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ObjectivesOlanzapine is used for treating bipolar disorder (BPD); however, the optimal initial dosing regimen is unclear. The present study aimed to investigate the optimal olanzapine initial dosage in patients with BPD via model-informed precision dosing (MIPD) based on a real-world study.MethodsThirty-nine patients with BPD from the real-world study were collected to construct the MIPD model.ResultsWeight, combined used quetiapine influenced olanzapine clearances in patients with BPD, where the clearance rates were 0.152:1 in patients with or without quetiapine under the same weight. We simulated olanzapine doses once a day or twice a day, of which twice a day was optimal. Without quetiapine, for twice-a-day olanzapine doses, 0.80, 0.70, and 0.60 mg/kg/day were suitable for 40- to 56-kg BPD patients, 56- to 74-kg BPD patients, and 74- to 100-kg BPD patients, respectively. With quetiapine, for twice-a-day olanzapine doses, 0.05 mg/kg/day was suitable for 40- to 100-kg BPD patients.ConclusionThis study was the first to investigate the optimal olanzapine initial dosage in patients with BPD via MIPD based on a real-world study, providing clinical reference for the precision medication of olanzapine in BPD patients.

Dapagliflozin has been used to treat patients with type 1 diabetes mellitus; however, the actual drug efficacy of dapagliflozin on glycated hemoglobin (HbA1c) and whether there is a rebound from dapagliflozin efficacy on HbA1c remain unknown. The present study aimed to explore the actual therapeutic effect and rebound situation of dapagliflozin on HbA1c in type 1 diabetes mellitus patients. A total of 1,594 type 1 diabetes mellitus patients were enrolled for analysis using a non-linear mixed effect model from randomized controlled trials from published literature works including two 5 mg/day dapagliflozin dosage groups and three 10 mg/day dapagliflozin dosage groups. The change rate of HbA1c from a baseline value was chosen as a dapagliflozin pharmacodynamic evaluation index. After deducting control group effects, the therapeutic effect of 5 and 10 mg/day dapagliflozin on HbA1c in type 1 diabetes mellitus patients had no significant difference. In addition, the actual maximal efficacy (AEmax) of dapagliflozin on HbA1c was -6.24% at week 9. When it reached the AEmax, the dapagliflozin pharmacodynamic rebound on HbA1c occurred, and when the treatment was continued for 0.5 and 1 year, the actual efficacies were -4.70% (75% AEmax) and -3.27% (52% AEmax), respectively. This was the first time to clarify the actual therapeutic effect and rebound situation of dapagliflozin on HbA1c in type 1 diabetes mellitus patients, providing a reference value for clinical practices.

The aim of the present study is to investigate the quantitative effects of sodium–glucose cotransporter-2 (SGLT-2) inhibitors on the quality of life in heart failure (HF) patients. A total of 14,674 HF patients from two dapagliflozin and three empagliflozin studies is included for analysis via the nonlinear mixed-effect modeling (NONMEM) software, among which the change rate of the Kansas City Cardiomyopathy Questionnaire (KCCQ) score is used as the evaluation index. There is no significant difference in the pharmacodynamics influencing the quality of life in HF patients between the SGLT-2 inhibitors: 10 mg/day dapagliflozin and 10 mg/day empagliflozin. For the clinical summary score (CSS), total symptom score (TSS), and overall summary score (OSS), the Emax of the SGLT-2 inhibitors on the quality of life in HF patients is 3.74%, 4.43%, and 4.84%, respectively, and ET50 is 2.23, 4.37, and 7.15 weeks, respectively. In addition, the time duration of achieving 25%, 50%, 75%, and 80% Emax is 0.75, 2.23, 6.69, and 8.92 weeks for the CSS; 1.46, 4.37, 13.11, and 17.48 weeks for the TSS; and 2.39, 7.15, 21.45, and 28.6 weeks for the OSS, respectively. Therefore, to reach the plateau period (80% of Emax) of SGLT-2 inhibitors on the CSS, TSS, and OSS, 10 mg/day dapagliflozin (or 10 mg/day empagliflozin) is required to be taken for 8.92 weeks, 17.48 weeks, and 28.6 weeks, respectively. This is the first time that the quantitative effects of SGLT-2 inhibitors on the quality of life in HF patients are being explored.

The purpose of this study was to analyze the time course and dose effect from metformin on body mass index (BMI) in children and adolescents by model-based meta-analysis (MBMA). Searching randomized controlled trial (RCT) studies of metformin on BMI in children and adolescents. The change rates of BMI from baseline values were used as indicator of evaluating metformin efficacy. A total of 18 RCT studies, 1,228 children and adolescents, were included for analysis, including patients with obesity, patients with type 1 diabetes mellitus, patients with nonalcoholic fatty liver, and patients with precocity. In order to achieve better effect of metformin on BMI in children and adolescents, the present study recommended that for patients with obesity, 1,000 mg/day metformin was required for at least 15.2 weeks and 60.8 weeks to achieve the plateau of metformin effect; for patients with type 1 diabetes mellitus, 1,000 mg/day metformin was required for at least 25.2 weeks and 100.8 weeks to achieve the plateau of metformin effect; for patients with nonalcoholic fatty liver, 1,000 mg/day metformin was required for at least 6.57 weeks and 26.28 weeks to achieve the plateau of metformin effect; for patients with precocity, 425 mg/day metformin was required for at least 12.4 weeks and 49.6 weeks to achieve the plateau of metformin effect. It was the first time to analyze the time course and dose effect from metformin on BMI and to recommend dosage and duration of treatment for metformin in children and adolescents with different disease types.

Sirolimus is already used in the treatment of tuberous sclerosis complex (TSC), however, with narrow therapeutic range and considerable inter- and intra-individual pharmacokinetic variability, making it hard to develop an appropriate sirolimus initial dosage regimen, especially in children with TSC. The aim of this study was to recommend the optimal sirolimus initial dosing regimen in pediatric patients with TSC. Underlying physiological and genetic factors were collected to explore the effects on clinical sirolimus concentrations by establishing a nonlinear mixed effect (NONMEM) model, and to further simulate the optimal sirolimus initial dosing regimen using Monte Carlo method in pediatric patients with TSC. The once-daily regimen and the twice-daily regimen were recommended, respectively. For once-daily regimen, the dosages of 0.10, 0.07, 0.05, 0.04, 0.03 mg/kg/day were recommended for children with weights of 5–10, 10–20, 20–30, 30–50, and 50–60 kg, respectively. For twice-daily regimen, the dosages of 0.04, 0.03, 0.02 mg/kg/day (the daily dose was divided evenly into two doses) were recommended for children with weights of 5–20, 20–40, 40–60 kg, respectively. The initial dosages of sirolimus in children with TSC were recommended for the first time.

Objectives: Olanzapine is used for treating bipolar disorder (BPD); however, the optimal initial dosing regimen is unclear. The present study aimed to investigate the optimal olanzapine initial dosage in patients with BPD via model-informed precision dosing (MIPD) based on a real-world study. Methods: Thirty-nine patients with BPD from the real-world study were collected to construct the MIPD model. Results: Weight, combined used quetiapine influenced olanzapine clearances in patients with BPD, where the clearance rates were 0.152:1 in patients with or without quetiapine under the same weight. We simulated olanzapine doses once a day or twice a day, of which twice a day was optimal. Without quetiapine, for twice-a-day olanzapine doses, 0.80, 0.70, and 0.60 mg/kg/day were suitable for 40- to 56-kg BPD patients, 56- to 74-kg BPD patients, and 74- to 100-kg BPD patients, respectively. With quetiapine, for twice-a-day olanzapine doses, 0.05 mg/kg/day was suitable for 40- to 100-kg BPD patients. Conclusion: This study was the first to investigate the optimal olanzapine initial dosage in patients with BPD via MIPD based on a real-world study, providing clinical reference for the precision medication of olanzapine in BPD patients. [ABSTRACT FROM AUTHOR]