Development of a Population Pharmacokinetic Model for Cyclosporine from Therapeutic Drug Monitoring Data.

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  • Additional Information
    • Source:
      Publisher: Hindawi Pub. Co Country of Publication: United States NLM ID: 101600173 Publication Model: eCollection Cited Medium: Internet ISSN: 2314-6141 (Electronic) NLM ISO Abbreviation: Biomed Res Int Subsets: MEDLINE
    • Publication Information:
      Original Publication: New York, NY : Hindawi Pub. Co.
    • Subject Terms:
      Drug Monitoring* ; Models, Biological*; Cyclosporine/*pharmacokinetics; Adult ; Cyclosporine/blood ; Female ; Humans ; Male
    • Abstract:
      Aim: To develop a population pharmacokinetic model for Uruguayan patients under treatment with cyclosporine (CsA) that can be applied to TDM. Patients and Methods . A total of 53 patients under treatment with CsA were included. 37 patients with at least one pharmacokinetic profile described with four samples were considered for model building, while the remaining 16 were considered for the assessments of predictive performances. Pharmacokinetic parameter estimation was performed using a nonlinear mixed effect modelling implemented in the Monolix® software (version 2019R1, Lixoft, France); meanwhile, simulations were performed in R v.3.6.0 with the mlxR package.
      Results: A two-compartment model with a first-order disposition model including lag time was used as a structural model. The final model was internally validated using prediction corrected visual predictive check (pcVPC) and other graphical diagnostics. A total of 621 CsA steady-state concentrations were analyzed for model development. Population estimates for the absorption constant (ka) and lag time were 0.523 h -1 and 0.512 h, respectively; apparent clearance (CL/F) was 30.3 L/h (relative standard error [RSE] ± 8.25%) with an interindividual variability of 39.8% and interoccasion variability of 38.0%; meanwhile, apparent clearance of distribution (Q/F) was 17.0 L/h (RSE ± 12.1%) with and interindividual variability of 53.2%. The covariate analysis identified creatinine clearance (ClCrea) as an individual factor influencing the Cl of CsA. The predictive capacity of the population model was demonstrated to be effective since predictions made for new patients were accurate for C1 and C2 (MPPEs below 50%). Bayesian forecasting improved significantly in the second and third occasions.
      Conclusion: A population pharmacokinetic model was developed to reasonably estimate the individual cyclosporine clearance for patients. Hence, it can be utilized to individualize CsA doses for prompt and adequate achievement of target blood concentrations of CsA.
      Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this article.
      (Copyright © 2021 Martín Umpiérrez et al.)
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    • Accession Number:
      83HN0GTJ6D (Cyclosporine)
    • Publication Date:
      Date Created: 20210430 Date Completed: 20210525 Latest Revision: 20220422
    • Publication Date:
      20240104
    • Accession Number:
      PMC8052134
    • Accession Number:
      10.1155/2021/3108749
    • Accession Number:
      33928146