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

Abstract

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 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.

Figures

Figure 1

Mean plasma concentration-vs.-time profiles for insulin aspart following subcutaneous injection; Panel A: profiles by BMI category. Range I (•), Rangel II (○), Rangel III (▪), Rangel IV (□). Panel B: profiles for degree of renal impairment. Normal (•), mild (○), moderate (▪), severe (□); Panel C: profiles for degree of hepatic impairment. Normal (•), mild (○), moderate (▪), severe (□)

Figure 2

Effects of obesity on the pharmacokinetics of insulin aspart; Panel A: CL/F vs. BMI value; Panel B: ln(Cmax) vs. BMI value; Panel C: ln(AUC0–1440) vs. BMI value

Figure 3

Effects of renal impairment on the pharmacokinetics of insulin aspart; Panel A: CL/F vs. creatinine clearance; Panel B: ln(Cmax) vs. creatinine clearance; Panel C: ln(AUC0–1440) vs. creatinine clearance

Figure 4

Effects of hepatic impairment on the pharmacokinetics of insulin aspart; Panel A: CL/F vs. Child-Pugh Score; Panel B: ln(Cmax) vs. Child-Pugh Score; Panel C: ln(AUC0–1440) vs. Child-Pugh Score