Insulin glulisine demonstrates equivalent bioefficacy with RHI. In an initial randomized, open-label crossover study with 16 healthy volunteers (mean age = 22 years, mean body mass index [BMI] = 23.9 kg/m2
) the euglycemic clamp technique was used to compare the molar efficacy of the two insulins (Becker et al 2005
). During a 2-hour continuous infusion, insulin glulisine and RHI had superimposible mean glucose infusion rates (GIR) and area under the glucose infusion rate time-curves at steady state (GIR-AUCSS
). Both insulins also presented equal total glucose exposure as measured by the glucose infusion rate time-curve from time 0 to clamp end (GIR-AUC0-clamp end
). The overall equivalent bioefficacy demonstrated that patients can switch from RHI to insulin glulisine on a unit-per-unit basis. A randomized, double-blind study also employing the euglycemic clamp technique in healthy volunteers was initiated to compare plasma concentrations and time action profiles of insulin glulisine, insulin lispro, and RHI (Becker et al 2003
). Median time to maximum plasma concentration (tmax
) and mean residence time (MRT) for insulin glulisine and insulin lispro were approximately half that of RHI (see ) (Becker et al 2003
Figure 3 Glulisine duration of activity shorter than regular human insulin (RHI)F. Reproduced with permission from Becker RHA, Frick A, Wessels D. 2003. Pharmacodynamics and pharmacokinetics of a new rapidly-acting insulin analog, insulin glulisine [abstract no. (more ...)
More recently, a larger randomized crossover study was conducted by Spitzer et al to evaluate the pharmacokinetics and pharmacodynamics of insulin glulisine versus insulin lispro in lean to obese individuals (Spitzer et al 2006
). Eighty healthy subjects were stratified into one of 4 groups based on BMI (<25, 25–<30, 30–<35, and >35 kg/m2
) and given insulin glulisine and insulin lispro at doses of 0.2 U/kg and 0.4 U/kg in random order over a 4-day study period with a euglycemic glucose clamp. GIR and insulin concentration (INS) were measured for 10 hours following the dose. Overall, onset of exposure and activity, as measured by INS-t10%
, was 6 minutes faster with insulin glulisine. Early insulin exposure and early metabolic action were consistently greater by 18%–30% with insulin glulisine than insulin lispro, which was significant in the total population and across a wide range of BMIs.
Insulin glulisine has been shown to maintain its rapid-acting kinetic profile in studies that enrolled patients with type 1 or 2 DM. In a randomized crossover study of 20 patients with type 1 DM, insulin glulisine was absorbed more quickly than RHI, although total availability did not differ between the insulins (Nosek et al 2004
). Patients received a 0.15 U/kg subcutaneous injection of either RHI 30 minutes pre-meal or insulin glulisine immediately before or 15 minutes post-meal. Mean AUC from 0 to 2 hours (AUC2
) was 7278 and 4258 μIU min/ML with insulin glulisine and RHI respectively (p < 0.05). However, mean insulin AUC from 0 to 6 hours (AUC6
) did not differ between groups (11,912 vs 11,550 μIU min/mL). Mean Cmax
, and tmax
were equivalent between the pre- and post-meal glulisine injections, indicating that the analogue is safe and effective when administered either before or after a meal. This may provide greater flexibility for patients, especially those prone to forgetting pre-meal injections.
In a comparison study of patients with type 2 DM, AUC2
was again significantly greater with insulin glulisine compared with RHI (7661 vs 4221), but at the end of the 10 hour clamp, AUC10
was comparable between these two insulins (18,408 vs 19,731 μIU min/mL) (Becker et al 2004
). This study, which also used insulin lispro as a comparator, confirmed that both of these rapid-acting insulin analogues have equivalent pharmacokinetic and pharmacodyamic profiles, which more closely mimic physiologic prandial insulin secretion compared with RHI.
The volume of distribution for insulin glulisine following intravenous administration is 13 L (vs 21 L for RHI) (Gabry 2004). Half-lives for insulin glulisine and RHI were measured at 13 and 17 minutes (intravenous administration) and 42 and 86 minutes (subcutaneous injection) respectively (Gabry 2004). The pharmacokinetics of insulin glulisine were comparable between various sites of subcutaneous injection (Frick et al 2003
). Following injection into abdominal, deltoid, or femoral sites in healthy volunteers, insulin glulisine demonstrated consistent pharmacokinetic parameters, including absolute bioavailability. It was noted that the use of the abdominal route led to slightly more rapid insulin delivery.