OBJECTIVES: Cyclosporin has been used for the treatment of pediatric refractory nephrotic syndrome (PRNS). However, the narrow therapeutic window and large pharmacokinetic variability make it difficult to individualize cyclosporin administration. Meanwhile, spironolactone has been reported to affect cyclosporin metabolism in PRNS patients. This study aims to explore the initial dosage optimization of cyclosporin in PRNS based on the impact of spironolactone co-administration. METHODS: Monte Carlo simulation based on a previously established cyclosporin population pharmacokinetic model for PRNS was used to design cyclosporin dosing regimen. RESULTS: In this study, the probability of drug concentration reaching the target and the convenience of times of administration were considered comprehensively. The optimal administration regimen in PRNS without spironolactone was 6, 5, 4 and 3 mg/kg cyclosporin split into two doses for the body weight of 5-8, 8-18, 18-46 and 46-70 kg, respectively. The optimal administration regimen in PRNS with spironolactone was 4, 3, 2 mg/kg cyclosporin split into two doses for body weight of 5-14, 14-65, and 65-70 kg, respectively. CONCLUSION: The cyclosporin dosing regimen for PRNS based on Monte Carlo simulation was systematically developed and the initial dosage optimization of cyclosporin in PRNS was recommended for the first time.
PURPOSE: The present study aims to explore the effects of tacrolimus on proteinuria in patients with idiopathic membranous nephropathy (IMN) and recommend an appropriate dosage schedule via machine learning method. METHODS: The Emax model was constructed to analyze the effects of tacrolimus on proteinuria in patients with IMN. Data were mined from published literature and machine learning was built up with Emax model, among which the efficacy indicator was proteinuria change rates from baseline. 463 IMN patients were included for modeling, and tacrolimus therapeutic window concentrations were 4-10 ng/ml. RESULTS: In machine learning model, the Emax from tacrolimus effecting proteinuria in IMN patients was -72.7%, the ET50 was 0.43 months, and the time to achieving 25% Emax, 50% Emax, 75% Emax, and 80% (plateau) Emax of tacrolimus on proteinuria in patients with IMN were 0.15, 0.43, 1.29, and 1.72 months, respectively. CONCLUSION: For achieving better therapeutic effects from tacrolimus on proteinuria in patients with IMN, tacrolimus concentration range need to be maintained at 4-10 ng/ml for at least 1.72 months.
Objective: Olanzapine has already been used to treat schizophrenia patients; however, the initial dosage recommendation when multiple drugs are used in combination, remains unclear. The purpose of this study was to explore the drug-drug interaction (DDI) of multiple drugs combined with olanzapine and to recommend the optimal administration of olanzapine in schizophrenia patients. Methods: In this study, we obtained olanzapine concentrations from therapeutic drug monitoring (TDM) database. In addition, related medical information, such as physiological, biochemical indexes, and concomitant drugs was acquired using medical log. Sixty-five schizophrenia patients were enrollmented for analysis using population pharmacokinetic model by means of nonlinear mixed effect (NONMEM). Results: Weight and combined use of aripiprazole significantly affected olanzapine clearance. Without aripiprazole, for once-daily olanzapine administration dosages, 0.6, 0.5 mg/kg/day were recommended for 40-70, and 70-100 kg schizophrenia patients, respectively; for twice-daily olanzapine administration dosages, 0.6, 0.5 mg/kg/day were recommended for 40-60, and 60-100 kg schizophrenia patients, respectively. With aripiprazole, for once-daily olanzapine administration dosages, 0.4, 0.3 mg/kg/day were recommended for 40-53, and 53-100 kg schizophrenia patients, respectively; for twice-daily olanzapine administration dosages, 0.4 mg/kg/day was recommended for 40-100 kg schizophrenia patients, respectively. Conclusion: Aripiprazole significantly affected olanzapine clearance, and when schizophrenia patients use aripiprazole, the olanzapine dosages need adjust. Meanwhile, we firstly recommended the optimal initial dosages of olanzapine in schizophrenia patients.
The dose-dependent pharmacological response to dapagliflozin in patients with type 2 diabetes mellitus (T2DM) with regard to weight loss remain unknown. The aim of the present study was to investigate the effects of dapagliflozin on weight loss in patients with T2DM. A total of 8,545 patients with T2DM from 24 randomized controlled trials reported in the literature were selected for inclusion in the study. Data from these trials were analyzed using maximal effect (Emax) models with nonlinear mixed effects modeling; the evaluation index was the body weight change rate from baseline values. Patients treated with 2.5 mg/day dapagliflozin exhibited an Emax of -3.04%, and the time taken for therapy to reach half of the Emax (ET50) was estimated to be 30.8 weeks for patients treated with this dose. Patients treated with 5, 10 and 20 mg/day dapagliflozin exhibited Emax values of -6.57, -4.12 and -3.23%, respectively, and their ET50 values were estimated to be 27.3, 20.4 and 4.23 weeks, respectively. The data indicated ideal linear relationships between individual predictions and observations, suggesting the optimal fitting of the final models. The present study is the first systematic analysis of the effect of dapagliflozin on weight loss in patients with T2DM. The application of dapagliflozin at 5 mg/day exhibited a greater weight loss effect compared with the other doses used, and the weight loss onset time shortened as the dose of dapagliflozin increased.
BACKGROUND: Delayed or missed dosages caused by poor medication compliance significantly affected the treatment of diseases in children. AIMS: The present study aimed to investigate the influence of delayed or missed dosages on sirolimus pharmacokinetics (PK) in pediatric tuberous sclerosis complex (TSC) patients and to recommend remedial dosages for nonadherent patients. METHODS: A published sirolimus population PK model in pediatric TSC patients was used to assess the influence of different nonadherence scenarios and recommend optimally remedial dosages based on Monte Carlo simulation. Thirteen nonadherent scenarios were simulated in this study, including delayed 2h, 4 h, 6 h, 8 h, 10 h, 12 h, 14 h, 16 h, 18 h, 20 h, 22 h, 23.5 h, and missed one dosage. Remedial dosing strategies contained 10-200% of scheduled dosages. The optimal remedial dosage was that with the maximum probability of returning the individual therapeutic range. RESULTS: For delayed or missed sirolimus dosages in pediatric TSC patients, when the delayed time was 0-8 h, 8-10 h, 10-18 h, 18-22.7 h, 22.7-24 h, 70%, 60%, 40%, 30%, 20% scheduled dosages were recommended to take immediately. When one dosage was missed, 120% of scheduled dosages were recommended at the next dose. CONCLUSION: It was the first time to recommend remedial dosages for delayed or missed sirolimus therapy caused by poor medication compliance in pediatric TSC patients based on Monte Carlo simulation. Meanwhile, the present study provided a potential solution for delayed or missed dosages in clinical practice.
Background: The appropriate initial dosage of tacrolimus is undefined in Chinese pediatric lung transplant patients with normal hematocrit values. The purpose of this study is to optimize the initial dose of tacrolimus in Chinese children who are undergoing lung transplantation and have normal hematocrit levels. Methods: The present study is based on a published population pharmacokinetic model of tacrolimus in lung transplant patients and uses the Monte Carlo simulation to optimize the initial tacrolimus dosage in Chinese children with lung transplantation within normal hematocrit levels. Results: Within normal hematocrit levels, for children with lung transplantation who do not carry the CYP3A5*1 gene and have no coadministration with voriconazole, it is recommended to administer tacrolimus at a dosage of 0.02â mg/kg/day, divided into two doses, for children weighing 10-32â kg, and a dosage of 0.03â mg/kg/day, also divided into two doses, for children weighing 32-40â kg. For children with lung transplantation who carry the CYP3A5*1 gene and have no coadministration with voriconazole, tacrolimus dosages of 0.02, 0.03, and 0.04â mg/kg/day split into two doses are recommended for children weighing 10-15, 15-32, and 32-40â kg, respectively. For children with lung transplantation who do not carry the CYP3A5*1 gene and have coadministration with voriconazole, tacrolimus dosages of 0.01 and 0.02â mg/kg/day split into two doses are recommended for children weighing 10-17 and 17-40â kg, respectively. For children with lung transplantation who carry the CYP3A5*1 gene and have coadministration with voriconazole, a tacrolimus dosage of 0.02â mg/kg/day split into two doses is recommended for children weighing 10-40â kg. Conclusions: It is the first time to optimize the initial dosage of tacrolimus in Chinese children undergoing lung transplantation within normal hematocrit.
BACKGROUND: The treatment of tacrolimus-induced post-transplantation diabetes mellitus (PTDM) has become a hot topic to improve the long-term survival of organ transplant patients, however whose pathogenesis has not been fully elucidated. In pancreas, the up-regulation of NF-κB has been reported to stimulate cytokine IL-1ß/TNF-α secretion, inducing pancreatic injury, meanwhile other studies have reported the inhibitory effect of rapamycin on NF-κB. PURPOSE: The aim of this study was to clarify the mechanism of tacrolimus-induced pancreatic injury and to explore the potential effect from small dose of sirolimus. METHODS: Wistar rats were randomly divided normal control (NC) group, PTDM group, sirolimus intervention (SIR) group. Transcriptomic analysis was used to screen potential mechanism of PTDM. Biochemical index detections were used to test the indicators of pancreatic injury. Pathological staining, immumohistochemical staining, immunofluorescent staining, western blot were used to verify the underlying mechanism. RESULTS: Compared with NC group, the level of insulin was significant reduction (P < 0.01), inversely the level of glucagon was significantly increase (P < 0.01) in PTDM group. Transcriptomic analysis indicated Syk/BLNK/NF-κB signaling was significantly up-regulated in PTDM group. Pathological staining, immumohistochemical staining, immunofluorescent staining, western blot verified Syk/BLNK/NF-κB and TNF-α/IL-1ß were all significantly increased (P < 0.05 or P < 0.01), demonstrating the mechanism of tacrolimus-induced pancreatic injury via Syk/BLNK/NF-κB signaling. In addition, compared with PTDM group, the levels of weight, FPG, AMY, and GSP in SIR group were significant ameliorative (P < 0.05 or P < 0.01), and the expressions of p-NF-κB, TNF-α/IL-1ß in SIR group were significantly reduction (P < 0.05 or P < 0.01), showing Syk/BLNK/NF-κB signaling promoted pancreatic injury induced by tacrolimus and potential protective effect from rapamycin reducing NF-κB. CONCLUSION: Syk/BLNK/NF-κB signaling promotes pancreatic injury induced by tacrolimus and rapamycin has a potentially protective effect by down-regulating NF-κB. Further validation and clinical studies are needed in the future.
NF-kappa B , Tacrolimus , Humans , Rats , Animals , NF-kappa B/metabolism , Sirolimus , Tumor Necrosis Factor-alpha , Rats, Wistar
OBJECTIVES: Cyclosporin is one of the therapeutic regimens for hemophagocytic lymphohistiocytosis (HLH); however, the optimal dosage of cyclosporine in children with HLH is unknown. It has been found that piperacillin-tazobactam affects the cyclosporine pharmacokinetic process in pediatric HLH patients. Thus, the purpose of the present study was to recommend cyclosporin dosage for pediatric HLH with and without piperacillin- tazobactam. METHODS: A previously established cyclosporine population pharmacokinetic model for pediatric HLH patients has been used in this study to recommend optimal dosage based on Monte Carlo simulation. The pediatric HLH patients have been included in eight weight groups (5, 10, 20, 30, 40, 50, 60, 70 kg) for sixteen dosages (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 mg/kg), split into one dose or two doses. RESULTS: The optimal cyclosporin dosages for children having HLH without piperacillin-tazobactam have been found to be 15, 13, 12, 11, 10, and 9 mg/kg, split into two doses for weights of 5-7, 7-10, 10-20, 20-28, 28-45, and 45-70 kg, respectively. For children with HLH, optimal cyclosporin dosages with piperacillin-tazobactam have been found to be 8 and 7 mg/kg, split into two doses for weights of 5-20 and 20-70 kg, respectively. CONCLUSION: It is the first time that the cyclosporin dosage regimens for HLH in children have been developed based on Monte Carlo simulation, and the initial dosage optimizations of cyclosporine in pediatric HLH patients have been recommended.
Cyclosporine , Lymphohistiocytosis, Hemophagocytic , Child , Humans , Cyclosporine/therapeutic use , Lymphohistiocytosis, Hemophagocytic/drug therapy , Piperacillin, Tazobactam Drug Combination/therapeutic use
BACKGROUND: The present study aimed to explore the quantitative effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on liver functions in patients with nonalcoholic fatty liver disease (NAFLD). RESEARCH DESIGN AND METHODS: A total of 4771 patients with NAFLD were included for analysis by means of nonlinear mixed effect modeling, where the change rates of liver functions were taken as the evaluation indexes so as to eliminate the potential baseline effects. RESULTS: For ALT and AST, the Emax of SGLT-2 inhibitors was -17.8% and -13.9%, respectively, and the ET50 was 6.86 weeks and 10 weeks, respectively. Furthermore, the duration time to achieve 25%, 50%, 75%, and 80% Emax were 2.3 weeks, 6.86 weeks, 20.6 weeks, 27.5 weeks in ALT, 3.4 weeks, 10 weeks, 30 weeks, 40 weeks in AST, respectively. Thus, to realize the plateau period (80% of Emax) of SGLT-2 inhibitors on ALT and AST in patients with NAFLD, 100 mg/day canagliflozin (or 10 mg/day dapagliflozin or 10 mg/day empagliflozin) needs to be taken for 20.6 weeks and 30 weeks, respectively. CONCLUSIONS: The present study explored the quantitative effects of SGLT-2 inhibitors on liver functions and recommends a therapeutic regimen in patients with NAFLD.
Diabetes Mellitus, Type 2 , Non-alcoholic Fatty Liver Disease , Sodium-Glucose Transporter 2 Inhibitors , Humans , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Non-alcoholic Fatty Liver Disease/drug therapy , Hypoglycemic Agents/therapeutic use , Diabetes Mellitus, Type 2/drug therapy , Glucose , Sodium
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.
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.
Lupus Erythematosus, Systemic , Sirolimus , Humans , Sirolimus/therapeutic use , Lupus Erythematosus, Systemic/drug therapy , Machine Learning
Objectives: The purpose of this study was to explore the effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on urine albumin to creatinine ratio (UACR) in type 2 diabetes mellitus (T2DM) patients and to recommend appropriate medication care scheme. Methods: 8371 T2DM patients from four dapagliflozin studies and two canagliflozin studies were collected for analyzing with nonlinear mixed effect model (NONMEM). The change rates of UACR from baseline were intended to be evaluation indicators. Results: In the present study, there was no significant difference in the effects on UACR using dapagliflozin or canagliflozin treatment in T2DM patients. The maximal effect (E max) and the treatment duration of reaching half of E max (ET50) from SGLT-2 inhibitors on UACR in T2DM patients were -19.2% and 0.448 weeks, respectively. Further, the treatment duration to reach 25%, 50%, 75%, and 80% E max was 0.150 weeks, 0.448 weeks, 1.344 weeks, and 1.792 weeks, respectively. Namely, for achieving the plateau period (80% of E max) of SGLT-2 inhibitors on UACR in T2DM patients, 10 mg/day dapagliflozin (or 100 mg/day canagliflozin) should be taken for at least 1.792 weeks. Conclusions: To our knowledge, the present study explored the effects of SGLT-2 inhibitors on UACR in T2DM patients, meanwhile, recommended appropriate medication care scheme for the first time.
Diabetes Mellitus, Type 2 , Sodium-Glucose Transporter 2 Inhibitors , Albumins , Canagliflozin/therapeutic use , Creatinine , Diabetes Mellitus, Type 2/chemically induced , Diabetes Mellitus, Type 2/drug therapy , Glucose , Humans , Hypoglycemic Agents/therapeutic use , Sodium , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use
The present study aimed to explore the effect of carnitine supplementation on body weight in patients with polycystic ovary syndrome (PCOS) and predict an appropriate dosage schedule using a machine-learning approach. Data were obtained from literature mining and the rates of body weight change from the initial values were selected as the therapeutic index. The maximal effect (Emax) model was built up as the machine-learning model. A total of 242 patients with PCOS were included for analysis. In the machine-learning model, the Emax of carnitine supplementation on body weight was -3.92%, the ET50 was 3.6 weeks, and the treatment times to realize 25%, 50%, 75%, and 80% (plateau) Emax of carnitine supplementation on body weight were 1.2, 3.6, 10.8, and 14.4 weeks, respectively. In addition, no significant relationship of dose-response was found in the dosage range of carnitine supplementation used in the present study, indicating the lower limit of carnitine supplementation dosage, 250 mg/day, could be used as a suitable dosage. The present study first explored the effect of carnitine supplementation on body weight in patients with PCOS, and in order to realize the optimal therapeutic effect, carnitine supplementation needs 250 mg/day for at least 14.4 weeks.
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.
Kidney Transplantation , Tacrolimus , Child , Cytochrome P-450 CYP3A/genetics , Genotype , Humans , Immunosuppressive Agents , Lung , Monte Carlo Method , Transplant Recipients , Voriconazole
The present study aimed to explore the effects of cimetidine on ciclosporin population pharmacokinetics and initial dose optimization in aplastic anemia patients. Aplastic anemia patients were used to establish a population pharmacokinetic model by the nonlinear mixed effect (NONMEM), and concentrations of ciclosporin were simulated by Monte Carlo method. With the same weight, the ciclosporin clearance rates were 0.387:1 in patients with or without cimetidine, respectively. In the measured ciclosporin concentrations, compared to aplastic anemia patients without cimetidine, ciclosporin concentrations were higher in patients with cimetidine (P < 0.01). Further research found that at the same body weight and same dose, ciclosporin concentrations in aplastic anemia patients with cimetidine were indeed higher than those in patients without cimetidine (P < 0.01). The initial recommended ciclosporin dose for patients without cimetidine were 7mg/kg splited into two doses for weight of 40-60kg, and 6mg/kg splited into two doses for weight of 60-100kg. The patients with cimetidine were recommended to take 3mg/kg ciclosporin splited into two doses for weight of 40-100kg. It was the first time to explore the effects of cimetidine on ciclosporin population pharmacokinetics and initial dose optimization in aplastic anemia patients. Patients coadministration of cimetidine, may need low ciclosporin dose.
Anemia, Aplastic , Cyclosporine , Anemia, Aplastic/drug therapy , Cimetidine/therapeutic use , Cyclosporine/pharmacokinetics , Cyclosporine/therapeutic use , Humans , Immunosuppressive Agents/pharmacokinetics , Immunosuppressive Agents/therapeutic use , Metabolic Clearance Rate
Aims: The present study is aimed at exploring the effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on weight in type 2 diabetes mellitus (T2DM) and therapeutic regimen recommendations. Methods: 20,019 patients with T2DM were enrolled. The maximal effect (E max) models, whose evaluation index was change rate of body weight from baseline value, were used to analyze data using nonlinear mixed effect modeling (NONMEM). Results: For SGLT-2 inhibitors, canagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin and tofogliflozin, the E max, and treatment duration to reach half of the maximal effects (ET50) were -3.72% and 3.35 weeks, -5.59% and 16.8 weeks, -2.84% and 3.42 weeks, -3.43% and 3.09 weeks, -3.04% and 4.38 weeks, and -2.45% and 3.16 weeks, respectively. In addition, for T2DM patients, 100 mg/day canagliflozin needs to be taken 13.4 weeks for the plateau of effect on weight; 10 mg/day empagliflozin needs to be taken 67.2 weeks for the plateau of effect on weight; 5 mg/day ertugliflozin needs to be taken 13.68 weeks for the plateau of effect on weight; 50 mg/day ipragliflozin needs to be taken 12.36 weeks for the plateau of effect on weight; 2.5 mg/day luseogliflozin needs to be taken 17.52 weeks for the plateau of effect on weight; 20 mg/day tofogliflozin needs to be taken 12.64 weeks for the plateau of effect on weight. Conclusions: This was the first study to explore effects of SGLT-2 inhibitors on weight in T2DM; meanwhile, the optimum dosages and treatment durations on weight from canagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, and tofogliflozin were recommended, respectively.
Diabetes Mellitus, Type 2 , Sodium-Glucose Transporter 2 Inhibitors , Diabetes Mellitus, Type 2/drug therapy , Glucose , Humans , Hypoglycemic Agents/pharmacology , Sodium , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use
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.
Benzhydryl Compounds/therapeutic use , Diabetes Mellitus, Type 1/drug therapy , Glucosides/therapeutic use , Hypoglycemic Agents/therapeutic use , Weight Loss/drug effects , Age Factors , Benzhydryl Compounds/administration & dosage , Body Weight , Dose-Response Relationship, Drug , Glucosides/administration & dosage , Humans , Hypoglycemic Agents/administration & dosage , Randomized Controlled Trials as Topic , Retrospective Studies
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.
Purpose: The study aimed to explore the effects of l-carnitine, acetyl-l-carnitine, and propionyl-l-carnitine on Body Mass in type 2 diabetes mellitus (T2DM) patients. Methods: Randomized controlled trial (RCT) studies of l-carnitine, acetyl-l-carnitine, and propionyl-l-carnitine in T2DM patients were searched. The change rates of Body Mass index (BMI) from baseline values were used as an evaluation indicator. The maximal effect (Emax) model by non-linear mixed-effect modeling (NONMEM) was used as the evaluation method. Results: A total of 10 RCT studies, 1239 T2DM patients were included for analysis, including eight studies of l-carnitine, one study of acetyl-l-carnitine, and one study of propionyl-l-carnitine. The study found that l-carnitine could reduce the Body Mass of T2DM patients. Based on only one study each for acetyl-l-carnitine and propionyl-l-carnitine, no significant effects were found in acetyl-l-carnitine or propionyl-l-carnitine. In addition, in order to achieve a plateau of efficacy (80% Emax), 2 g/day l-carnitine was required for at least 2 weeks. Conclusions: Two g/day l-carnitine was required for at least 2 weeks to affect Body Mass in T2DM patients, and no significant effects were found in acetyl-l-carnitine or propionyl-l-carnitine.
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.
