Extrapolation of physiologically based pharmacokinetic model for tacrolimus from renal to liver transplant patients

Itohara, Kotaro; Yano, Ikuko; Nakagawa, Shoichi; Yonezawa, Atsushi; Omura, Tomohiro; Imai, Shoichi; Sawada, Atsuro; Kobayashi, Takashi; Tochio, Akira; Sakai, Kaoru; Taura, Kojiro; Ogawa, Osamu; Matsubara, Kazuo

doi:10.1016/j.dmpk.2021.100423

Cited by 5 publications

(4 citation statements)

References 40 publications

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“…However, the reported CL/F values were 13.5–17.9 L/h in renal or cardiac recipients if concomitant drug administration was not considered, 9,19 showing a slightly higher value than our result (6.89 L/h). We have previously reported that hepatic function in liver transplant patients would be slightly lower than that in renal transplant patients 20 . Therefore, the lower CL/F value may be due to differences in the target population.…”

Section: Discussionmentioning

confidence: 90%

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Population pharmacokinetics of everolimus in adult liver transplant patients: Comparison to tacrolimus disposition and extrapolation to pediatrics

Itohara

Yano

Nakagawa

et al. 2022

Clinical Translational Sci

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Everolimus has recently been used to prevent graft rejection in liver transplantation and reduces the incidence of kidney dysfunction caused by calcineurin inhibitors. In this study, a population pharmacokinetic analysis was conducted to improve the individualization of everolimus therapy. Japanese post-liver transplant patients whose blood everolimus concentrations were measured between March 2018 and December 2020 were included in this study. A nonlinear mixedeffect modeling program was used to explore covariates that affect everolimus pharmacokinetics. Individual everolimus pharmacokinetic parameters estimated by the post-hoc Bayesian analysis using the final model were compared with the tacrolimus dose per trough concentration (D/C) ratio in each patient. The final model was extrapolated to pediatric liver transplant patients for external evaluation. A total of 937 concentrations from 87 adult patients were used in the model-building process. Everolimus clearance was significantly affected by the estimated glomerular filtration rate, concomitant use of fluconazole, sex, as well as total daily dose of everolimus (TDM effect). The estimated individual apparent clearance of everolimus by the post-hoc Bayesian analysis was moderately correlated with the D/C ratio of tacrolimus in each patient (R 2 = 0.330, p < 0.0001).The estimation accuracy in pediatric patients was considerably high, except for one infant out of 13 patients. In conclusion, population pharmacokinetic analysis clarified several significant covariates for everolimus pharmacokinetics in liver transplant patients. Everolimus pharmacokinetics moderately correlated with tacrolimus pharmacokinetics and could be extrapolated from adult to pediatric patients by body size correction, except for infants.

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Section: Discussionmentioning

confidence: 90%

“…We have previously reported that hepatic function in liver transplant patients would be slightly lower than that in renal transplant patients. 20 Therefore, the lower CL/F value may be due to differences in the target population. Patients with a lower eGFR had a decreased CL/F of everolimus.…”

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics of everolimus in adult liver transplant patients: Comparison to tacrolimus disposition and extrapolation to pediatrics

Itohara

Yano

Nakagawa

et al. 2022

Clinical Translational Sci

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“…For hepatic impairment populations three of the studies were conducted using Simcyp (Watanabe et al, 2022;X Wu et al, 2022;Ladumor et al, 2023) and one using PK-Sim (L Xu et al, 2022). For the studies that considered both RI and HI populations one used PK-Sim (Fan et al, 2022), one used Simcyp (Itohara et al, 2022) and one used Gastroplus (Zhao et al, 2022). This distribution of software packages differs somewhat from what was reported in 2015, perhaps unsurprisingly as software development is highly dynamic with new options becoming available frequently.…”

Section: Model Development Applications and Verificationmentioning

confidence: 99%

Physiologically Based Pharmacokinetic Modeling of Small Molecules: How Much Progress Have We Made?

Isoherranen

2024

Drug Metabolism and Disposition

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Physiologically based pharmacokinetic (PBPK) models of small molecules have become mainstream in drug development and in academic research. The use of PBPK models is continuously expanding with the majority of work now focusing on predictions of drug-drug interactions, drug-disease interactions, and changes in drug disposition across lifespan. Recently, publications that use PBPK modeling to predict drug disposition during pregnancy and in organ impairment have increased reflecting the advances in incorporating diverse physiological changes into the models. Due to the expanding computational power and diversity of modeling platforms available, the complexity of PBPK models has also increased. Academic efforts have provided clear advances in better capturing human physiology in PBPK models and incorporating more complex mathematical concepts into PBPK models. Examples of such advances include the segregated gut model with a series of gut compartments allowing modeling of physiological blood flow distribution within an organ and zonation of metabolic enzymes, and series compartment liver models allowing simulations of hepatic clearance for high extraction drugs. Despite these advances in academic research, the progress in assessing model quality and defining model acceptance criteria based on the intended use of the models has not kept pace. This review suggests that awareness of the need for predefined criteria for model acceptance has increased but many manuscripts still lack description of scientific justification and/or rationale for chosen acceptance criteria. As artificial intelligence and machine learning approaches become more broadly accepted, these tools offer promise for development of comprehensive assessment for existing observed data and analysis of model performance.

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“…For tacrolimus, PBPK modelling has been helpful in the assessment of drug–drug interactions [ 7 , 8 , 9 , 10 , 11 ], the influence of drug substance properties [ 12 , 13 , 14 ] and the causes of exposure variability in adults [ 15 , 16 , 17 , 18 ]. However, the paediatric population remains under-investigated, with only Emoto et al and Zhao et al [ 7 , 16 ] including this specific population and only Emoto et al exploring exposure variability.…”

Section: Introductionmentioning

confidence: 99%

Investigating Tacrolimus Disposition in Paediatric Patients with a Physiologically Based Pharmacokinetic Model Incorporating CYP3A4 Ontogeny, Mechanistic Absorption and Red Blood Cell Binding

Van der Veken,

Brouwers,

Ozbey

et al. 2023

Pharmaceutics

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Tacrolimus is a crucial immunosuppressant for organ transplant patients, requiring therapeutic drug monitoring due to its variable exposure after oral intake. Physiologically based pharmacokinetic (PBPK) modelling has provided insights into tacrolimus disposition in adults but has limited application in paediatrics. This study investigated age dependency in tacrolimus exposure at the levels of absorption, metabolism, and distribution. Based on the literature data, a PBPK model was developed to predict tacrolimus exposure in adults after intravenous and oral administration. This model was then extrapolated to the paediatric population, using a unique reference dataset of kidney transplant patients. Selecting adequate ontogeny profiles for hepatic and intestinal CYP3A4 appeared critical to using the model in children. The best model performance was achieved by using the Upreti ontogeny in both the liver and intestines. To mechanistically evaluate the impact of absorption on tacrolimus exposure, biorelevant in vitro solubility and dissolution data were obtained. A relatively fast and complete release of tacrolimus from its amorphous formulation was observed when mimicking adult or paediatric dissolution conditions (dose, fluid volume). In both the adult and paediatric PBPK models, the in vitro dissolution profiles could be adequately substituted by diffusion-layer-based dissolution modelling. At the level of distribution, sensitivity analysis suggested that differences in blood plasma partitioning of tacrolimus may contribute to the variability in exposure in paediatric patients.

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Extrapolation of physiologically based pharmacokinetic model for tacrolimus from renal to liver transplant patients

Cited by 5 publications

References 40 publications

Population pharmacokinetics of everolimus in adult liver transplant patients: Comparison to tacrolimus disposition and extrapolation to pediatrics

Population pharmacokinetics of everolimus in adult liver transplant patients: Comparison to tacrolimus disposition and extrapolation to pediatrics

Physiologically Based Pharmacokinetic Modeling of Small Molecules: How Much Progress Have We Made?

Investigating Tacrolimus Disposition in Paediatric Patients with a Physiologically Based Pharmacokinetic Model Incorporating CYP3A4 Ontogeny, Mechanistic Absorption and Red Blood Cell Binding

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