Kong, Daming

Roberts, Jason A

Lipman, Jeffrey

Taccone, Fabio Silvio

Cohen-Wolkowiez, Michael

Sime, Fekade B

Tsai, Danny

De Cock, Pieter A J G

Jaruratanasirikul, Sutep

Dhaese, Sofie A M

Udy, Andrew A

Felton, Timothy W

Michelet, Robin

Thibault, Céline

Koomen, Jeroen V

Eleveld, Douglas J

Struys, Michel M R F

De Waele, Jan J

Colin, Pieter J

2024-12-25

The pharmacokinetics (PK) of piperacillin/tazobactam (PIP/TAZ) is highly variable across different patient populations and there are controversies regarding non-linear elimination as well as the fraction unbound of PIP (f). This has led to a plethora of subgroup-specific models, increasing the risk of misusing published models when optimising dosing regimens. In this study, we aimed to develop a single model to simultaneously describe the PK of PIP/TAZ in diverse patient populations and evaluate the current dosing recommendations by predicting the PK/pharmacodynamics (PD) target attainment throughout life.Population PK models were separately built for PIP and TAZ based on data from 13 studies in various patient populations. In the development of those single-drug models, postnatal age (PNA), postmenstrual age (PMA), total body weight (TBW), height, and serum creatinine (SCR) were tested as covariates. Subsequently, a combined population PK model was established and the correlations between the PK of PIP and TAZ were tested. Monte Carlo simulations were performed based on the final combined model to evaluate the current dosing recommendations.The final combined model for PIP/TAZ consisted of four compartments (two for each drug), with covariates including TBW, PMA, and SCR. For a 70-kg, 35-year-old patient with SCR of 0.83 mg L, the PIP values for V, CL, V and Q were 10.4 L, 10.6 L h, 11.6 L and 15.2 L h, respectively, and the TAZ values were 10.5 L, 9.58 L h, 13.7 L and 16.8 L h, respectively. The CL for both drugs show maturation in early life, reaching 50% at 54.2 weeks PMA. With advancing age, CL of TAZ declines to 50% at 61.6 years PMA, whereas CL of PIP declines more slowly, reaching 50% at 89.1 years PMA. The f was estimated as 64.5% and non-linear elimination was not supported by our data. The simulation results indicated considerable differences in PK/PD target attainment for different patient populations under current recommended dosing regimens.We developed a combined population PK model for PIP/TAZ across a broad range of patients covering the extremes of patient characteristics. This model can be used as a robust a priori model for Bayesian forecasting to achieve individualised dosing. The simulations indicate that adjustments based on the allometric theory as well as maturation and decline of CL of PIP may help the current dosing recommendations to provide consistent target attainment across patient populations.

Department of Anesthesiology, University of Groningen, University Medical Center Groningen, P. O. Box 30001, 9700 RB, Groningen, The Netherlands.

University of Queensland Centre for Clinical Research, Faculty of Medicine, University of Queensland, Herston, Brisbane, QLD, Australia.

Pharmacy Department, Royal Brisbane and Women's Hospital, Brisbane, Australia.

Department of Intensive Care, Royal Brisbane and Women's Hospital, Brisbane, Australia.

Nimes University Hospital, University of Montpellier, Nimes, France.

Nimes University Hospital, University of Montpellier, Nimes, France.

Jamieson Trauma Institute, Royal Brisbane and Women's Hospital, University of Queensland, Brisbane, Australia.

Department of Intensive Care, Hôpital Universitaire de Bruxelles (HUB), Université Libre de Bruxelles (ULB), Brussels, Belgium.

Department of Pediatrics, Duke University, Durham, NC, USA.

University of Queensland Centre for Clinical Research, Faculty of Medicine, University of Queensland, Herston, Brisbane, QLD, Australia.

University of Queensland Centre for Clinical Research, Faculty of Medicine, University of Queensland, Herston, Brisbane, QLD, Australia.

Department of Intensive Care Medicine, Alice Springs Hospital, Alice Springs, NT, Australia.

Pharmacy Department, Alice Springs Hospital, Alice Springs, NT, Australia.

Department of Pharmacy, Ghent University Hospital, De Pintelaan 185, 9000, Ghent, Belgium.

Department of Basic and Applied Medical Sciences, Ghent University, De Pintelaan 185, 9000, Ghent, Belgium.

Department of Paediatric Intensive Care, Ghent University Hospital, De Pintelaan 185, 9000, Ghent, Belgium.

Division of Pharmacology, Leiden Academic Centre for Drug Research, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.

Department of Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, 90110, Thailand.

Department of Nephrology and Infectious Diseases, Saint John's Hospital, Ruddershove 10, 8000, Bruges, Belgium.

Department of Intensive Care and Hyperbaric Medicine, The Alfred Hospital, Commercial Road, Melbourne, VIC, 3181, Australia.

Division of Infection, Immunity to Infection and Respiratory Medicine, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.

Acute Intensive Care Unit, Manchester University NHS Foundation Trust, Manchester, UK.

Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany.

Department of Pediatrics, CHU Sainte-Justine, Montreal, Canada.

Research Center, CHU Sainte-Justine, Montreal, Canada.

Department of Anesthesiology, University of Groningen, University Medical Center Groningen, P. O. Box 30001, 9700 RB, Groningen, The Netherlands.

Department of Anesthesiology, University of Groningen, University Medical Center Groningen, P. O. Box 30001, 9700 RB, Groningen, The Netherlands.

Department of Anesthesiology, University of Groningen, University Medical Center Groningen, P. O. Box 30001, 9700 RB, Groningen, The Netherlands.

Department of Basic and Applied Medical Sciences, Ghent University, De Pintelaan 185, 9000, Ghent, Belgium.

Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000, Ghent, Belgium.

Department of Intensive Care Medicine, Ghent University Hospital, De Pintelaan 185, 9000, Ghent, Belgium.

Department of Anesthesiology, University of Groningen, University Medical Center Groningen, P. O. Box 30001, 9700 RB, Groningen, The Netherlands. p.j.colin@umcg.nl.

Clin Pharmacokinet . 2024 Dec 25. doi: 10.1007/s40262-024-01460-6. Online ahead of print.

1179-1926

https://pubmed.ncbi.nlm.nih.gov/39722108/?otool=iaurydwlib

https://hdl.handle.net/10137/13900

A Pooled Pharmacokinetic Analysis for Piperacillin/Tazobactam Across Different Patient Populations: From Premature Infants to the Elderly.

Journal Article

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