The use of metformin in patients with chronic kidney disease : what dose should be prescribed?

Metformin is widely used in the treatment of type 2 diabetes mellitus (T2DM). It is largely cleared by the kidneys and according to Product Information, it is contraindicated in patients with chronic kidney disease (CKD) due to the potential risk of lactic acidosis. The risk of metformin- associated lactic acidosis (MALA), however, is extremely rare. One of the shortcomings of the literature is that the use of metformin in patients with kidney disease and other risk factors for lactic acidosis is largely unknown. In three publications, the aims of this thesis were to investigate the pharmacokinetics of metformin, its usage in patients with CKD and the risk factors for MALA. The population pharmacokinetics of metformin in healthy subjects and patients with T2DM was investigated (Paper 1). Creatinine clearance (CLCR) and body weight were important covariates of the clearance (CL/F) and volume of distribution (VC/F) parameters, respectively. Variant transporters of metformin were not influential covariates. The model was used to simulate maximum daily doses of metformin at each level of kidney function to ensure metformin concentrations remained below 5 mg/L. A study was conducted in patients with CKD (CLCR <40 mL/min; N = 24) to investigate metformin and lactate concentrations (Paper 2). Patients with CKD can tolerate low doses of metformin, metformin concentrations did not exceed 5 mg/L, and lactate concentrations were below 5 mmol/L, the upper limit for a diagnosis of lactic acidosis. Lastly, 15 cases of MALA were collected to investigate metformin concentrations and risk factors for MALA (Paper 3). The collection of metformin concentrations enabled MALA to be categorised into three forms and for a model of pathogenesis to be proposed. The data suggests an involvement of metformin and the other acute conditions of the patient in the development of MALA. These findings add to our understanding of the pharmacokinetics of metformin and safe usage of metformin in patients with CKD. Dosage selection in the light of kidney function, can ensure metformin concentrations remains below 5 mg/L. These studies highlighted the value of monitoring metformin concentrations and metformin doses in patients with CKD to reduce the risk of MALA

A physiologically based pharmacokinetic model of clopidogrel in populations of European and Japanese ancestry: An evaluation of CYP2C19 activity

Treatment response to clopidogrel is associated with CYP2C19 activity through the formation of the active H4 metabolite. The aims of this study were to develop a physiologically based pharmacokinetic (PBPK) model of clopidogrel and its metabolites for populations of European ancestry, to predict the pharmacokinetics in the Japanese population by CYP2C19 phenotype, and to investigate the effect of clinical and demographic factors. A PBPK model was developed and verified to describe the two metabolic pathways of clopidogrel (H4 metabolite, acyl glucuronide metabolite) for a population of European ancestry using plasma data from published studies. Subsequently, model predictions in the Japanese population were evaluated. The effects of CYP2C19 activity, fluvoxamine coadministration (CYP2C19 inhibitor), and population-specific factors (age, sex, BMI, body weight, cancer, hepatic, and renal dysfunction) on the pharmacokinetics of clopidogrel and its metabolites were then characterized. The predicted/observed ratios for clopidogrel and metabolite exposure parameters were acceptable (twofold acceptance criteria). For all CYP2C19 phenotypes, steady-state AUC0-τ of the H4 metabolite was lower for the Japanese (e.g., EM, 7.69 [6.26–9.45] ng·h/ml; geometric mean [95% CI]) than European (EM, 24.8 [20.4–30.1] ng·h/ml, p <.001) population. In addition to CYP2C19-poor metabolizer phenotype, fluvoxamine coadministration, hepatic, and renal dysfunction were found to reduce H4 metabolite but not acyl glucuronide metabolite concentrations. This is the first PBPK model describing the two major metabolic pathways of clopidogrel, which can be applied to populations of European and Japanese ancestry by CYP2C19 phenotype. The differences between the two populations appear to be determined primarily by the effect of varying CYP2C19 liver activity

The variability in beta-cell function in placebo-treated subjects with type 2 diabetes: application of the weight-HbA1c-insulin-glucose (WHIG) model

AIM: The weight‐glycosylated haemoglobin (HbA1C)‐insulin‐glucose (WHIG) model describes the effects of changes in weight on insulin sensitivity (IS) in newly diagnosed, obese subjects receiving placebo treatment. This model was applied to a wider population of placebo‐treated subjects, to investigate factors influencing the variability in IS and β‐cell function. METHODS: The WHIG model was applied to the WHIG dataset (Study 1) and two other placebo datasets (Studies 2 and 3). Studies 2 and 3 consisted of nonobese subjects and subjects with advanced type 2 diabetes mellitus (T2DM). Body weight, fasting serum insulin (FSI), fasting plasma glucose (FPG) and HbA1c were used for nonlinear mixed‐effects modelling (using NONMEM v7.2 software). Sources of interstudy variability (ISV) and potential covariates (age, gender, diabetes duration, ethnicity, compliance) were investigated. RESULTS: An ISV for baseline parameters (body weight and β‐cell function) was required. The baseline β‐cell function was significantly lower in subjects with advanced T2DM (median difference: Study 2: 15.6%, P < 0.001; Study 3: 22.7%, P < 0.001) than in subjects with newly diagnosed T2DM (Study 1). A reduction in the estimated insulin secretory response in subjects with advanced T2DM was observed but diabetes duration was not a significant covariate. CONCLUSION: The WHIG model can be used to describe the changes in weight, IS and β‐cell function in the diabetic population. IS remained relatively stable between subjects but a large ISV in β‐cell function was observed. There was a trend towards decreasing β‐cell responsiveness with diabetes duration, and further studies, incorporating subjects with a longer history of diabetes, are required