Efficacy and Safety of Gabapentinoids for Acute Herpes Zoster Neuralgia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: his study aimed to systematically evaluate the clinical efficacy of gabapentin and pregabalin in the treatment of acute herpes zoster neuralgia, including pain control and the occurrence of adverse effects. METHOD: A systematic computerized search was conducted in October 2023 in PubMed, Embase, Web of Science, Cochrane Library, VIP, CNKI, and Wanfang databases. Data from randomized controlled trials comparing gabapentin analogs for the treatment of acute herpes zoster neuralgia were searched. Endpoints were visual analog scores (VAS) and adverse effects at 1, 2, and 4 weeks. Data from studies that met the inclusion criteria were extracted for meta-analysis and sensitivity analysis using Revman 5.4 and Stata16. RESULTS: The study included 292 patients from 6 RCTs. Of these, 118 were in the gabapentin-treated group, 37 were in the pregabalin-treated group, and 137 were in the placebo-controlled group. The gabapentin group showed superior pain reduction compared to the placebo group (P<0.05), but adverse events were more frequent. CONCLUSION: Gabapentin can effectively reduce acute herpes zoster neuralgia in patients. Pregabalin requires additional randomized controlled trials to supplement the analysis. PROSPERO REGISTRATION: CRD42023446643.

High doses of rosuvastatin induce impaired branched-chain amino acid catabolism and lead to insulin resistance.

NEW FINDINGS: What is the central question of this study? Is there a risk of developing diabetes associated with statin treatment? What is the underlying mechanism of the increased incidence rate of new-onset diabetes in patients treated with rosuvastatin? What is the main finding and its importance? Rosuvastatin therapy reduced intraperitoneal glucose tolerance and changed the catabolism of branched-chain amino acid (BCAAs) in white adipose tissue and skeletal muscle. Protein phosphatase 2Cm knockdown completely abolished the effects of insulin and rosuvastatin on glucose absorption. This study provides mechanistic support for recent clinical data on rosuvastatin-related new-onset diabetes and underscores the logic for intervening in BCAA catabolism to prevent the harmful effects of rosuvastatin. ABSTRACT: Accumulating evidence indicates that patients treated with rosuvastatin have an increased risk of developing new-onset diabetes. However, the underlying mechanism remains unclear. In this study, we administered rosuvastatin (10 mg/kg body weight) to male C57BL/6J mice for 12 weeks and found that oral rosuvastatin dramatically reduced intraperitoneal glucose tolerance. Rosuvastatin-treated mice showed considerably higher serum levels of branched-chain amino acids (BCAAs) than control mice. They also showed dramatically altered expression of BCAA catabolism-related enzymes in white adipose tissue and skeletal muscle, including downregulated mRNA expression of BCAT2 and protein phosphatase 2Cm (PP2Cm) and upregulated mRNA expression of branched-chain ketoacid dehydrogenase kinase (BCKDK). The levels of BCKD in the skeletal muscle were reduced in rosuvastatin-treated mice, which was associated with lower PP2Cm protein levels and increased BCKDK levels. We also investigated the effects of rosuvastatin and insulin administration on glucose metabolism and BCAA catabolism in C2C12 myoblasts. We observed that incubation with insulin enhanced glucose uptake and facilitated BCAA catabolism in C2C12 cells, which was accompanied by elevated Akt and glycogen synthase kinase 3 ß (GSK3ß) phosphorylation. These effects of insulin were prevented by co-incubation of the cells with 25 µM rosuvastatin. Moreover, the effects of insulin and rosuvastatin administration on glucose uptake and Akt and GSK3ß signaling in C2C12 cells were abolished when PP2Cm was knocked down. Although the relevance of these data, obtained with high doses of rosuvastatin in mice, to therapeutic doses in humans remains to be elucidated, this study highlights a potential mechanism for the diabetogenic effects of rosuvastatin, and suggests that BCAA catabolism could be a pharmacological target for preventing the adverse effects of rosuvastatin.

Genetic polymorphisms in metabolic enzymes and transporters have no impact on mycophenolic acid pharmacokinetics in adult kidney transplant patients co-treated with tacrolimus: A population analysis.

WHAT IS KNOWN AND OBJECTIVE: Mycophenolate mofetil, an ester prodrug of mycophenolic acid (MPA), is widely used to prevent graft rejection after kidney transplantation. The pharmacokinetic (PK) of MPA has been extensively studied, which revealed a high degree of variability. An integrated population PK (PopPK) model of MPA and its main metabolite mycophenolic acid glucuronide (MPAG) was developed using the adult patients who underwent kidney transplant and were administered oral mycophenolate mofetil combined with tacrolimus. METHODS: In total, 917 MPA and 740 MPAG concentrations in191 adult patients were analysed via nonlinear mixed-effects modelling. The concentration-time data were adequately described using a chain compartment model, including central and peripheral compartments for MPA and a central compartment for MPAG. Stepwise forward inclusion and backward elimination procedures were used to investigate the effects of genetic polymorphisms, including in UGT1A8, UGT1A9, UGT2B7, ABCB1, ABCC2, ABCG2, SLCO1B1, SLCO1B3, and HNF1α. RESULTS AND DISCUSSION: These genetic polymorphisms in metabolic enzymes and transporters have no obvious impact on the PK of MPA in adult patients who underwent kidney transplant and were co-treated with tacrolimus. The post-transplant time, serum albumin, and creatinine clearance were identified as significant covariates affecting the PK of MPA and MPAG, which should be considered in the clinical use of mycophenolate mofetil. WHAT IS NEW AND CONCLUSION: We established a PopPK model of MPA and MPAG in Chinese adult patients who underwent kidney transplant and were co-treated with tacrolimus. Genetic polymorphisms in metabolic enzymes and transporters showed no obvious impact on MMF PK. A model-informed dosing strategy was proposed by the established model, and MMF dose adjustment should be based on ALB levels and the post-transplantation time.

Population pharmacokinetics of unbound valproic acid in pediatric epilepsy patients in China: a protein binding model.

PURPOSE: The purpose of this study was to establish a protein binding model of unbound valproic acid (VPA) based on Chinese pediatric patients with epilepsy and provide a reference for clinical medication. METHODS: A total of 313 patients were included and both their total and unbound VPA concentrations (375 pairs of concentrations) were measured. NONMEM software was used for population pharmacokinetic modeling. The stepwise method was used to screen the potential covariates. Goodness-of-fit plot, bootstrap, and visual predictive check were used for model evaluation. In addition, dose recommendations for typical patients aged 0 to 16 years were proposed by Monte Carlo simulations. RESULTS: A one-compartment model of first-order absorption and first-order elimination was used to describe the pharmacokinetic characteristics of unbound VPA, and the linear non-saturable binding equation was introduced to describe the protein binding. Body weight, age-based maturation, and co-medicated with lamotrigine could affect the CL/F of unbound and bound VPA. Model evaluation showed satisfactory robustness of the final model. The dosing regimens for children aged 0 to 16 years were proposed based on the final established model. CONCLUSION: We developed a population pharmacokinetic model of unbound and bound VPA that took account of protein binding. The VPA dosing regimen in pediatric patients with epilepsy needs to be optimized by the body weight, age, and co-medications.

Population pharmacokinetic and optimization of polymyxin B dosing in adult patients with various renal functions.

AIMS: Current FDA-approved label recommends that the dosage of polymyxin B should be adjusted according to renal function. However, the correlation between polymyxin B pharmacokinetics (PK) and creatinine clearance (CrCL) is poor. This study aimed to develop a population PK model of polymyxin B in adult patients with various renal functions and to identify a dosing strategy. METHODS: A retrospective PK study was performed in 32 adult patients with various renal function. Nonlinear mixed effects modelling was applied to build a population PK model of polymyxin B followed by Monte Carlo simulations which designed polymyxin B dosing regimens across various renal function. RESULTS: Polymyxin B PK analyses included 112 polymyxin B concentrations at steady state from 32 adult patients, in which 71.9% of them were critically ill. In the final PK model, CrCL was the significant covariate on CL (typical value 1.59 L/h; between-subject variability 13%). The mean (SD) individual empirical Bayesian estimate of CL was 1.75 (0.43) L/h. In addition, a new dosing strategy combining the PK/pharmacodynamic (PD) targets and Monte Carlo simulation indicated that the reduction of polymyxin B dose in patients with renal insufficiency improved the probability of achieving optimal exposure. For severe infections caused by organisms with minimum inhibitory concentration (MIC) ≥ 2 mg/L, a high daily dose of polymyxin B might be possible for bacterial eradication, but the risk of nephrotoxicity is increased. CONCLUSIONS: Renal function plays a significant role in polymyxin B PK, and the dose of polymyxin B should be adjusted according to CrCL in patients with renal insufficiency.

Population pharmacokinetics of the anti-PD-1 antibody camrelizumab in patients with multiple tumor types and model-informed dosing strategy.

Camrelizumab, a programmed cell death 1 (PD-1) inhibitor, has been approved for the treatment of patients with relapsed or refractory classical Hodgkin lymphoma, nasopharyngeal cancer and non-small cell lung cancer. The aim of this study was to perform a population pharmacokinetic (PK) analysis of camrelizumab to quantify the impact of patient characteristics and to investigate the appropriateness of a flat dose in the dosing regimen. A total of 3092 camrelizumab concentrations from 133 patients in four clinical trials with advanced melanoma, relapsed or refractory classical Hodgkin lymphoma and other solid tumor types were analyzed using nonlinear mixed effects modeling. The PKs of camrelizumab were properly described using a two-compartment model with parallel linear and nonlinear clearance. Then, covariate model building was conducted using stepwise forward addition and backward elimination. The results showed that baseline albumin had significant effects on linear clearance, while actual body weight affected intercompartmental clearance. However, their impacts were limited, and no dose adjustments were required. The final model was further evaluated by goodness-of-fit plots, bootstrap procedures, and visual predictive checks and showed satisfactory model performance. Moreover, dosing regimens of 200 mg every 2 weeks and 3 mg/kg every 2 weeks provided similar exposure distributions by model-based Monte Carlo simulation. The population analyses demonstrated that patient characteristics have no clinically meaningful impact on the PKs of camrelizumab and present evidence for no advantage of either the flat dose or weight-based dose regimen for most patients with advanced solid tumors.

Pharmacokinetics and pharmacogenetics of high-dose methotrexate in Chinese adult patients with non-Hodgkin lymphoma: a population analysis.

PURPOSE: High-dose methotrexate (HD-MTX) is widely used in the treatment of non-Hodgkin lymphoma (NHL), but the pharmacokinetic properties of HD-MTX in Chinese adult patients with NHL have not yet been established through an approach that integrates genetic covariates. The purposes of this study were to identify both physiological and pharmacogenomic covariates that can explain the inter- and intraindividual pharmacokinetic variability of MTX in Chinese adult patients with NHL and to explore a new sampling strategy for predicting delayed MTX elimination. METHODS: A total of 852 MTX concentrations from 91 adult patients with NHL were analyzed using the nonlinear mixed-effects modeling method. FPGS, GGH, SLCO1B1, ABCB1 and MTHFR were genotyped using the Sequenom MassARRAY technology platform and were screened as covariates. The ability of different sampling strategies to predict the MTX concentration at 72 h was assessed through maximum a posteriori Bayesian forecasting using a validation dataset (18 patients). RESULTS: A two-compartment model adequately described the data, and the estimated mean MTX clearance (CL) was 6.03 L/h (9%). Creatinine clearance (CrCL) was identified as a covariate for CL, whereas the intercompartmental clearance (Q) was significantly affected by the body surface area (BSA). However, none of the genotypes exerted a significant effect on the pharmacokinetic properties of MTX. The percentage of patients with concentrations below 0.2 µmol/L at 72 h decreased from 65.6 to 42.6% when the CrCL decreased from 90 to 60 ml/min/1.73 m2 with a scheduled dosing of 3 g/m2, and the same trend was observed with dose regimens of 1 g/m2 and 2 g/m2. Bayesian forecasting using the MTX concentrations at 24 and 42 h provided the best predictive performance for estimating the MTX concentration at 72 h after dosing. CONCLUSIONS: The MTX population pharmacokinetic model developed in this study might provide useful information for establishing personalized therapy involving MTX for the treatment of adult patients with NHL.

Effect of Protein Binding on Exposure of Unbound and Total Mycophenolic Acid: A Population Pharmacokinetic Analysis in Chinese Adult Kidney Transplant Recipients.

OBJECTIVES: The population pharmacokinetic (popPK) characteristics of total mycophenolic acid (tMPA) have been investigated in various ethnic populations. However, investigations of popPK of unbound MPA (uMPA) are few. Thus, a popPK analysis was performed to: (1) characterize the PK of uMPA and tMPA and its 7-O-mycophenolic acid glucuronide (MPAG) metabolite in kidney transplant patients cotreated with cyclosporine (CsA), and (2) identify the clinically significant covariates that explain variability in the dose-exposure relationship. METHODS: A total of 740 uMPA, 741 tMPA, and 734 total MPAG (tMPAG) concentration-time data from 58 Chinese kidney transplant patients receiving MPA in combination with CsA were analyzed using NONMEM® software with the stochastic approximation expectation maximization (SAEM) followed by the important sampling (IMP) method. The influence of covariates was tested using a stepwise procedure. RESULTS: The PK of uMPA and unbound MPAG (uMPAG) were characterized by a two- and one-compartment model with first-order elimination, respectively. A linear protein binding model was used to link uMPA and tMPA. Apparent clearance (CL/F) and central volume of distribution (VC/F) of uMPA (CLuMPA/F and VCuMPA/F, respectively) and protein binding rate constant (k B) were estimated to be 851 L/h [relative standard error (RSE), 7.1%], 718 L (18.5%) and 53.4/h (2.3%), respectively. For uMPAG, the population values (RSE) of CL/F (CLuMPAG) and VC/F (VCuMPAG/F) were 5.71 L/h (4.4%) and 29.9 L (7.7%), respectively. Between-subject variability (BSVs) on CLuMPA/F, VCuMPA/F, CLuMPAG/F, and VCuMPAG/F were 51.0, 80.0, 31.8 and 48.4%, respectively, whereas residual unexplained variability (RUVs) for uMPA, tMPA, and uMPAG were 47.0, 45.9, and 22.0%, respectively. Significant relationships were found between k B and serum albumin (ALB) and between CLuMPAG/F and glomerular filtration rate (GFR). Additionally, model-based simulation showed that changes in ALB concentrations substantially affected tMPA but not uMPA exposure. CONCLUSIONS: The established model adequately described the popPK characteristics of the uMPA, tMPA, and MPAG. The estimated CLuMPA/F and unbound fraction of MPA (FUMPA) in Chinese kidney transplant recipients cotreated with CsA were comparable to those published previously in Caucasians. We recommend monitoring uMPA instead of tMPA to optimize mycophenolate mofetil (MMF) dosing for patients with lower ALB levels.

Systematic external evaluation of published population pharmacokinetic models for tacrolimus in adult liver transplant recipients.

BACKGROUND: Diverse tacrolimus population pharmacokinetic (popPK) models in adult liver transplant recipients have been established to describe the PK characteristics of tacrolimus in the last two decades. However, their extrapolated predictive performance remains unclear. Therefore, in this study, we aimed to evaluate their external predictability and identify their potential influencing factors. METHODS: The external predictability of each selected popPK model was evaluated using an independent dataset of 84 patients with 572 trough concentrations prospectively collected from Huashan Hospital. Prediction- and simulation-based diagnostics and Bayesian forecasting were conducted to evaluate model predictability. Furthermore, the effect of model structure on the predictive performance was investigated. RESULTS: Sixteen published popPK models were assessed. In prediction-based diagnostics, the prediction error within ± 30% was below 50% in all the published models. The simulation-based normalised prediction distribution error test and prediction- and variability-corrected visual predictive check indicated large discrepancies between the observations and simulations in most of the models. Bayesian forecasting showed improvement in model predictability with two to three prior observations. Additionally, the predictive performance of the nonlinear Michaelis-Menten model was superior to that of linear one- and two-compartment models with first-order elimination, indicating the underlying nonlinear kinetics of tacrolimus in liver transplant recipients, which was consistent with the findings in adult kidney transplant recipients. CONCLUSIONS: The published models performed inadequately in prediction- and simulation-based diagnostics. Bayesian forecasting may improve the predictive performance of the models. Furthermore, nonlinear kinetics of tacrolimus may be mainly caused by the properties of the drug itself, and incorporating nonlinear kinetics may be considered to improve model predictability.

Clinical Evaluation of the Tolerability and Pharmacokinetics of Azilsartan, a Potent Angiotensin Receptor Blocker, in Healthy Chinese Subjects.

Azilsartan (AZL), the active metabolite of azilsartan medoxomil, is the newest angiotensin receptor blocker that has been approved for the treatment of hypertension in 2012 in Japan. The present study aimed to evaluate the safety and pharmacokinetic properties of AZL in healthy Chinese subjects. We performed 2 phase 1 studies to investigate the pharmacokinetics and safety of AZL in healthy Chinese adults after a single dose (20 mg or 40 mg) or multiple doses of AZL (40 mg/d for 7 days; Study I) and after a single 40-mg dose under the fasted and fed conditions (Study II). Noncompartmental analysis and nonlinear mixed-effects modeling were used to analyze the pharmacokinetic properties of AZL. Twenty-seven healthy volunteers (14 men and 13 women) aged 20-32 years were enrolled and completed the study. During single dosing of AZL, the pharmacokinetics of AZL exhibited a linear profile between dosage and area under the concentration-time curve. There is no AZL accumulation after multiple doses. Food had no effect on the pharmacokinetic characteristics of AZL. AZL concentrations were best fit with a 2-compartment model, and the typical value of clearance was 1.63 L/h. Body weight had an impact on both the apparent clearance and peripheral volume of distribution. The pharmacokinetic parameters were consistent with previous studies in non-Chinese subjects. Model-based simulations indicated that a 45-kg subject would have approximately double the AZL exposure of a 90-kg subject. Whether the exposure difference has clinical significance needs to be confirmed in further studies among patients.

Evaluation of the Effectiveness of Clinical Pharmacists' Consultation in the Treatment of Infectious Diseases: A Single-Arm, Prospective Cohort Study.

Background: With the implementation of Antimicrobial Stewardship Program, clinical pharmacists' consultation (CPC) for infectious diseases (ID) is gradually adopted by many hospitals in China. We conducted a cohort study to evaluate the effectiveness of CPC in ID treatment on patient outcomes and potential determinants. Methods: Based on a registry database, a prospective cohort study was conducted in Guizhou Provincial People's Hospital. The main exposure factor was whether clinician adopted the suggestion from clinical pharmacist. The outcome was effective response rate (ERR) of ID patients. The variables associated with the outcome (e.g., age, gender, severity of infection, liver function, and kidney function) were also prospectively recorded. A multilevel model was performed to analyze the factors related to ERR. Results: A total of 733 ID inpatients were included in the final analysis according to the predesigned inclusion and exclusion criteria. The proportion of clinical pharmacists' suggestions adopted by clinicians and ERR were 88.13 and 69.03%, respectively. Significant data aggregation (P < 0.05) for individuals at the level of department was observed. According to the two-level variance component model, liver dysfunction (Adjusted Odds Ratio (AOR) = 0.649, 95%Credible Interval (CI): 0.432-0.976), severity of infection (AOR = 0.602, 95%CI: 0.464-0.781), and adopting the suggestion from pharmacist (AOR = 1.738, 95%CI: 1.028-2.940) had significant association with ERR. Conclusion: Our study suggests that the effect of CPC on ID treatment is significant. The policy/decision makers or hospital managers should be cognizant of the critical value of clinical pharmacists in ID treatment.

Systematic external evaluation of published population pharmacokinetic models of mycophenolate mofetil in adult kidney transplant recipients co-administered with tacrolimus.

AIMS: Various mycophenolate mofetil (MMF) population pharmacokinetic (popPK) models have been developed to describe its PK characteristics and facilitate its optimal dosing in adult kidney transplant recipients co-administered with tacrolimus. However, the external predictive performance has been unclear. Thus, this study aimed to comprehensively evaluate the external predictability of published MMF popPK models in such populations and investigate the potential influencing factors. METHODS: The external predictability of qualified popPK models was evaluated using an independent dataset. The evaluation included prediction- and simulation-based diagnostics, and Bayesian forecasting. In addition, factors influencing model predictability, especially the impact of structural models, were investigated. RESULTS: Fifty full PK profiles from 45 patients were included in the evaluation dataset and 11 published popPK models were identified and evaluated. In prediction-based diagnostics, the prediction error within ±30% was less than 50% in most published models. The prediction- and variability-corrected visual predictive check and posterior predictive check showed large discrepancies between the observations and simulations in most models. Moreover, the normalized prediction distribution errors of all models did not follow a normal distribution. Bayesian forecasting demonstrated an improvement in the model predictability. Furthermore, the predictive performance of two-compartment (2CMT) models incorporating the enterohepatic circulation (EHC) process was not superior to that of conventional 2CMT models. CONCLUSIONS: The published models showed large variability and unsatisfactory predictive performance, which indicated that therapeutic drug monitoring was necessary for MMF clinical application. Further studies incorporating potential covariates need to be conducted to investigate the key factors influencing model predictability of MMF.

Optimization and application of an HPLC method for quantification of inosine-5'-monophosphate dehydrogenase activity as a pharmacodynamic biomarker of mycophenolic acid in Chinese renal transplant patients.

BACKGROUND: The immunosuppressive agent mycophenolic acid (MPA) is a non-competitive, reversible inhibitor of inosine-5'-monophosphate dehydrogenase (IMPDH). Thus, IMPDH activity can serve as a potential pharmacodynamic biomarker to optimize dosing of MPA. METHODS: Peripheral blood mononuclear cells were isolated from 2 mL blood samples and an in vitro enzymatic reaction was subsequently performed for 120 min. To determine IMPDH activity in Chinese healthy volunteers and renal transplant patients, a high performance liquid chromatography assay was established and validated by subtracting adenosine monophosphate (AMP) from blank samples for eliminating exogenous AMP interference. RESULTS: The accuracy of our method ranged between -0.8% and 12.5%, and the precision ranged between 0.7% and 6.3%. The mean value of IMPDH activity across 11 healthy volunteers was 46.60 ±â€¯14.28 µmol/s/mol AMP. A negative relationship between MPA concentration and IMPDH activity was observed in four renal transplant patients treated with MPA 13 days post-transplantation, while the inhibitory rate of IMPDH activity ranged from 24% to 42%. CONCLUSION: A bioanalytical assay for IMPDH quantification was optimized and evaluated. The differences in the pharmacodynamics of MPA between Asians and Caucasians may provide some evidence for dosing differences among ethnicities.