Population Pharmacodynamic Models of Risperidone on PANSS Total Scores and Prolactin Levels in Schizophrenia.

Currently, research predominantly focuses on evaluating clinical effects at specific time points while neglecting underlying patterns within the treatment process. This study aims to analyze the dynamic alterations in PANSS total scores and prolactin levels in patients with schizophrenia treated with risperidone, along with the influencing covariates. Using data from an 8-week randomized, double-blind, multicenter clinical trial, a population pharmacodynamic model was established for the PANSS total scores of and prolactin levels in patients treated with risperidone. The base model employed was the Emax model. Covariate selection was conducted using a stepwise forward inclusion and backward elimination approach. A total of 144 patients were included in this analysis, with 807 PANSS total scores and 531 prolactin concentration values. The PANSS total scores of the patients treated with risperidone decreased over time, fitting a proportionally parameterized sigmoid Emax model with covariates including baseline score, course of the disease, gender, plasma calcium ions, and lactate dehydrogenase levels. The increase in prolactin levels conformed to the ordinary Emax model, with covariates encompassing course of the disease, gender, weight, red blood cell count, and triglyceride levels. The impacts of the baseline scores and the course of the disease on the reduction of the PANSS scores, as well as the influence of gender on the elevation of prolactin levels, each exceeded 20%. This study provides valuable quantitative data regarding PANSS total scores and prolactin levels among patients undergoing risperidone treatment across various physiological conditions.

Clinical efficacy and modeling evaluation of He-wei-zhi-xie capsules in treating diarrhea patients / 中国临床药理学与治疗学

AIM: To evaluate the clinical efficacy and safety of He-wei-zhi-xie (HWZX) capsules in diarrhea patients. METHODS: The clinical study was conducted in 35 clinical trials centers from October 2015 to December 2017 by multicenter, prospective, open and uncontrolled design methods. The primary efficacy endpoint is the effective rate of diarrhea, the secondary endpoints include recovery rate of diarrhea, recovery time of diarrhea, number of irregular stools and Leeds dyspepsia questionnaire. The pharmacodynamics model of time course was established by nonlinear mixed effect model, and the effect of covariates on pharmacodynamic parameters was investigated. The safety measures were the incidence of adverse events, adverse reactions and the laboratory test indicators. RESULTS: A total of 2 285 cases were included in full analysis set. The effective rate of diarrhea was 90.8%, and the diarrhea recovery rate was 77.3%. The median time of recovery was 3 days, and the Leeds score was reduced by 3.6 points. It is found that baseline has a significant effect on model parameter E

Prediction of the human in vivo antiplatelet effect of S- and R-indobufen using population pharmacodynamic modeling and simulation based on in vitro platelet aggregation test

Indobufen (Ibustrin®), a reversible inhibitor of platelet aggregation, exists in two enantiomeric forms in 1:1 ratio. Here, we characterized the anti-platelet effect of S- and R-indobufen using response surface modeling using NONMEM® and predicted the therapeutic doses exerting the maximal efficacy of each enantioselective S- and R-indobufen formulation. S- and R-indobufen were added individually or together to 24 plasma samples from drug-naïve healthy subjects, generating 892 samples containing randomly selected concentrations of the drugs of 0–128 mg/L. Collagen-induced platelet aggregation in platelet-rich plasma was determined using a Chrono-log Lumi-Aggregometer. Inhibitory sigmoid I(max) model adequately described the anti-platelet effect. The S-form was more potent, whereas the R-form showed less inter-individual variation. No significant interaction was observed between the two enantiomers. The anti-platelet effect of multiple treatments with 200 mg indobufen twice daily doses was predicted in the simulation study, and the effect of S- or R-indobufen alone at various doses was predicted to define optimal dosing regimen for each enantiomer. Simulation study predicted that 200 mg twice daily administration of S-indobufen alone will produce more treatment effect than S-and R-mixture formulation. S-indobufen produced treatment effect at lower concentration than R-indobufen. However, inter-individual variation of the pharmacodynamic response was smaller in R-indobufen. The present study suggests the optimal doses of R-and S-enantioselective indobufen formulations in terms of treatment efficacy for patients with thromboembolic problems. The proposed methodology in this study can be applied to the develop novel enantio-selective drugs more efficiently.

A Simulation Study of Propofol Effect-Site Concentration for Appropriate Sedation in Pediatric Patients Undergoing Brain MRI: Pharmacodynamic Analysis

PURPOSE: We aimed to establish the propofol effect-site concentration (Ce) for appropriate sedation by pharmacodynamic analysis and to determine the propofol Ce during occurrence of sedation-related side effects in pediatric patients undergoing brain magnetic resonance imaging (MRI). MATERIALS AND METHODS: In 50 pediatric patients scheduled for brain MRI, sedation was induced with 2.0 mg/kg propofol; additional propofol doses were 0.5–1 mg/kg. Propofol Ce was simulated by inputting the propofol administration profiles of patients into a pediatric compartmental model (Choi model). The relationship between propofol Ce and probabilities of sedation and recovery were analyzed using a sigmoidal Emax model. The simulated propofol Ce for sedation-related side effects was investigated. Population model parameters were estimated using the Nonlinear Mixed-Effects Modelling software. RESULTS: The mean values of propofol Ce₅₀ for sedation during the preparation, scanning, and recovery phases were 1.23, 0.43, and 0.39 µg/mL. The simulated propofol Ce values during oxygen desaturation (SpO₂<90%) (3 patients; 6%), hypotension (16 patients; 32%), and bradycardia (12 patients; 24%) were 3.01±0.04, 2.05±0.63, and 2.41±0.89 µg/mL, respectively. CONCLUSION: The required propofol Ce₅₀ for applying monitors during the preparation phase before the start of MRI was higher than the propofol Ce₅₀ required during the scanning phase. During low-intensity stimulation phases, such as scanning, propofol bolus dose should be strictly titrated not to exceed the propofol Ce that can lead to oxygen desaturation because of the relatively low propofol Ce (Ce₉₅, 1.43 µg/mL) required for sedation in most patients.

Setting up population pharmacokinetics/pharmacodynamics model of VPA in children with epilepsy by NONMEM software / 中国临床药理学与治疗学

AIM: To set up population pharmacokinetics/pharmacodynamics (PPK/PD) model of valproate (VPA) in children with epilepsy in China, and promote reasonable use of antiepileptic drugs(AEDs)in clinical practice. METHODS: Sparse data of VPA serum concentrations from 246 pediatric children were collected. These patients were divided into three groups: PPK-Model group ([WTBX]n=146), to calculate PPK parameter values of VPA and set up a PPK model; PPK-Valid group ([WTBX]n=100), to valid the PPK model; and PPD group ([WTBX]n=69), to set up PPK/PD model. Based on the data of PPK-Model group and PPK-Valid group, a PPK model of VPA in children with epilepsy in China was successfully set up by using NONMEM software by ourselves. Now, using the data of 69 patients in PPD group who were on VPA monotherapy and this PPK model, we set up PPK/PD model by NONMEM software. Efficacy of epilepsy treatment was divided into 5 grades according to the percentage of seizure frequency decreased (PSFD%): grade 1: PSFD% was 100%; grade 2: PSFD% was 75%-100%; grade 3: PSFD% was 50%-75%; grade 4: PSFD% was 25%-50%; grade 5: PSFD% was less than 25%. The quantitive relationship between the VPA serum concentrations and the probability for its efficacy score was characterized by Logistic regression analysis with NONMEM. RESULTS: Logistic regression analysis showed that, VPA serum concentrations and the probability for its efficacy grades 5, 4, 3, 2, and 1 were (23 ?g?ml -1, 5, 50%), (30 ?g?ml -1, 4, 32.3%), (50 ?g?ml -1, 3, 26.3%), (65 ?g?ml -1, 2, 36.5%), (78 ?g?ml -1, 1, 50%), and (100 ?g?ml -1, 1, 84.2%)respectively. CONCLUSION: A PPK/PD model of VPA in children with epilepsy in China is successfully established by using NONMEM software, and the probability of efficacy grade for any concentration can be calculated. It will be valuable to facilitate individualized dosage regimen.