Search

What Is Known and Objectives: The present study aimed to predict the effect of sirolimus on disease activity in patients with systemic lupus erythematosus (SLE) using machine learning and to recommend appropriate sirolimus dosage regimen for patients with SLE. Methods: The Emax model was selected for machine learning, where the evaluation indicator was the change rate of systemic lupus erythematosus disease activity index from baseline value. Results: A total 103 patients with SLE were included for modelling, where the Emax, ET50 were −53.9%, 1.53 months in the final model respectively, and the evaluation of the final model was good. Further simulation found that the follow‐up time to achieve 25%, 50%, 75% and 80% (plateau) Emax of sirolimus effecting on disease activity in patients with SLE were 0.51, 1.53, 4.59 and 6.12 months, respectively. In addition, the sirolimus dosage was flexible and adjusted according to drug concentration, where the intersection of sirolimus concentration range included in this study was about 8–10 ng/ml. What Is New and Conclusions: This study was the first time to predict the effect of sirolimus on disease activity in patients with SLE and in order to achieve better therapeutic effect maintaining a concentration of 8–10 ng/ml sirolimus for at least 6.12 months was necessary. [ABSTRACT FROM AUTHOR]

What is Known and Objectives: The initial tacrolimus dose regimen in paediatric lung transplant recipients is unknown. The present study optimized the initial tacrolimus dose regimen for paediatric lung transplant recipients. Methods: This study was based on a published population pharmacokinetic model of tacrolimus in lung transplant recipients and used Monte Carlo simulations to recommend an initial dose regimen of tacrolimus in paediatric lung transplant recipients. Results: Without voriconazole, the tacrolimus doses recommended for paediatric lung transplant recipients who were not CYP3A5*1 carriers were 0.02, 0.03, and 0.04 mg/kg/day, split into two doses, for weights of 10–16, 16–30, and 30–40 kg, respectively. For paediatric lung transplant recipients who were CYP3A5*1 carriers, the tacrolimus doses of 0.03, 0.04, 0.05, and 0.06 mg/kg/day, split into two doses, were recommended for weights of 10–16, 16–25, 25–30, and 30–40 kg, respectively. With voriconazole, the tacrolimus dose recommended for paediatric lung transplant recipients who were not CYP3A5*1 carriers was 0.02 mg/kg/day, split into two doses, for weights of 10–40 kg. For paediatric lung transplant recipients who were CYP3A5*1 carriers, tacrolimus doses of 0.02 and 0.03 mg/kg/day, split and two doses, were recommended for weights of 10–24 and 24–40 kg, respectively. What is New and Conclusions: This study developed tacrolimus dose regimens for the first time for paediatric lung transplant recipients using Monte Carlo simulation and optimized initial dosage in paediatric lung transplant recipients. [ABSTRACT FROM AUTHOR]

What is known and objectives: Dapagliflozin was the first oral treatment approved in type 1 diabetes mellitus (T1DM) patients, simultaneously improving body weight. However, the time course and dose effect of dapagliflozin on loss of weight in T1DM patients was still unknown. The present study aimed to investigate quantitative relationship between dapagliflozin and loss of weight in T1DM patients based on Model‐based Meta‐analysis. Methods: Five dapagliflozin dosage groups, two of them were 5 mg/day and three of them were 10 mg/day, 1612 T1DM patients were analysed with maximal effect (Emax) model, and evaluation index was change rate of body weight from baseline value. Results: In these T1DM patients, dosages were not incorporated into model, indicating no significant dose‐response relationship between 5 and 10 mg/day affecting loss of weight. Emax and the treatment duration to reach half of the maximal effects (ET50) of dapagliflozin influencing loss of weight in T1DM patients were −4.9% and 10.4 weeks, and the duration to achieve 25%, 50%, 75%, and 80% (plateau) of Emax were 3.5, 10.4, 31.2, and 41.6 weeks. What is new and conclusions: It was the first time to explore quantitative relationship between dapagliflozin and loss of weight in T1DM patients. To achieve the plateau period in loss of weight, 5 mg/day dapagliflozin was required for at least 41.6 weeks. [ABSTRACT FROM AUTHOR]

What is known and objectives: Tacrolimus is used to treat patients with lupus nephritis; however, its time course and dose effect on proteinuria in lupus nephritis patients remain unknown. The purpose of this study was to determine the time course and dose effect of tacrolimus on proteinuria in lupus nephritis patients via model‐based meta‐analysis (MBMA). Methods: PubMed, Web of Science, Cochrane Library and ClinicalTrials.gov databases were systematically searched for information on the efficacy of tacrolimus against proteinuria in lupus nephritis patients. Useful data were extracted to build a model for the population studied using a non‐linear mixed‐effect model (NONMEM). This model was applied to simulate time course of tacrolimus on proteinuria using Monte Carlo simulations. Results: Ten clinical studies that recruited 222 patients with lupus nephritis were included. Based on various diagnostic plots, we found that the established model described the observed data reasonably well. In addition, the typical Emax and ET50 of tacrolimus for 24‐hour proteinuria in lupus nephritis patients were −5.88 g and 0.37 months, respectively. The baseline value of 24‐hour proteinuria affected Emax. No significant dose‐response relationship was observed in the range of tacrolimus concentration used in the present study (3‐10 ng/mL), indicating that the effect of tacrolimus on proteinuria depends on effective concentration range and not the dose. However, the time course relationship was obvious; the efficacy of tacrolimus increased over time, reaching a plateau (80% Emax) at approximately 1.48 months from the beginning of treatment. What is new and conclusion: When the concentration range of tacrolimus is maintained at 3‐10 ng/mL, at least 1.48 months of treatment is required to achieve a better outcome with regard to proteinuria in lupus nephritis patients. [ABSTRACT FROM AUTHOR]

Summary: What is known and objectives: Tacrolimus is widely used for kidney transplantation in children. However, the narrow therapeutic window and considerable interindividual and intraindividual variabilities make tacrolimus untoward to design an optimum dosage for paediatric personalized medicine. Our research aims to establish the tacrolimus population pharmacokinetics (PPK) of Chinese paediatric kidney transplantation patients and to distinguish covariates impacting variabilities. Methods: Chinese paediatric kidney transplantation patients treated with tacrolimus between January 2014 and April 2018 from Children's Hospital of Fudan University were retrospectively analysed. A total of 51 Chinese paediatric kidney transplantation patients were analysed using non‐linear mixed effects modelling (NONMEM). The effects of population characteristics, biological features and drug combination were assessed. The final PPK model was evaluated using visual inspection of routine diagnostic plots and the internal validation method of bootstrap. Results: Our data met the condition of a one‐compartment model, and the final model was CL/F = 32.7 × (WT/70)0.75 × (1 – WZ × 0.341) × (HGB/97)−0.508; V/F = 1890 × (WT/70) × (POD/57)0.816, where WT, WZ, HGB and POD were weight, Wuzhi capsule (extracted from schisandra sphenanthera, whose primary efficient constituents are schisantherin A, schisandrol B, schisandrin etc, and often used to treat drug‐induced hepatitis in Chinese organ transplant patients), haemoglobin and post‐transplant day, respectively. What is new and conclusion: The tacrolimus PPK model in Chinese paediatric kidney transplantation patients was developed, and Wuzhi capsule and haemoglobin influence tacrolimus elimination in paediatric kidney transplantation patients. [ABSTRACT FROM AUTHOR]