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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

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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.

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Availability of data and materials

Data supporting the results of this study are available upon reasonable request.

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Author information

Authors and Affiliations

  1. Department of Infectious Diseases, AC Camargo Cancer Center, Professor Antonio Prudente Street, N. 211, São Paulo-SP, 01509-001, Brazil

    João Paulo Telles, Rodrigo Reghini & Ivan Leonardo França e Silva

  2. Department of Clinical Pharmacy, AC Camargo Cancer Center, São Paulo-SP, Brazil

    Mariana Suelotto Diegues, Karen Cristina Migotto & Olivia de Souza Borges

  3. Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro-RJ, Brazil

    Brenda Vianna Gavazza & Fernanda de Lima Moreira

  4. Laboratory of Immunopathology, Nucleus of Biological Sciences Research, Federal University of Ouro Preto, Ouro Preto-MG, Brazil

    Leonardo Pinto

  5. Department of Intensive Care Unit, AC Camargo Cancer Center, São Paulo-SP, Brazil

    Pedro Caruso

  6. Department of Pharmaceutics Lake Nona, University of Florida, Orlando-FL, USA

    Stephan Schmidt

Authors
  1. João Paulo Telles
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  2. Mariana Suelotto Diegues
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Contributions

JPT—conceptualization, data extraction, writting, review; MD—data extraction, writing; KM—data extraction; OB—conceptualization, data extraction; RR—data extraction; BV—data analysis, figures preparation; LP—data analysis, review; PC—conceptualization, supervision, review; ILFS—conceptualization, supervision, review; SS—data analysis, review; FLM—conceptualization, orientation, data analysis, writting, review.

Corresponding author

Correspondence to João Paulo Telles.

Ethics declarations

Ethical Approval

This study was approved by the Research Ethics Committee of AC Camargo Cancer Center (CAE 56419722.0.0000.5432).

Consent to participate

Not applicable: retrospective study.

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Not applicable: retrospective study.

Competing interests

The authors declare no conflict of interest.

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Key Points

• A poor correlation was found between amikacin CL and 8 GFR estimating equations.

• Amikacin CL was twice slower than the predicted in patients with eGFR > 29 mL/min.

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Supplementary file1 (DOCX 16 KB)

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Telles, J.P., Diegues, M.S., Migotto, K.C. et al. 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. Eur J Clin Pharmacol 79, 1003–1012 (2023). https://doi.org/10.1007/s00228-023-03516-1

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