Lu Chen (1)*, Koen P. van Rhee (1,2)*, Roeland E. Wasmann (3,4,5), Elke H.J. Krekels (1), Marinus J Wiezer (6), Eric P.A. van Dongen (7), Paul. E. Verweij (4,8), Roger J.M. Brüggemann (3,4)#, Catherijne A.J. Knibbe (1,9)#
(1) Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre of Drug Research, Leiden University, Leiden, The Netherlands; (2) Department of Clinical Pharmacy, Tergooi Hospital, Hilversum, The Netherlands; (3) Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands; (4) Center of Expertise in Mycology Radboudumc/CWZ, Nijmegen, The Netherlands; (5) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa; (6) Department of Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands; (7) Department of Anesthesiology, St. Antonius Hospital, Nieuwegein, The Netherlands; (8) Department of Medical Microbiology, Radboud University Medical Centre, Nijmegen, the Netherlands; (9) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands.
Objectives: Fluconazole is frequently used for the treatment of (invasive) Candida infections. Obesity, and especially morbid obesity, is known to influence the pharmacokinetics of many drugs, which may lead to therapeutic failure or toxicity. Even though the prevalence of obesity is increasing worldwide, this population is often not included in clinical studies, and thus tailored dosing recommendations are often lacking. This study characterizes the pharmacokinetics of fluconazole in obese and non-obese subjects using a semi-simultaneous oral and IV study design. The results are used to derive dosing regimens for this special patient population.
Methods: A total of 421 fluconazole concentration measurements from 25 participants (all Caucasian, 48% female, normal renal function) were obtained from a prospective pharmacokinetic study on fluconazole in obese subjects undergoing bariatric surgery (n = 17, BMI ≥ 35 kg/m2, median weight, 148 kg; range 106-173 kg) and non-obese healthy subjects (n = 8, 18.5 ≤ BMI < 30 kg/m2, median weight, 77.2 kg; range 61.0-93.5 kg) aged between 18 and 65 years. Participating individuals received a single oral dose of 400 mg fluconazole as a capsule, followed by 400 mg IV over 20 minutes two hours later. Dense sampling over 48 h was implemented with 8 samples collected after the oral dose and 10 samples after the IV dose.
Population pharmacokinetic modelling was performed using NONMEM (v7.3.0). First-order absorption (with and without absorption lag time), transit compartment models, mixed first-order and zero-order absorption, and Weibull function were investigated to describe fluconazole absorption [1-3]. Sex, age, body size measures, and liver and kidney function indices were tested as covariates for relevant parameters. The objective function value (OFV), relative standard errors of < 50%, the plausibility of the obtained parameter values, and split goodness-of-fit plots for the oral versus IV phase were used to evaluate the performance of different (absorption) models. Model validation was assessed by the jack-knife method and normalized prediction distribution error analysis (n=1000).
Results: A one-compartment disposition model with three absorption transit compartments and first-order elimination best described the data upon oral and IV administration of fluconazole. Absorption rate constant (ka) was 2.69 (95% confidence interval [CI] 2.14-3.24) h-1, bioavailability (F) 87.5% (CI 74.3%-100%), clearance 0.908 (CI 0.855-0.961) L/h for a 70 kg subject, and volume of distribution (Vd) 38.5 (CI 36.6-40.4) L for a 70 kg female subject. Higher total body weight (TBW) (P<0.001) was significantly associated with a larger Vd described by a power function with an exponent of 0.567 (CI 0.449-0.685, P<0.001). In addition to this, male subjects were found to have 26.9% (CI 15.8%-38.0%) higher Vd than female subjects of the same TBW. Implementation of lean body weight on Vd resulted in a similar decrease in OFV compared to TBW and sex (42.3 and 43.2, respectively), however, the combination of TBW and sex was preferred over lean body weight for the ease of clinical implementation of model-derived dosing recommendations. Inclusion of TBW on clearance using a power function (exponent of 0.390, CI 0.234-0.546) led to a significant improvement in the model fit (P<0.001). None of the kidney function indices resulted in a further statistically significant decrease in the log-likelihood. The inter-individual variability on ka and Vd was 46.0% and 7.30%, respectively, while a high inter-individual variability on F (95% distribution interval 43.9-98.4%) was identified. Model validation procedures indicated no influential individuals and good predictive model performance.
Conclusions: Our results show that lower fluconazole exposure is achieved in heavier compared to lighter subjects and in males compared to female subjects early after initiation of treatment, and therefore a higher dose may be needed for heavier patients and a higher loading dose for males in comparison to females. High interindividual variability in exposure should be anticipated upon oral dosing.
References:
[1] Zhou H. J Clin Pharmacol, 2003, 43 (3): 211-227.
[2] Savic R. M., et al. J Pharmacokinet Pharmacodyn, 2007, 34 (5): 711-726.
[3] Ruiz-Garcia A., et al. Pharmaceutics, 2020, 12 (4).
Reference: PAGE 29 (2021) Abstr 9834 [www.page-meeting.org/?abstract=9834]
Poster: Drug/Disease Modelling - Infection