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Population Pharmacokinetic Model for Unbound Concentrations of Daptomycin in Patients with MRSA Including Patients Undergoing Hemodialysis

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Abstract

Background and Objective

Unbound daptomycin concentrations are responsible for pharmacologically beneficial and adverse effects, although most previous reports have been limited to the use of total concentrations. We developed a population pharmacokinetic model to predict both total and unbound daptomycin concentrations.

Methods

Clinical data were collected from 58 patients with methicillin-resistant Staphylococcus aureus including patients undergoing hemodialysis. A total of 339 serum total and 329 unbound daptomycin concentrations were used for model construction.

Results

Total and unbound daptomycin concentration was explained by a model that assumed first-order distribution with two compartments, and first-order elimination. Normal fat body mass was identified as covariates. Renal function was incorporated as a linear function of renal clearance and independent non-renal clearance. The unbound fraction was estimated to be 0.066 with a standard albumin of 45 g/L and standard creatinine clearance of 100 mL/min. Simulated unbound daptomycin concentration was compared with minimum inhibitory concentration as a measure of clinical effectiveness and exposure-level-related induction of creatine phosphokinase elevation. The recommended doses were 4 mg/kg for patients with severe renal function [creatinine clearance (CLcr) ≤ 30 mL/min] and 6 mg/kg for patients with mild to moderate renal function (CLcr > 30 and ≤ 60 mL/min). A simulation indicated that dose adjusted by body weight and renal function improved target attainment.

Conclusions

This population pharmacokinetics model for unbound daptomycin could help clinicians to select the appropriate dose regimen for patients undergoing daptomycin treatment and reduce associated adverse effects.

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Authors and Affiliations

  1. Department of Medical Pharmaceutics, Faculty of Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan

    Saki Takahashi, Chika Ogami & Hideto To

  2. Laboratory of Clinical Pharmacometrics, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba, 274-8555, Japan

    Yasuhiro Tsuji

  3. Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand

    Nick Holford

  4. Department of Clinical Pharmacokinetics and Pharmacodynamics, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Hidefumi Kasai

  5. Department of Clinical Infectious Diseases, Toyama University Graduate School of Medicine and Pharmaceutical Sciences, 2630 Sugitani, Toyama, 930-0194, Japan

    Hitoshi Kawasuji & Yoshihiro Yamamoto

Authors
  1. Saki Takahashi
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Corresponding author

Correspondence to Yasuhiro Tsuji.

Ethics declarations

Funding

This study was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number JP20K07189 and the Nihon University Multidisciplinary Research Grant for 2020. The funding organization did not participate in the study design, collection, analysis, and interpretation of data, writing of the report, or decision to submit the article for publication.

Conflict of Interest

The authors have no conflicts of interest to declare.

Ethical Approval

The present study was conducted with the approval of the ethics committees of the University of Toyama (approval number: R2012133 revised) and Nihon University (School of Pharmacy, approval numbers: 20–005 and 20–012) and was conducted in compliance with the Declaration of Helsinki.

Consent to Participate

Informed consent was obtained to participate in the study.

Consent for Publication

Not applicable.

Availability of Data and Material

No data are available.

Code Availability

A NONMEM code of population pharmacokinetics model will be made available on reasonable request.

Author Contributions

S.T., Y.T., and C.O. contributed to the acquisition of data, participated in the study design, analyzed and interpreted the data, and drafted the manuscript. N.H. helped with writing the manuscript. H.K. (Hidefumi Kasai) and H.T. contributed to the conception, design, and interpretation of the data. H.K. (Hitoshi Kawasuji) and Y.Y. were the clinical investigators of the trial and were responsible for the medical care of the trial participants, communication with the research ethics committee, protocol, informed consent, data integrity, and reporting. All the authors meet the ICME authorship criteria. All the authors approved the final version of the manuscript.

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Takahashi, S., Tsuji, Y., Holford, N. et al. Population Pharmacokinetic Model for Unbound Concentrations of Daptomycin in Patients with MRSA Including Patients Undergoing Hemodialysis. Eur J Drug Metab Pharmacokinet 48, 201–211 (2023). https://doi.org/10.1007/s13318-023-00820-0

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