Pharmacokinetics, Safety, and Tolerability of Metformin in Healthy Elderly Subjects

Abstract

Age-related physiological changes are known to alter the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs. Metformin is commonly used as first-line medication for management of diabetes in elderly patients. However, the PK and PD of metformin have not been sufficiently studied in elderly subjects. Here, 12 elderly subjects, aged 65 to 85 years, and 20 younger healthy volunteers were orally administered 750 mg of metformin 2 hours after dinner, followed by administration of a second dose (500 mg) 12 hours later. An oral glucose tolerance test (OGTT) was performed 2 hours after the second dose, with 75 g of glucose administered. Blood samples were collected at specific time points after the second metformin dose for the assessment of PK and the glucose-lowering effect of metformin. Elderly subjects exhibited 1.7 and 2.0 times higher average Cmax and AUC∞ than the younger subjects, respectively (P = .007 and .001, respectively), and t1/2 was comparable between the elderly and younger subjects. However, relative glucose level changes from baseline after metformin administration tended to be lower in elderly subjects. Systemic exposure to metformin was elevated by 50% or more in elderly subjects, whereas the glucose-lowering effect was similar compared to younger subjects after 2 doses of metformin.

Metformin in autosomal dominant polycystic kidney disease: experimental hypothesis or clinical fact?

“…Beyond some gastrointestinal symptoms, its most serious side effect, lactic acidosis, is observed only when GFR is below 30 ml/min [ 20 ], far below the cut-off value accepted for a patient to enter the ongoing trials (eGFR> 60 ml/min). This profile will be hopefully maintained also in non-diabetic patients and the fearsome risk of hypoglycemia should remain negligible: clinical trials using metformin in diabetes prevention, in fact, have shown no case of hypoglycemia occurring as serious adverse effect during nearly 18.000 subjects/year of follow-up [ 21 ], nor hypoglycemia is described in obese non-diabetic children assuming the drug [ 22 ], nor in normal subjects after an acute load of metformin [ 23 ]. Such tolerability is a crucial point in a long lasting treatment.…”

Metformin alleviates aging-associated cellular senescence of human adipose stem cells and derived adipocytes

“…During expansion, cells were exposed (or not) to 25 μmol/L metformin (Merck, Sigma Aldrich, St. Quentin Fallavier, France). The metformin concentration chosen in our study is close to Cmax observed in ederly subjects, which exhibited higher average Cmax than younger subjects (Jang, Chung et al 2016). At a late passage (P11), cells were exposed (or not) to 0.1 μmol/L compound C (Merck, Sigma Aldrich).…”

A Whole-Body Physiologically Based Pharmacokinetic Model Characterizing Interplay of OCTs and MATEs in Intestine, Liver and Kidney to Predict Drug-Drug Interactions of Metformin with Perpetrators

“…A report showed that gender and race (Caucasians, Blacks, and Hispanics) little affected AUC of metformin [ 120 ]. The elderly subjects (68 ± 2 years) were reported to exhibit 1.7 and 2.0 times higher average C max and AUC than the younger subjects (23 ± 3 years) [ 93 ]. Subjects used in the prediction were young and healthy, excluding effects of both ages and disease on metformin disposition.…”