Risk monitoring and pharmacovigilance of programmed cell death protein 1 / programmed cell death 1 ligand 1 in cancer patients after solid organ transplantation.

INTRODUCTION: Several medications are available for the treatment of cancer, and monoclonal antibodies that target PD-1 and PD-L1 represent first-line options for cancer. PD-1 promotes the ability of the immune system to recognize and attack cancer cells by activating T cells. PD-1 also activates the autoimmune system. This activation causes healthy cells in the body to be attacked by the immune system, resulting in immune-related adverse events (irAE). The objective of this study was to comprehensively evaluate the adverse events of rejection reactions in real-world solid organ transplant patients using monoclonal antibodies that target PD-1/PD-L1. METHODS: Data from 2016-2021 were extracted from the U.S. Food and Drug Administration(FDA) Adverse Reporting System (FAERS) to describe the rejection reaction in patients with solid organ transplantation cases after using PD-1/PD-L1 inhibitors approved by the FDA. The reporting odds ratio (ROR) with 95% confidence interval (CI) for rejection reaction was calculated for each PD-1/PD-L1 inhibitor. A disproportionality signal was defined when the lower limit of 95% CI>1. RESULTS: The FAERS database recorded 11,935 adverse events related to solid organ transplantation. Among these reports, 117 showed that various PD-1/PD-L1 inhibitors exhibited a strong correlation with solid organ transplantation rejection. The 3 medicines with the incidence of rejection reaction include avelumab (1), nivolumab (79) and pembrolizumab (37). The average time of solid organ transplantation rejection associated with PD1 / PD-L1 inhibitors was 40.64 days. Of those patients who experienced solid organ transplant rejection, a total of 24.79% died. CONCLUSION: This study found that PD-1/PD-L1 inhibitor use in patients with solid organ transplantation was associated with donor organ rejection. This information serves as a pharmacovigilance signal that we need to continue to track in the real world.

Medication therapy of high-dose methotrexate: An evidence-based practice guideline of the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society.

AIMS: 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 synthesize available evidence. A multicentre cross-sectional study was conducted using questionnaires to evaluate patients' perception and willingness concerning 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 administration (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), and management of toxicities. Of these, 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 administration to health care providers.

Guideline for the evaluation of prescription appropriateness.

Evaluation of prescriptions is a necessary process of evaluating the appropriateness of clinical drug usage, discovering existing problems, and formulating solutions. There are challenges for professionals within hospital medical departments and for clinicians and pharmacists who have clinical questions relating to inappropriate or abnormal prescriptions as identified by the electronic evaluation system of prescription. Medications are usually used correctly according to the drug instructions or guidelines. At present, there are no relevant domestic or international guidelines, or principles or standards for identifying inappropriate or abnormal prescriptions. To develop the guideline for evaluation of prescriptions appropriateness in clinical practice, the Pharmaceutical Affairs Commission of the Chinese Hospital Association formed the guideline working group consisting of multidisciplinary experts. The guideline working group summarized clinical questions in the evaluation of prescriptions, searched for supporting evidence, and reached a consensus for recommendations. The guideline contains 6 recommendations for evaluating prescription appropriateness, and the general principle of these recommendations is that clinicians should provide drug instructions, guidelines, or moderate evidence supporting the prescription, and the evaluators will then judge the prescription to be either appropriate or irrational. The recommendations resolve common clinical questions, using supporting examples, explanations and a flow chart. The evaluation of prescription appropriateness could be made more systematic and transparent based on this guideline's conclusions.

A Multiview Model for Detecting the Inappropriate Use of Prescription Medication: Machine Learning Approach.

BACKGROUND: The inappropriate use of prescription medication has recently garnered worldwide attention, but most national policies do not effectively provide for early detection or timely intervention. OBJECTIVE: This study aimed to develop and assess the validity of a model that can detect the inappropriate use of prescription medication. This effort combines a multiview and topic matching method. The study also assessed the validity of this approach. METHODS: A multiview extension of the latent Dirichlet allocation algorithm for topic modeling was chosen to generate diagnosis-medication topics, with data obtained from the Chinese Monitoring Network for Rational Use of Drugs (CMNRUD) database. Topic mapping allowed for calculating the degree to which diagnoses and medications were similarly distributed and, by setting a threshold, for identifying prescription misuse. The Beijing Regional Prescription Review Database (BRPRD) database was used as the gold standard to assess the model's validity. We also conducted a sensitivity analysis using random samples of validated prescriptions and evaluated the model's performance. RESULTS: A total of 44 million prescriptions were used to generate topics using the diagnoses and medications from the CMNRUD database. A random sample (15,000 prescriptions) from the BRPRD was used for validation, and it was found that the model had a sensitivity of 81.8%, specificity of 47.4%, positive-predictive value of 14.5%, and negative-predictive value of 96.0%. The model showed superior stability under different sampling proportions. CONCLUSIONS: A method that combines multiview topic modeling and topic matching can detect the inappropriate use of prescription medication. This model, which has mediocre specificity and moderate sensitivity, can be used as a primary screening tool and will likely complement and improve the process of manually reviewing prescriptions.

Delayed High-dose Methotrexate Excretion and Influencing Factors in Osteosarcoma Patients.

BACKGROUND: High-dose methotrexate (HD-MTX) with folinic acid (leucovorin) rescue is "gold standard" therapy for osteosarcoma. Plasma concentrations of methotrexate (MTX) are closely related to its efficacy and toxicity. Delayed excretion of MTX can lead to serious adverse reactions that may result in treatment cessation, irreversible organ damage, and death. This study focused on the incidence of delayed excretion of MTX in Chinese osteosarcoma patients. METHODS: A total of 1277 osteosarcoma patients were treated with HD-MTX chemotherapy (4291 cycles) from 2010 to 2015. Factors that could influence delayed excretion of MTX (gender, age, number of chemotherapy cycles, and serum concentration of MTX) were analyzed. RESULTS: The incidence of delayed excretion of MTX (serum concentrations at 24 h [C24 h] >5 µmol/L) and severe delayed excretion of MTX (C24 h >20 µmol/L) were 6.19% and 0.86% per patient, and 2.31% and 0.26% per cycle of treatment, respectively. The incidence of severe delayed excretion of MTX was associated with gender, age, and C24 h. CONCLUSIONS: Precaution of delayed excretion of MTX is needed during osteosarcoma treatment using HD-MTX. An optimal individualized rescue strategy can be created with consideration of gender, age, and C24 h.

Population pharmacokinetics of high-dose methotrexate after intravenous administration in Chinese osteosarcoma patients from a single institution.

BACKGROUND: High-dose methotrexate (HD-MTX) with folinic acid (leucovorin) rescue is the gold standard therapy in the treatment of osteosarcoma. The plasma concentration of MTX is closely related to efficacy and toxicity. There are large individual differences. Many authors have described the pharmacokinetic (PK) profile of MTX regarding osteosarcoma under a variety of circumstances. However, no data concerning Chinese osteosarcoma patient PKs using the nonlinear mixed effects models (NONMEM) have been previously reported. The goals of this study were to establish the population pharmacokinetics (PPK) of HD-MTX treatment in Chinese osteosarcoma patients, and to explore the influence of patient covariates and between-occasion variability on drug disposition. METHODS: An intravenous HD-MTX solution (10 g/m 2 ) was given 274 times to 148 osteosarcoma patients. MTX plasma concentrations were measured at 0, 6, 12, 24, 48 and 72 h after commencement of the infusion, and the fluorescence polarization immunoassay was used to determine MTX plasma concentrations. The PPK model and parameters were estimated using NONMEM software. The effects of fixed-effect factors were evaluated, and the final regression model was obtained. RESULTS: The following population parameters were obtained using a two-compartment model: CL1 (clearance of central compartment): (CL1 ) = CL1TV × [1 - θ CL1- MTXNUM × MTXNUM] × [1 - θ CL1- CrCl1 × (CrCl1 - 1.89)] × e ηCL1i (L/h). V1 (central volume): (V1)i = V1TV × e ηV1i (L). CL2 (clearance of peripheral compartment): (CL2)i = CL2TV × [1 - θCL2 - BODY AREA × (body area - 1.62)] × e ηCL2i (L/h). V2 (peripheral compartment): (V2 )i = V2TV × [1 - θ V2-bodyarea × (bodyarea-1.62)] × e ηV2i (L). The PPK parameters (RSD%) were CL1, V1, CL2 and V2 with values of 6.20 L/h (8.48%), 19.6 L (extremely small), 0.0172 L/h (50.9%) and 0.515 L (39.1%), respectively. Creatinine clearance and the number of methotrexate chemotherapy cycles before MTX infusion had a significant effect on the CL1, and body surface area had a significant effect on the CL2 and the V2 (P < 0. 01). CONCLUSIONS: A good fit was derived for the PPK. The model could be used to provide guidance for MTX treatment and reduce adverse effects.