Pharmacokinetics of insulin aspart in obesity, renal impairment, or hepatic impairment

Aims To assess the effects of body mass index, renal impairment (creatinine clearance), and hepatic impairment (Child-Pugh Score) on the pharmacokinetics of insulin aspart. Methods Pharmacokinetics of insulin aspart (injected subcutaneously in the abdomen immediately before a Boost((R)) standardized meal) were characterized in: (1) diabetic subjects with four ranges of BMI values (n = 23); (2) diabetic subjects with varying degrees of renal impairment (normal, n = 6 vs. two ranges of impairment, n = 12); and (3) nondiabetic patients with varying degrees of hepatic impairment (normal, n = 6 vs. three ranges of impairment, n = 18). Results There was no correlation between any pharmacokinetic variable and the degree of renal or hepatic impairment. Increasing obesity was associated with a decreased apparent clearance per kg body weight (beta = -0.0005, SE = 0.0001; P = 0.002), an increased t(1/2) (beta = 3.513, SE = 1.636; P = 0.044), and an increased ln(AUC(0-360)) and ln(AUC(0-1440)) (beta = 0.030, SE = 0.013; P = 0.032 and beta = 0.039, SE = 0.0132; P = 0.006, respectively). However, obesity-related changes were smaller than individual variations in parameters. Conclusions Renal impairment, hepatic impairment, or BMI do not affect the pharmacokinetics of insulin aspart in a clinically significant manner. Abbreviations AUC(0-1440), area under the plasma concentration curve; BMI, body-mass index; CLcr, renal clearance of creatinine; CL/F, apparent clearance; CL/F/kg, body weight-adjusted apparent clearance; C-max, maximal plasma concentration; FBG, fasting blood glucose; GFR, glomerular filtration rate; HI, human insulin; MRT, mean residence time; PK, pharmacokinetics; t(1/2), half life; t(max), time to maximum concentration; Vz/F, apparent volume of distribution.