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

Lu Chen; Koen P. Van Rhee; Roeland E. Wasmann; Elke H.J. Krekels; Marinus J. Wiezer; Eric P.A. Van Dongen; Paul E. Verweij; Paul D. Van Der Linden; Roger J. Brüggemann; Catherijne A.J. Knibbe

doi:10.1093/jac/dkac160

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

Lu Chen, Koen P. Van Rhee, Roeland E. Wasmann, Elke H.J. Krekels, Marinus J. Wiezer, Eric P.A. Van Dongen, Paul E. Verweij, Paul D. Van Der Linden, Roger J. Brüggemann, Catherijne A.J. Knibbe

Research output: Contribution to journal › Article › peer-review

7 Citations (Scopus)

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.

Original language	English
Pages (from-to)	2217-2226
Number of pages	10
Journal	Journal of Antimicrobial Chemotherapy
Volume	77
Issue number	8
DOIs	https://doi.org/10.1093/jac/dkac160
Publication status	Published - 1 Aug 2022
Externally published	Yes

Keywords

Adult
Body Weight
Female
Fluconazole/pharmacokinetics
Humans
Male
Mycoses/drug therapy
Obesity/complications
Prospective Studies

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10.1093/jac/dkac160

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Chen, L., Van Rhee, K. P., Wasmann, R. E., Krekels, E. H. J., Wiezer, M. J., Van Dongen, E. P. A., Verweij, P. E., Van Der Linden, P. D., Brüggemann, R. J., & Knibbe, C. A. J. (2022). Total bodyweight and sex both drive pharmacokinetic variability of fluconazole in obese adults. Journal of Antimicrobial Chemotherapy, 77(8), 2217-2226. https://doi.org/10.1093/jac/dkac160

@article{7c47302e269540798502cca5af9d9c81,

title = "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.",

keywords = "Adult, Body Weight, Female, Fluconazole/pharmacokinetics, Humans, Male, Mycoses/drug therapy, Obesity/complications, Prospective Studies",

author = "Lu Chen and {Van Rhee}, {Koen P.} and Wasmann, {Roeland E.} and Krekels, {Elke H.J.} and Wiezer, {Marinus J.} and {Van Dongen}, {Eric P.A.} and Verweij, {Paul E.} and {Van Der Linden}, {Paul D.} and Br{\"u}ggemann, {Roger J.} and Knibbe, {Catherijne A.J.}",

note = "{\textcopyright} The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: [email protected].",

year = "2022",

month = aug,

day = "1",

doi = "10.1093/jac/dkac160",

language = "English",

volume = "77",

pages = "2217--2226",

journal = "Journal of Antimicrobial Chemotherapy",

issn = "0305-7453",

publisher = "Oxford University Press",

number = "8",

}

TY - JOUR

T1 - Total bodyweight and sex both drive pharmacokinetic variability of fluconazole in obese adults

AU - Chen, Lu

AU - Van Rhee, Koen P.

AU - Wasmann, Roeland E.

AU - Krekels, Elke H.J.

AU - Wiezer, Marinus J.

AU - Van Dongen, Eric P.A.

AU - Verweij, Paul E.

AU - Van Der Linden, Paul D.

AU - Brüggemann, Roger J.

AU - Knibbe, Catherijne A.J.

PY - 2022/8/1

Y1 - 2022/8/1

N2 - 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.

AB - 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.

KW - Adult

KW - Body Weight

KW - Female

KW - Fluconazole/pharmacokinetics

KW - Humans

KW - Male

KW - Mycoses/drug therapy

KW - Obesity/complications

KW - Prospective Studies

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UR - https://www.mendeley.com/catalogue/232a6128-7fcc-3ce2-97d0-18ec4cdbb23f/

U2 - 10.1093/jac/dkac160

DO - 10.1093/jac/dkac160

M3 - Article

C2 - 35613035

AN - SCOPUS:85135381097

SN - 0305-7453

VL - 77

SP - 2217

EP - 2226

JO - Journal of Antimicrobial Chemotherapy

JF - Journal of Antimicrobial Chemotherapy

IS - 8

ER -

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

Abstract

Keywords

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