Failure to predict amikacin elimination in critically ill patients with cancer based on the estimated glomerular filtration rate: applying PBPK approach in a therapeutic drug monitoring study.

Abstract

PURPOSE:

The aim of this work was to integrate the Therapeutic Drug Monitoring (TDM) with the model-informed precision dosing (MIPD) approach, using Physiologically-based Pharmacokinetic/Pharmacodynamic (PBPK/PD) modelling and simulation, to explore the relationship between amikacin exposure and estimated glomerular filtration rate (GFR) in critically ill patients with cancer.

METHODS:

In the TDM study, samples from 51 critically-ill patients with cancer treated with amikacin were analysed. Patients were stratified according to renal function based on GFR status. A full-body PBPK model with 12 organs model was developed using Simcyp V. 21, including steady-state volume of distribution of 0.21 L/kg and renal clearance of 6.9 L/h in healthy adults. PK parameters evaluated were within the 2-fold error range.

RESULTS:

During the validation step, predicted vs observed amikacin clearance values after single infusion dose in patients with normal renal function, mild and moderate renal impairment were 7.6 vs 8.1 L/h (7.5 mg/kg dose); 3.8 vs 4.5 L/h (1500 mg dose) and 2.2 vs 3.1 L/h (25 mg/kg dose), respectively. However, predicted vs observed amikacin clearance after a single dose infusion of 1400 mg in critically-ill patients with cancer were 1.46 vs 1.63 (P = 0.6406) L/h (severe), 2.83 vs 1.08 (P < 0.05) L/h (moderate), 4.23 vs 2.49 (P = 0.0625) L/h (mild) and 7.41 vs 3.36 (P < 0.05) L/h (normal renal function).

CONCLUSION:

This study demonstrated that estimated GFR did not predict amikacin elimination in critically-ill patients with cancer. Further studies are necessary to find amikacin PK covariates to optimize the pharmacotherapy in this population. Therefore, TDM of amikacin is imperative in cancer patients.

• Authors: João Paulo Telles, Mariana Suelotto Diegues, Karen Cristina Migotto, Olivia de Souza Borges, Rodrigo Reghini, Brenda Vianna Gavazza, Leonardo Pinto, Pedro Caruso, Ivan Leonardo França E Silva, Stephan Schmidt, Fernanda de Lima Moreira
• Journal: European journal of clinical pharmacology (Eur J Clin Pharmacol) Vol. 79 Issue 7 Pg. 1003-1012 (Jul 2023) ISSN: 1432-1041 [Electronic] Germany
• PMID: 37256410 (Publication Type: Journal Article)
• Copyright: © 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Chemical References

• Amikacin
• Anti-Bacterial Agents

Topics

• Adult
• Humans
• Amikacin (therapeutic use)
• Critical Illness (therapy)
• Glomerular Filtration Rate
• Drug Monitoring
• Neoplasms (drug therapy)
• Anti-Bacterial Agents (therapeutic use)