Implications for IV posaconazole dosing in the era of obesity.

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.

• Authors: 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
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 75 Issue 4 Pg. 1006-1013 (04 01 2020) ISSN: 1460-2091 [Electronic] England
• PMID: 31971567 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.

Chemical References

• Antifungal Agents
• Triazoles
• posaconazole

Topics

• Antifungal Agents
• Humans
• Obesity, Morbid (drug therapy)
• Prospective Studies
• Triazoles