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

Autor: Kotaro Itohara, Ikuko Yano, Shunsaku Nakagawa, Mitsuhiro Sugimoto, Machiko Hirai, Atsushi Yonezawa, Satoshi Imai, Takayuki Nakagawa, Daiki Hira, Takashi Ito, Koichiro Hata, Etsuro Hatano, Tomohiro Terada, Kazuo Matsubara
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Clinical and Translational Science, Vol 15, Iss 11, Pp 2652-2662 (2022)
Druh dokumentu: article
ISSN: 1752-8062
1752-8054
DOI: 10.1111/cts.13389
Popis: Abstract 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 mixed‐effect 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 (R2 = 0.330, p
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