The human PBPK model of metformin got a good fit to the experimental data and reflects the experimentally similar concentration-time profile with varying doses (500,1000,1500mg) and multiple dosing regimens (Figure 3).įigure 3. Similarly, in brain tissue, the difference indicates a complex transport mechanism at the blood-brain barrier that is not covered by the model. The primary reason for the difference between model and experimental data is that the parameters concerning active excretion of metformin parameters were estimated by simultaneously running simulation for the PO and IV. Differences were also significant in the intestinal compartment, where the AUC24 and T1/2 were 22% and 35% lower respectively. In the portal vein compartment, Cmax and AUC24 were lower than the experimental data by 22% and 34% respectively in the model simulation. Most of the concentration-time profile in mice matched with experimental data except few tissues like plasma, heart, liver, kidney and brain. Simulation generated metformin concentration-time profile in major compartment of Metformin action following a single PO dose of 50 mg/kg in mice. The concentration-time profile of 50 mg/kg metformin in various compartments in mice can be observed in Figure 2.įigure 2. The concentration-time profile obtained from the model simulation was compared with the experimentally determined data. PBPK model of metformin consisting various organs/tissues compartments. Human models were simulated with a single PO dose and multiple PO doses with eight administration in 12 h intervals.įigure 1. The Mice model was simulated with a single PO dose and single IV dose of 50mg/kg of Metformin. The mice PBPK model consisted of 20 compartments lacking 1 compartment i.e. Metformin doses ranging from 500 to 1500 mg given as per-oral (PO) or intravenous (IV) have been analyzed through simulation of PBPK model in a 70kg adult human. This ODE based PBPK model included 21 tissues and body fluid compartments and can simulate metformin concentration in the stomach, small intestine, liver, kidney, heart, skeletal muscle adipose, and brain depending on the body weight, dose, and administration regimen (Figure 1). This model can be potentially used as a decision support tool for patient-specific therapy development. ![]() has developed an ordinary differential equation (ODE) based PBPK model of metformin in mice which along with in-vitro data was extrapolated to create a human PBPK model that can be personalized by customising measurable values (such as tissue volume, blood flow) and time-course profile of metformin concentration in blood and urine after a single dose of metformin. Physiology based pharmacokinetic model (PBPK) development is widely used in pharmaceutical companies to study drug distribution at different organs/tissues. Despite broader use, there is insufficient data for metformin concentration-time profiles in different human tissues which restricts the pharmacokinetic apprehension and limits the development of patient-specific precision therapies. Food and Drug Administration) approved drug, commonly prescribed to manage T2D. Metformin, a biguanide derivative, is a FDA (U.S. Zake2021 - PBPK model of metformin in mice and humans December 2021, Model of the Month by Krishna Kumar Tiwari Original model - BIOMD0000001027, BIOMD0000001028, BIOMD0000001029, BIOMD0000001039ĭiabetes mellitus, commonly known as Type 2 diabetes (T2D), is an aggregative metabolic disorder where blood glucose levels increase higher than normal levels, due to improper insulin release or an inadequate response of cells to insulin.
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