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A joint population pharmacokinetic model to assess the high variability of whole-blood and intracellular tacrolimus in early adult renal transplant recipients.
Mao, Junjun; Zeng, Fang; Qin, Weiwei; Hu, Min; Xu, Luyang; Cheng, Fang; Zhong, Mingkang; Zhang, Yu.
Afiliación
  • Mao J; Department of Pharmacy, Huashan Hospital, Fudan University, 12 Middle Urumqi Road, Shanghai 200040, China. Electronic address: jmao12@fudan.edu.cn.
  • Zeng F; Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jie Fang Road, Wuhan, Hubei 430022, China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, 1277 Jie Fang Road, Wuhan, Hubei 430022, China.
  • Qin W; Department of Pharmacy, Huashan Hospital, Fudan University, 12 Middle Urumqi Road, Shanghai 200040, China.
  • Hu M; Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jie Fang Road, Wuhan, Hubei 430022, China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, 1277 Jie Fang Road, Wuhan, Hubei 430022, China.
  • Xu L; Department of Pharmacy, Huashan Hospital, Fudan University, 12 Middle Urumqi Road, Shanghai 200040, China.
  • Cheng F; Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jie Fang Road, Wuhan, Hubei 430022, China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, 1277 Jie Fang Road, Wuhan, Hubei 430022, China.
  • Zhong M; Department of Pharmacy, Huashan Hospital, Fudan University, 12 Middle Urumqi Road, Shanghai 200040, China. Electronic address: mkzhong_hs@126.com.
  • Zhang Y; Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jie Fang Road, Wuhan, Hubei 430022, China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, 1277 Jie Fang Road, Wuhan, Hubei 430022, China. Electron
Int Immunopharmacol ; 137: 112535, 2024 Aug 20.
Article en En | MEDLINE | ID: mdl-38908078
ABSTRACT
Tacrolimus (TAC) has high pharmacokinetic (PK) variability during the early transplantation period. The relationships between whole-blood and intracellular TAC concentrations and clinical outcomes remain controversial. This study identifies the factors affecting the PK variability of TAC and characterizes the relationships between whole-blood and intracellular TAC concentrations. Data regarding whole-blood TAC concentrations of 1,787 samples from 215 renal transplant recipients (<90 days postoperative) across two centers and intracellular TAC concentrations (648 samples) digitized from previous studies were analyzed using nonlinear mixed-effects modeling. The effects of potential covariates were screened, and the distribution of whole-blood to intracellular TAC concentration ratios (RWBIC) was estimated. The final model was evaluated using bootstrap, goodness of fit, and prediction-corrected visual predictive checks. The optimal dosing regimens and target ranges for each type of immune cell subsets were determined using Monte Carlo simulations. A two-compartment model adequately described the data, and the estimated mean TAC CL/F was 23.6 L·h-1 (relative standard error 11.5 %). The hematocrit level, CYP3A5*3 carrier status, co-administration with Wuzhi capsules, and tapering prednisolone dose may contribute to the high variability of TAC PK variability during the early post-transplant period. The estimated RWBIC of all TAC concentrations in peripheral blood mononuclear cells (PBMCs) was 4940, and inter-center variability of PBMCs was observed. The simulated TAC target range in PBMCs was 20.2-85.9 pg·million cells-1. Inter-center variability in intracellular concentrations should be taken into account in further analyses. TAC dosage adjustments can be guided based on PK/PD variability and simulated intracellular concentrations.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Trasplante de Riñón / Tacrolimus / Inmunosupresores Límite: Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Revista: Int Immunopharmacol Asunto de la revista: ALERGIA E IMUNOLOGIA / FARMACOLOGIA Año: 2024 Tipo del documento: Article Pais de publicación: Países Bajos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Trasplante de Riñón / Tacrolimus / Inmunosupresores Límite: Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Revista: Int Immunopharmacol Asunto de la revista: ALERGIA E IMUNOLOGIA / FARMACOLOGIA Año: 2024 Tipo del documento: Article Pais de publicación: Países Bajos