MET, an oral hypoglycaemic agent belonging to the class of biguanides is the first-line agent for managing T2DM. According to the American Diabetes Association, MET can be given alone or in combination with other agents for the management of T2DM along with lifestyle modification and diet.1 MET is historically connected to Galega officinalis, a guanidine-rich herb used to treat diabetic symptoms in Europe in the 1700s. MET was first synthesized in 1922 and approved for treating T2DM in Europe in 1958. In 1995, MET was introduced into the US market and is still the most prescribed drug for T2DM worldwide.2 The anti-diabetic effect of MET is achieved by inhibiting hepatic glucose production, increasing peripheral glucose utilization, and increasing insulin-mediated glucose uptake. Additional benefits of MET therapy include cost-effectiveness, no weight gain, and non-hypoglycaemic effect.3 MET has several other pharmacological actions aside from glucose reduction, including cardioprotective effects, antitumor activity, immunosuppressive effects, and anti-aging properties, and it also reduces the hyperandrogenic symptoms of polycystic ovarian syndrome.4

The currently available MET oral solid dosage forms are in the form of Immediate-Release (IR) and Extended-Release (XR) tablets. IR tablets of MET are available in various doses like 500, 850, and 1000 mg, whereas XR tablets are in 500, 750, and 1000 mg doses. The dosage regimen for the management of T2DM is not fixed and can be individualized based on effectiveness and tolerance level without exceeding the maximum daily dose of 2000 mg.5 Even though the significance of MET therapy is known, patients are showing poor adherence and compliance to the dosing regimens and treatment. The major barriers to patient compliance are swallowing difficulty (dysphagia) due to the large tablet size and rough coatings; and Gastrointestinal (GI) side effects such as abdominal discomfort, diarrhoea, cramps, nausea, and vomiting.6 MET use is limited in conditions characterized by high plasma concentrations, such as renal and hepatic impairment, because of higher plasma drug concentration; it leads to MET-associated Lactic Acidosis (LA) (a condition of elevated blood lactate level). The United States Food and Drug Administration (USFDA) recommends that before starting MET therapy, the glomerular filtration rate should be estimated and MET will contraindicate in patients with a glomerular filtration rate below 30 mL/min/1.73 m2. The maximum feasible dose in such patients is between 250 to 500 mg.7

IV MET administration has no direct effect on the fasting blood glucose level, insulin, and glucagon production in healthy individuals compared to oral administration. This could be linked with the hypothesis of local GI action of MET rather than systemic drug concentration.8 In a study on T2DM patients with MET on and off therapy, it was shown that withdrawal of MET is associated with reductions in gut hormones such as Glucagon-Like Peptide-1 (GLP-1), gastric inhibitory polypeptide, and peptide tyrosine-tyrosine, which confirms that MET has a gut-based local effect and could be used as a novel approach for the treatment of T2DM.9 The ileum part of the intestine predominantly contains L cells, which are responsible for the secretion of incretin hormones. These hormones play an important role in blood sugar regulation by increasing insulin secretion and decreasing glucagon release.10 MET improves GLP-1 concentration in the gut either by a direct effect on L cells or by reducing dipeptidyl peptidase-4 activity, an enzyme responsible for the degradation of GLP-1. MET-associated alteration of the bile acid pool also results in GLP-1 secretion by stimulating bile acid receptors in the L cells.11 The absorption of MET is mainly taking place from the duodenum and jejunum. Targeting the drug release onto the ileum is achieved by formulating DR MET tablets. Site targeting can elevate its glucose-lowering efficacy with less systemic intolerance and GI side effects when compared with MET IR and XR formulations. Another important objective of delaying MET release is minimizing the systemic exposure, thereby reducing the incidence of LA in renal-impaired patients, and providing a diabetic treatment option for chronic kidney failure patients.12

The formulation and manufacturing of MET DR tablets are reported in the literature. The primary objective of MET DR is to reduce BA without compromising the therapeutic efficacy, thereby reducing GI intolerance and LA.13 MET DR is studied in several clinical trials, including phases 1 and 2 studies. The phase 1 study consists of a comparative BA of MET DR with currently marketed formulations of IR and XR tablets in healthy volunteers. The results of the study proved that MET DR had a lower BA than IR and XR MET formulations. The phase 2 clinical trial was a placebo-controlled, dose-ranging study in patients with T2DM over 12 weeks. In this study, the patients were randomly assigned to receive either MET DR (600, 800, or 1000 mg Once Daily), or placebo, or MET XR (1000 or 2000 mg Once Daily). The treatment with MET DR produced a clinically significant reduction in the blood glucose level and was well tolerated when compared with MET XR tablets.14 Currently, a pivotal phase 3 clinical trial of MET DR is ongoing on T2DM patients with normal renal function and stage 3 chronic kidney disease to ensure the safety and efficacy of the product.15

PBPK models are mechanistic mathematical models, which describe the PK properties of drug substances and drug products.16 The main advantage of this model is that, by using physiologically integrated mathematical equations, it can predict the in vivo PK of the drug, which, subsequently minimizes the preclinical and clinical studies and is also useful for life cycle management and regulatory requirements. Other widely used applications of PBPK models are the prediction of drug-drug interactions, dose and dosage regimen, and human PK from preclinical PK data.17 PBPK models are composed of several compartments that represent the various organs and tissues of the body that are connected by circulating blood systems. The tissue volume and blood flow rate define each compartment. The drug’s PK in these compartments is described by a series of differential equations.18 PBPK modelling for MET was developed to predict the PK profiles in diabetic patients, pregnant women, geriatrics, and impaired renal populations.19,20 The present study aims to develop a PBPK model for MET DR tablets for predicting the BA of the dosage form for managing T2DM in renal failure patients.