Observational studyThe AAPS journal2014
Determination of the most influential sources of variability in tacrolimus trough blood concentrations in adult liver transplant recipients: a bottom-up approach.
Observational study in The AAPS journal, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers, 2 of them syntheses that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
19 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- Toward a robust tool for pharmacokinetic-based personalization of treatment with tacrolimus in solid organ transplantation: A model-based meta-analysis approach.British journal of clinical pharmacology · 2019Pooled it
- Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation Approaches: A Systematic Review of Published Models, Applications, and Model Verification.Drug metabolism and disposition: the biological fate of chemicals · 2015Pooled it
- Unbound Plasma, Total Plasma, and Whole-Blood Tacrolimus Pharmacokinetics Early After Thoracic Organ Transplantation.Clinical pharmacokinetics · 2020Trial
- Pharmacokinetics of Once-Daily Extended-Release Tacrolimus Tablets Versus Twice-Daily Capsules in De Novo Liver Transplant.Clinical pharmacology in drug development · 2019Trial
- Analytical Models to Optimize Tacrolimus Dosing in Solid Organ Transplantation: A Systematic Review.Pharmaceutics · 2026Review
- Challenges in optimizing tacrolimus therapy in patients treated with rifampin: A case series.British journal of clinical pharmacology · 2025Article
- State of Art of Dose Individualization to Support tacrolimus drug monitoring: What's Next?Transplant international : official journal of the European Society for Organ Transplantation · 2025Review
- Steroid-tacrolimus drug-drug interaction and the effect of CYP3A genotypes.British journal of clinical pharmacology · 2024Article
- Guidance on Selecting Optimal Steady-State Tacrolimus Concentrations for Continuous IV Perfusion: Insights from Physiologically Based Pharmacokinetic Modeling.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Tacrolimus Dose Requirement inTransplant international : official journal of the European Society for Organ Transplantation · 2024Article
- A Physiologically Based Pharmacokinetic Approach to Recommend an Individual Dose of Tacrolimus in Adult Heart Transplant Recipients.Pharmaceutics · 2023Article
- Article
- Discussion on machine learning technology to predict tacrolimus blood concentration in patients with nephrotic syndrome and membranous nephropathy in real-world settings.BMC medical informatics and decision making · 2022Article
- Variability of Tacrolimus Trough Concentration in Liver Transplant Patients: Which Role of Inflammation?Pharmaceutics · 2021Article
- Recent advances in precision medicine for individualized immunosuppression.Current opinion in organ transplantation · 2020Article
- Predictive engines based on pharmacokinetics modelling for tacrolimus personalized dosage in paediatric renal transplant patients.Scientific reports · 2020Article
- Carbapenem-Resistant Enterobacteriaceae in Solid Organ Transplantation: Management Principles.Current infectious disease reports · 2019Review
- A Theoretical Physiologically-Based Pharmacokinetic Approach to Ascertain Covariates Explaining the Large Interpatient Variability in Tacrolimus Disposition.CPT: pharmacometrics & systems pharmacology · 2019Article
- Artificial neural network model for predicting the bioavailability of tacrolimus in patients with renal transplantation.PloS one · 2018Article
Corrections and comments
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Authors and funding
9 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Tacrolimus, an immunosuppressant drug, presents a narrow therapeutic window and a large pharmacokinetic variability with poor correlation between drug dosing regimen and blood concentration. The objective was to identify predictive factors influencing tacrolimus trough concentrations (C0) using a bottom-up approach. A physiologically based pharmacokinetic (PBPK) model of tacrolimus was proposed, taking into account the body weight, the proportion of fat (P(fat)), hematocrit, lipid fraction of organs, typical intrinsic clearance (CLi(typ)), CYP3A5 genotype of liver donor, plasma unbound fraction of tacrolimus (fu(p)), and concomitant drugs (CYP3A4 inhibitors). For the evaluation of the PBPK model, mean C0 and concentrations 2 h after oral dose of tacrolimus were compared with those from 66 liver transplant recipients included in a multicentric pharmacokinetic study and were found very close. Tacrolimus concentration profiles were simulated in a virtual population defined by a set of covariate values similar to those from the real population. The sensitivity of tacrolimus C0 with respect to each covariate has been tested to identify the most influential ones. With the range of covariate values tested, the impact of each covariate on tacrolimus C0 may be ranked as follows: fu(p), CLi(typ), bioavailability, body weight, hematocrit, CYP3A5 polymorphism, P(fat), and CYP3A4 inhibitory drug-drug interactions. Values for initial dosing regimen of tacrolimus in order to reach a C0 of 10 ng/ml at day 5 (assuming a constant dosing schedule) as a function of CYP3A5 donor genotype and patient's hematocrit and body weight are proposed.
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