Population Pharmacokinetic Analysis and Dosing Optimization Based on Unbound Daptomycin Concentration and Cystatin C in Nonobese Elderly Patients with Hypoalbuminemia and Chronic Kidney Disease

Masaru Samura, Keisuke Takada, Risako Yamamoto, Hayato Ito, Fumio Nagumo, Masaki Uchida, Takenori Kurata, Sakura Koshioka, Yuki Enoki, Kazuaki Taguchi, Ryuji Higashita, Norifumi Kunika, Koji Tanikawa, Kazuaki Matsumoto

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: This study evaluated the population pharmacokinetics of daptomycin in nonobese elderly patients with hypoalbuminemia and chronic kidney disease (CKD) using the glomerular filtration rate estimated from cystatin C (eGFRcys) and estimated its optimal dose. Methods: We performed population pharmacokinetic analysis of the unbound concentrations of daptomycin. The probability of target attainment of 90% for achieving an area under the concentration–time curve of unbound daptomycin at steady state/ minimum inhibitory concentration ratio of ≥66.6 was stochastically simulated. Results: In the population pharmacokinetic analysis of 25 patients aged ≥65 years, the two-compartment model using eGFRcys and age as covariates of clearance in central compartment of unbound daptomycin were optimal. The unbound fraction rate (fu) was 0.05–0.14. According to the Monte Carlo simulation, the optimal doses for patients with eGFRcys of 20–60 mL/min and aged 65–95 years were calculated as 200–500 mg q24h. Conclusion: These results suggest that establishing the dose using total concentrations may result in under- or overestimation caused by alterations in fu. The optimal dose for nonobese elderly patients with hypoalbuminemia and CKD depends on eGFRcys and age, and a standard dose may be insufficient for some patients.

Original languageEnglish
JournalPharmaceutical research
DOIs
Publication statusAccepted/In press - 2021

Keywords

  • chronic kidney disease
  • cystatin C
  • daptomycin
  • elderly patients
  • population pharmacokinetics

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

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