Pharmacokinetics and safety of glimepiride at clinically effective doses in diabetic patients with renal impairment

The pharmacokinetics, efficacy and safety of glimepiride were investigated in a single- and a multiple-dose open study in patients with non-insulin-dependent diabetes mellitus and renal impairment and an initial creatinine clearance above 10 ml/min. Patients were divided into three groups with creatinine clearance above 50 ml/min, 20-50 ml/min and under 20 ml/min. Fifteen fasting patients received a single dose of 3 mg glimepiride and serial blood and urine samples were taken over 24 h for pharmacokinetic and efficacy analyses: A further 16 patients received glimepiride over a 3-month period, an initial dose of 1 mg glimepiride being adjusted within the range 1 to 8 mg to achieve good glucose control. Pharmacokinetic evaluation was done on day 1 and after 3 months. Mean relative total clearance and mean volume of distribution of both single (41.6 ml/min and 8.47 Litres, respectively, when creatinine clearance was above 50 ml/min) and multiple doses of glimepiride increased in proportion to the degree of renal impairment (to 91.1 ml/min and 14.98 litres, respectively, when creatinine clearance was below 20 ml/min, single dose), whereas the terminal half-life and mean time remained unchanged. Lower relative total clearance and renal clearance of both glimepiride metabolites correlated significantly with lower creatinine clearance values. Of the 16 patients 12 required between 1 and 4 mg glimepiride to stabilize their fasting blood glucose. Glimepiride was well-tolerated and there were no drug-related adverse events. In conclusion glimepiride is safe, effective and has clearly-definable pharmacokinetics in diabetic patients with renal impairment. The increased plasma elimination of glimepiride with decreasing kidney function is explainable on the basis of altered protein binding with an increase in unbound drug.