects. For therapeutic use of posaconazole, a dose increase is required in patients above 140 kg. For prophylaxis, a 300 mg IV dose is adequate. For oral treatment, these recommendations can act as a starting point followed by therapeutic drug monitoring.

Original languageEnglish
Pages (from-to)1006-1013
Number of pages8
JournalJournal of Antimicrobial Chemotherapy
Volume75
Issue number4
DOIs
Publication statusPublished - 1 Apr 2020
Externally publishedYes

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