Several systematic reviews have been published on tacrolimus (TAC) population pharmacokinetic (PPK) modeling; however, most of them have focused on the transplant patient population. This study investigated TAC population pharmacokinetic characteristics in non-transplant patients through a systematic review of TAC population pharmacokinetic studies carried out in this patient population, with the aim of clarifying factors affecting TAC pharmacokinetic behavior and promoting individualized TAC-based treatment in non-transplant patients. The Cochrane Library, PubMed, and Embase databases, as well as Chinese databases (SinoMed, Wanfang, and China National Knowledge Infrastructure) and related references, were searched using a non-linear mixed-effects modeling approach, from the time of inception of the databases to July 2022, to identify TAC population pharmacokinetic studies modeled in non-transplant patients. Eighteen studies, all from Asian countries (China and Korea), were included in this study. Of these studies, 56% and 28% were carried out in pediatric and adult patients, respectively. Over half of the studies (56%) were conducted in patients with nephrotic syndrome. Combined medications, body weight, genetic polymorphisms, and physiological function were the most common covariates affecting TAC clearance, and variability in the apparent volume of distribution was largely explained by body weight. In addition, only 2 studies assessed the developed models through external evaluation. In non-transplanted patients, factors that affect TAC pharmacokinetics include combined medications, body weight, genetic polymorphisms, and physiological function. Recent investigations have focused mainly on Asian populations, and expanded trials that will use external evaluations for relevant model assessment are required to investigate generalizability to other ethnic populations.

Objectives: A lot of medication risks related to high-dose methotrexate (HDMTX) therapy still remain to be identified and standardized. This study aims to establish an evidence-based practice guideline for individualized medication of HDMTX. Methods: The practice guideline was launched by the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society. The guideline was developed following the WHO handbook for guideline development and the methodology of evidence-based medicine (EBM). The guideline was initially registered in the International Practice Guidelines Registry Platform (IPGRP-2017CN021). Systematic reviews were conducted to synthesis available evidence. A multicenter cross-sectional study was conducted by questionnaires to evaluate patients’ perception and willingness on individualized medication of HDMTX. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to rate the quality of evidence and to grade the strength of recommendations. Results: Multidisciplinary working groups were included in this guideline, including clinicians, pharmacists, methodologists, pharmacologists and pharmacoeconomic specialists. A total of 124 patients were involved to integrate patient values and preferences. Finally, the guideline presents 28 recommendations, regarding evaluation prior to medication (renal function, liver function, pleural effusion, comedications, genetic testing), pre-treatment and routine dosing regimen, therapeutic drug monitoring (necessity, method, timing, target concentration), leucovorin rescue (initial timing, dosage regimen and optimization), management of toxicities. Of them, 12 are strong recommendations. Conclusions: We developed an evidence-based practice guideline with respect to HDMTX medication using a rigorous and multidisciplinary approach. This guideline provides comprehensive and practical recommendations involving the whole process of HDMTX medication to health care providers.