Total bodyweight and sex both drive pharmacokinetic variability of fluconazole in obese adults

Abstract

Background Fluconazole is commonly used to treat or prevent fungal infections. It is typically used orally but in critical situations, IV administration is needed. Obesity may influence the pharmacokinetics and therapeutic efficacy of a drug. In this study, we aim to assess the impact of obesity on fluconazole pharmacokinetics given orally or IV to guide dose adjustments for the obese population. Methods We performed a prospective pharmacokinetic study with intensive sampling in obese subjects undergoing bariatric surgery (n = 17, BMI ≥ 35 kg/m2) and non-obese healthy controls (n = 8, 18.5 ≤ BMI < 30.0 kg/m2). Participants received a semi-simultaneous oral dose of 400 mg fluconazole capsules, followed after 2 h by 400 mg IV. Population pharmacokinetic modelling and simulation were performed using NONMEM 7.3. Results A total of 421 fluconazole concentrations in 25 participants (total bodyweight 61.0–174 kg) until 48 h after dosing were obtained. An estimated bioavailability of 87.5% was found for both obese and non-obese subjects, with a 95% distribution interval of 43.9%–98.4%. With increasing total bodyweight, both higher CL and Vd were found. Sex also significantly impacted Vd, being 27% larger in male compared with female participants. Conclusions In our population of obese but otherwise healthy individuals, obesity clearly alters the pharmacokinetics of fluconazole, which puts severely obese adults, particularly if male, at risk of suboptimal exposure, for which adjusted doses are proposed.

Pharmacokinetics and Bioequivalence of Fluconazole Capsules Manufactured in France and China in Healthy Chinese Participants: Open‐Label, Randomized, Single‐Dose, 2‐Way, Crossover Bioequivalence Study Under Fasted and Fed Conditions

“…The study population was mostly composed of male participants (69.4%), and sex has previously been identified as a potential factor that could influence the PK of fluconazole 18 . However, as our study was a crossover study, with all participants receiving both the test and reference fluconazole capsules, the difference observed in t max cannot be explained by the sex of the participants.…”

Patients with Obesity Should be Recognised as a Special Patient Population During Drug Development of Antibacterial and Antifungal Agents; A Call to Action

“…To motivate our position presented in this viewpoint, literature on the influence of body weight on clearance of commonly used antibiotic and antifungal agents in otherwise healthy, i.e., non-infectious, individuals with (morbid) obesity was reviewed [ 6 , 7 , 10 – 26 ]. Studies reporting on intravenously (iv) administered drugs were included and those only providing clearance for an obese and non-obese cohort without specifying an equation describing clearance over a large weight span were excluded.…”

“…We identified 19 reports describing the influence of body weight on clearance of antimicrobial agents, i.e., 13 antibacterial agents and 6 antifungal agents. Either a non-significant, moderate or a strong influence of weight on clearance was identified for 7/19 (37 %), 8/19 (42 %) and 4/19 (21 %) antimicrobial agents, respectively [ 6 , 7 , 10 – 26 ].…”

“…The drugs anidulafungin, caspofungin, ceftaroline, fluconazole, meropenem, micafungin, posaconazole and tedizolid are also given at fixed dosages, yet their clearance is reported to be influenced by body weight and therefore individuals with obesity may be at risk of underexposure [ 10 , 12 , 15 , 18 , 19 , 21 , 24 , 25 ]. These drugs may require higher maintenance dosages when the same exposure is aimed for, yet the need and magnitude of dose increase depends on the exact influence of body weight on clearance and the width of the therapeutic window.…”