Aims The aim of the present study was to quantitate the hypoglycaemic effects of dipeptidyl peptidase‐4 inhibitors (DPP‐4i), glucagon‐like peptide‐1 receptor agonists (GLP‐1r) and sodium glucose cotransporter 2 inhibitors (SGLT2i) as add‐on treatments to metformin monotherapy in patients with type 2 diabetes mellitus (T2DM) using a model‐based meta‐analysis (MBMA). Methods A systematic literature search of public databases was conducted to develop models that describe the time courses of the fasting plasma glucose (FPG)‐ and haemoglobin A1c (HbA1c)‐lowering effects of three antidiabetic classes using NONMEM 7.3.0. Results Seventy‐six publications were eligible for this study, and 873 FPG and 1086 HbA1c values were collected. We developed a physiological indirect response model that described the time courses of FPG and HbA1c and simulated reductions in these values 90 days after the initiation of add‐on treatments. FPG and HbA1c reductions with once weekly exenatide, liraglutide and dulaglutide were greater than those with other drugs. Mean changes from baseline FPG and HbA1c with these drugs were as follows: exenatide (−22.5 and −16.6%), liraglutide (−22.1 and −16.3%), and dulaglutide (−19.3 and −14.3%). The hypoglycaemic effects of DPP‐4i and SGLT2i were similar. Conclusions Once weekly exenatide, liraglutide and dulaglutide provided better hypoglycaemic effects among the antidiabetic drugs analysed. Long‐acting GLP‐1r appears to be more useful for T2DM patients inadequately controlled with metformin monotherapy.

AIMSHMG-CoA reductase inhibitors are available for use in low density lipoprotein-cholesterol (LDL-C) lowering therapy. The purposes of this study were to develop a population pharmacodynamic (PPD) model to describe the time course for the LDL-C lowering effects of statins and assess the efficacy of combination therapy based on electronic medical records. METHODSPatient backgrounds, laboratory tests and prescribed drugs were collected retrospectively from electronic medical records. Patients who received atorvastatin, pitavastatin or rosuvastatin were enrolled. A physiological indirect response model was used to describe the changes observed in LDL-C concentrations. The PPD analysis was performed using NONMEM 7.2.0 with the first order conditional estimation method with interaction (FOCE-INTER). RESULTSAn indirect response Imax model, based on the 2863 LDL-C concentrations of 378 patients, successfully and quantitatively described the time course for the LDL-C lowering effects of three statins. The combination of ezetimibe, a cholesterol absorption inhibitor, decreased the LDL synthesis rate (Kin) by 10.9%. A simulation indicated that the combined treatment of ezetimibe with rosuvastatin (2.5 mg day CONCLUSIONSA newly constructed PPD model supported previous evidence for the beneficial effects of ezetimibe combined with rosuvastatin. In addition, the established framework is expected to be applicable to other drugs without pharmacokinetic data in clinical practice. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• There is currently no population pharmacodynamic model to describe the time course for the low density lipoproteincholesterol (LDL-C) lowering effects of statins with regards to covariate factors (e.g. co-medicated drugs), which may enhance clinical efficacy, based on information obtained from electronic medical records in a general hospital. WHAT THIS STUDY ADDS• The indirect response model successfully and quantitatively described the time course for the LDL-C lowering effects of statins (atorvastatin, pitavastatin and rosuvastatin) and the efficacy of ezetimibe.• Patients with higher baseline LDL-C concentrations are recommended to receive a combination with ezetimibe rather than an increased dose of rosuvastatin.• The established framework is expected to be applicable to other drugs without pharmacokinetic data in clinical practice and may detect influential factors for drug therapy.

Tazobactam/ceftolozane is a combination of a b-lactamase inhibitor and a cephalosporin antibiotic, with recommended dosage for patients with normal renal function of tazobactam 0.5 g/ceftolozane 1 g administered as a 1-h intravenous infusion every 8 h. The doses in patients with moderate and severe renal impairment are recommended to be reduced by half and 1/4th, respectively. The dose in patients undergoing dialysis is a single loading dose of 750 mg followed after 8 h by a 150 mg maintenance dose. In order to evaluate pharmacokinetics (PK) in Japanese patients, individual Bayes PK parameters were derived using the previously developed population PK models. Furthermore, attainment of PK/pharmacodynamic target in Japanese patients was calculated to confirm the recommended dosage.Based on PK data from 200 Japanese patients in the phase 3 studies, including patients with mild and moderate renal impairment, individual tazobactam/ceftolozane PK parameters were derived. No clinically relevant difference was observed in tazobactam/ceftolozane exposures between Japanese and non-Japanese patients. All Japanese patients achieved a target percent of time that free ceftolozane concentrations are above the minimum inhibitory concentration (MIC) of 30% for MICs of up to 8 mg/mL. Also for tazobactam, all Japanese patients achieved a target percent of time that the free tazobactam concentration exceeds a threshold concentration (1 mg/mL) of 20%. The results suggest that the doses will be efficacious in the Japanese population.The results indicate that the recommended dose in patients with normal renal function or renal impairment is appropriate in Japanese patients.

The aim of this study was to develop a population pharmacodynamic (PPD) model to describe uric acid (UA)-lowering effects in patients treated with febuxostat based on electronic medical records in 2 independent hospitals (university and city hospitals). Interhospital differences in the PPD model were also evaluated. We conducted the following 2 approaches to build the PPD models. A PPD model was developed separately using individual hospital data, and structural models and covariates between the two hospitals were compared (approach A). Another PPD model was developed using all available data from both hospitals, and differences between the 2 hospitals were evaluated by performing a covariate analysis on all PPD parameters (approach B). PPD analyses were performed by NONMEM using data from 358 patients. In both approaches, one indirect response model was established. In approach A, 2 diuretics (loops and thiazides) and renal function tests (Scr or BUN) were selected as covariates for the UA baseline level (serum UA levels just before the febuxostat treatment), whereas 2 diuretics and BUN were selected in approach B. A covariate analysis indicated that loops and thiazides increased UA baseline levels by 7%-14% and 6%-11%, respectively. In approach B, "hospital" was identified as a significant covariate for the UA baseline level; the baseline level was 7% higher in the city hospital. A PPD analysis may provide a precise description of the time course of the UA-lowering effects of febuxostat and quantitatively detect an interhospital difference in the UA baseline level.

No abstract