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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.

SUBMITTER: Wasmann RE

PROVIDER: S-EPMC7069473 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Implications for IV posaconazole dosing in the era of obesity.

Wasmann Roeland E RE Smit Cornelis C van Donselaar Marieke H MH van Dongen Eric P A EPA Wiezer René M J RMJ Verweij Paul E PE Burger David M DM Knibbe Catherijne A J CAJ Brüggemann Roger J M RJM

The Journal of antimicrobial chemotherapy 20200401 4

<h4>Background</h4>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.<h4>Methods</h4>We performed a prospective study investigating the pharmacokinetics of posaconazole in morbidly obese ...[more]

PMID: 31971567

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Project description:IMPORTANCE:Obesity affects nearly one-sixth of US children and results in alterations to body composition and physiology that can affect drug disposition, possibly leading to therapeutic failure or toxic side effects. The depth of available literature regarding obesity's effect on drug safety, pharmacokinetics, and dosing in obese children is unknown. OBJECTIVE:To perform a systematic literature review describing the current evidence of the effect of obesity on drug disposition in children. EVIDENCE REVIEW:We searched the MEDLINE, Cochrane, and EMBASE databases (January 1, 1970-December 31, 2012) and included studies if they contained data on drug clearance, volume of distribution, or drug concentration in obese children (aged ?18 years). We compared exposure and weight-normalized volume of distribution and clearance between obese and nonobese children. We explored the association between drug physicochemical properties and clearance and volume of distribution. FINDINGS:Twenty studies met the inclusion criteria and contained pharmacokinetic data for 21 drugs. The median number of obese children studied per drug was 10 (range, 1-112) and ages ranged from newborn to 29 years (1 study described pharmacokinetics in children and adults together). Dosing schema varied and were either a fixed dose (6 [29%]) or based on body weight (10 [48%]) and body surface area (4 [19%]). Clinically significant pharmacokinetic alterations were observed in obese children for 65% (11 of 17) of the studied drugs. Pharmacokinetic alterations resulted in substantial differences in exposure between obese and nonobese children for 38% (5 of 13) of the drugs. We found no association between drug lipophilicity or Biopharmaceutical Drug Disposition Classification System class and changes in volume of distribution or clearance due to obesity. CONCLUSIONS AND RELEVANCE:Consensus is lacking on the most appropriate weight-based dosing strategy for obese children. Prospective pharmacokinetic trials in obese children are needed to ensure therapeutic efficacy and enhance drug safety.

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Implications for IV posaconazole dosing in the era of obesity.

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Implications for IV posaconazole dosing in the era of obesity.

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