Model-Informed Precision Dosing of Tacrolimus: A Systematic Review of Population Pharmacokinetic Models and a Benchmark Study of Software Tools.

Publisher: Country of Publication: Switzerland NLM ID: 7606849 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1179-1926 (Electronic) Linking ISSN: 03125963 NLM ISO Abbreviation: Clin Pharmacokinet Subsets: MEDLINE

Publication: [Switzerland] : Adis, part of Springer Science+Business Media
Original Publication: New York, ADIS Press.

Tacrolimus*/pharmacokinetics ; Tacrolimus*/administration & dosage ; Immunosuppressive Agents*/pharmacokinetics ; Immunosuppressive Agents*/administration & dosage ; Software* ; Models, Biological*; Humans ; Organ Transplantation/methods ; Cytochrome P-450 CYP3A/genetics ; Cytochrome P-450 CYP3A/metabolism ; Bayes Theorem ; Precision Medicine/methods ; Benchmarking ; Computer Simulation

Background and Objective: Tacrolimus is an immunosuppressant commonly administered after solid organ transplantation. It is characterized by a narrow therapeutic window and high variability in exposure, demanding personalized dosing. In recent years, population pharmacokinetic models have been suggested to guide model-informed precision dosing of tacrolimus. We aimed to provide a comprehensive overview of population pharmacokinetic models and model-informed precision dosing software modules of tacrolimus in all solid organ transplant settings, including a simulation-based investigation of the impact of covariates on exposure and target attainment.
Methods: We performed a systematic literature search to identify population pharmacokinetic models of tacrolimus in solid organ transplant recipients. We integrated selected population pharmacokinetic models into an interactive software tool that allows dosing simulations, Bayesian forecasting, and investigation of the impact of covariates on exposure and target attainment. We conducted a web survey amongst model-informed precision dosing software tool providers and benchmarked publicly available tools in terms of models, target populations, and clinical integration.
Results: We identified 80 population pharmacokinetic models, including 44 one-compartment and 36 two-compartment models. The most frequently retained covariates on clearance and distribution parameters were cytochrome P450 3A5 polymorphisms and body weight, respectively. Our simulation tool, hosted at https://lpmx.shinyapps.io/tacrolimus/ , allows thorough investigation of the impact of covariates on exposure and target attainment. We identified 15 model-informed precision dosing software tool providers, of which ten offer a tacrolimus solution and nine completed the survey.
Conclusions: Our work provides a comprehensive overview of the landscape of available tacrolimus population pharmacokinetic models and model-informed precision dosing software modules. Our simulation tool allows an interactive thorough exploration of covariates on exposure and target attainment.
(© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Erratum in: Clin Pharmacokinet. 2024 Oct;63(10):1511. doi: 10.1007/s40262-024-01438-4. (PMID: 39446277)

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1SHAA24N Research Foundation Flanders (FWO); 1803521N Research Foundation Flanders (FWO); 1830517N Research Foundation Flanders (FWO)

WM0HAQ4WNM (Tacrolimus)
0 (Immunosuppressive Agents)
EC 1.14.14.1 (Cytochrome P-450 CYP3A)
EC 1.14.14.1 (CYP3A5 protein, human)

Date Created: 20240920 Date Completed: 20241029 Latest Revision: 20241030

20241031

10.1007/s40262-024-01414-y

39304577