Voriconazole exposure is influenced by inflammation: A population pharmacokinetic model

D Abraham van den Born; Anne-Grete Märtson; Anette Veringa; Nieko C Punt; Tjip S van der Werf; Jan-Willem C Alffenaar; Marieke G G Sturkenboom; Daan J Touw

doi:10.1016/j.ijantimicag.2023.106750

Voriconazole exposure is influenced by inflammation: A population pharmacokinetic model

D Abraham van den Born, Anne-Grete Märtson, Anette Veringa, Nieko C Punt, Tjip S van der Werf, Jan-Willem C Alffenaar, Marieke G G Sturkenboom, Daan J Touw^*

^*Corresponding author for this work

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

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Abstract

BACKGROUND: Voriconazole is an antifungal drug used for the treatment of invasive fungal infections. Due to highly variable drug exposure, therapeutic drug monitoring (TDM) has been recommended. TDM may be helpful to accurately predict exposure but covariates like severe inflammation influencing voriconazole metabolism have not been included in the population pharmacokinetic (popPK) models suitable for routine TDM.

OBJECTIVES: The aim of this study was to investigate whether the effect of inflammation, reflected by C-reactive protein (CRP), could improve a popPK model that can be applied in clinical care.

PATIENTS AND METHODS: Data from two previously conducted studies were included in the popPK modelling. PopPK modelling was performed using Edsim++. Different popPK models were compared by Akaike Information Criterion and goodness-of-fit plots.

RESULTS: In total, 1060 voriconazole serum concentrations were included from 54 patients. The final model was a one-compartment model with nonlinear elimination. Only CRP was a significant covariate and was included in the final model and affected the maximum rate of enzyme activity (V max). For the final popPK model mean volume of distribution (Vd) was 145 L (CV%=61%), mean Michaelis-Menten constant (Km) was 5.7 mg/L (CV%=119%), mean V max was 86.4 mg/h (CV%=99%) and mean bioavailability (F) was 0.83 (CV%=143%). Internal validation using bootstrapping resulted in median values close to the population parameter estimates.

CONCLUSIONS: This one compartment model with nonlinear elimination and CRP as a covariate adequately described voriconazole pharmacokinetics.

Original language	English
Article number	106750
Number of pages	7
Journal	International journal of antimicrobial agents
Volume	61
Early online date	8-Feb-2023
DOIs	https://doi.org/10.1016/j.ijantimicag.2023.106750
Publication status	Published - Apr-2023

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@article{506ac619c1c04565b1fc7460c23742fd,

title = "Voriconazole exposure is influenced by inflammation: A population pharmacokinetic model",

abstract = "BACKGROUND: Voriconazole is an antifungal drug used for the treatment of invasive fungal infections. Due to highly variable drug exposure, therapeutic drug monitoring (TDM) has been recommended. TDM may be helpful to accurately predict exposure but covariates like severe inflammation influencing voriconazole metabolism have not been included in the population pharmacokinetic (popPK) models suitable for routine TDM.OBJECTIVES: The aim of this study was to investigate whether the effect of inflammation, reflected by C-reactive protein (CRP), could improve a popPK model that can be applied in clinical care.PATIENTS AND METHODS: Data from two previously conducted studies were included in the popPK modelling. PopPK modelling was performed using Edsim++. Different popPK models were compared by Akaike Information Criterion and goodness-of-fit plots.RESULTS: In total, 1060 voriconazole serum concentrations were included from 54 patients. The final model was a one-compartment model with nonlinear elimination. Only CRP was a significant covariate and was included in the final model and affected the maximum rate of enzyme activity (V max). For the final popPK model mean volume of distribution (Vd) was 145 L (CV%=61%), mean Michaelis-Menten constant (Km) was 5.7 mg/L (CV%=119%), mean V max was 86.4 mg/h (CV%=99%) and mean bioavailability (F) was 0.83 (CV%=143%). Internal validation using bootstrapping resulted in median values close to the population parameter estimates. CONCLUSIONS: This one compartment model with nonlinear elimination and CRP as a covariate adequately described voriconazole pharmacokinetics.",

author = "{Abraham van den Born}, D and Anne-Grete M{\"a}rtson and Anette Veringa and Punt, {Nieko C} and {van der Werf}, {Tjip S} and Alffenaar, {Jan-Willem C} and Sturkenboom, {Marieke G G} and Touw, {Daan J}",

note = "Copyright {\textcopyright} 2023. Published by Elsevier Ltd.",

year = "2023",

month = apr,

doi = "10.1016/j.ijantimicag.2023.106750",

language = "English",

volume = "61",

journal = "International journal of antimicrobial agents",

issn = "0924-8579",

publisher = "Elsevier Bedrijfsinformatie b.v.",

}

TY - JOUR

T1 - Voriconazole exposure is influenced by inflammation

T2 - A population pharmacokinetic model

AU - Abraham van den Born, D

AU - Märtson, Anne-Grete

AU - Veringa, Anette

AU - Punt, Nieko C

AU - van der Werf, Tjip S

AU - Alffenaar, Jan-Willem C

AU - Sturkenboom, Marieke G G

AU - Touw, Daan J

PY - 2023/4

Y1 - 2023/4

N2 - BACKGROUND: Voriconazole is an antifungal drug used for the treatment of invasive fungal infections. Due to highly variable drug exposure, therapeutic drug monitoring (TDM) has been recommended. TDM may be helpful to accurately predict exposure but covariates like severe inflammation influencing voriconazole metabolism have not been included in the population pharmacokinetic (popPK) models suitable for routine TDM.OBJECTIVES: The aim of this study was to investigate whether the effect of inflammation, reflected by C-reactive protein (CRP), could improve a popPK model that can be applied in clinical care.PATIENTS AND METHODS: Data from two previously conducted studies were included in the popPK modelling. PopPK modelling was performed using Edsim++. Different popPK models were compared by Akaike Information Criterion and goodness-of-fit plots.RESULTS: In total, 1060 voriconazole serum concentrations were included from 54 patients. The final model was a one-compartment model with nonlinear elimination. Only CRP was a significant covariate and was included in the final model and affected the maximum rate of enzyme activity (V max). For the final popPK model mean volume of distribution (Vd) was 145 L (CV%=61%), mean Michaelis-Menten constant (Km) was 5.7 mg/L (CV%=119%), mean V max was 86.4 mg/h (CV%=99%) and mean bioavailability (F) was 0.83 (CV%=143%). Internal validation using bootstrapping resulted in median values close to the population parameter estimates. CONCLUSIONS: This one compartment model with nonlinear elimination and CRP as a covariate adequately described voriconazole pharmacokinetics.

AB - BACKGROUND: Voriconazole is an antifungal drug used for the treatment of invasive fungal infections. Due to highly variable drug exposure, therapeutic drug monitoring (TDM) has been recommended. TDM may be helpful to accurately predict exposure but covariates like severe inflammation influencing voriconazole metabolism have not been included in the population pharmacokinetic (popPK) models suitable for routine TDM.OBJECTIVES: The aim of this study was to investigate whether the effect of inflammation, reflected by C-reactive protein (CRP), could improve a popPK model that can be applied in clinical care.PATIENTS AND METHODS: Data from two previously conducted studies were included in the popPK modelling. PopPK modelling was performed using Edsim++. Different popPK models were compared by Akaike Information Criterion and goodness-of-fit plots.RESULTS: In total, 1060 voriconazole serum concentrations were included from 54 patients. The final model was a one-compartment model with nonlinear elimination. Only CRP was a significant covariate and was included in the final model and affected the maximum rate of enzyme activity (V max). For the final popPK model mean volume of distribution (Vd) was 145 L (CV%=61%), mean Michaelis-Menten constant (Km) was 5.7 mg/L (CV%=119%), mean V max was 86.4 mg/h (CV%=99%) and mean bioavailability (F) was 0.83 (CV%=143%). Internal validation using bootstrapping resulted in median values close to the population parameter estimates. CONCLUSIONS: This one compartment model with nonlinear elimination and CRP as a covariate adequately described voriconazole pharmacokinetics.

U2 - 10.1016/j.ijantimicag.2023.106750

DO - 10.1016/j.ijantimicag.2023.106750

M3 - Article

C2 - 36758777

SN - 0924-8579

VL - 61

JO - International journal of antimicrobial agents

JF - International journal of antimicrobial agents

M1 - 106750

ER -

Voriconazole exposure is influenced by inflammation: A population pharmacokinetic model

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