COMPARATIVE PHARMACOKINETICS AND GLUCODYNAMICS OF 2 HUMAN INSULIN MIXTURES

OBJECTIVE - To compare and contrast the pharmacokinetics and glucodyna mics of two insulin mixtures, one of 50% NPH human insulin and 50% Reg ular human insulin (50/50) and one of 70% NPH human insulin and 30% Re gular human insulin (70/30), in healthy male volunteers after subcutan eous administrations of 0.3 U/kg. RESEARCH DESIGN AND METHODS - We adm inistered single doses of 50/50 and 70/10 insulins to 18 volunteers in a randomized crossover fashion. All subjects received 0.3 U/kg of eac h mixture separated by al least 7 days. Each dose was given after an o vernight fast and during a glucose clamp to maintain a euglycemic stat e. We measured serum insulin and C-peptide concentrations through freq uent blood sampling after each treatment. Pharmacokinetic measurements were calculated from insulin data corrected for C-peptide, including maximum insulin concentration (C-max), time to maximum insulin concent ration (t(max)), terminal rate constant (beta), area under the curve f rom 0 to infinity (AUC(0)(infinity)), and mean residence time (MRT). P harmacodynamic measurements were summarized from C-peptide concentrati ons (minimum C-peptide concentration [C-min], time to minimum C-peptid e concentration [t(min)], area between the C-peptide baseline and the C-peptide suppression curve [AOC(c)], absolute maximal difference from baseline [S-diff] and glucose clamp measurements. The glucose clamp m easurements included maximum infusion rates (R(max)) and time to R(max ) (TR(max)) from glucose infusion rate (GIR) documentation, as well as cumulative glucose infused during the first 4 h ((4)(0)G(tot)) and to tal glucose infused (G(tot)) during the study. RESULTS - For the pharm acokinetic assessment, statistically greater values of insulin C-max a nd beta were found for the 50/50 mixture, whereas the 70/30 mixture ha d a greater MRT. Statistical differences were also detected in glucody namics, with greater values of R(max) and (4)(0)G(tot) found with the 50/50 mixture. Notably, differences were not detected for insulin AUC( 0)(infinity) and G(tot) values. CONCLUSIONS - Higher insulin concentra tions and a greater initial response were present with the 50/50 mixtu re, but the two mixtures had equivalent bioavailability and cumulative effects. These results support use of the 50/50 mixture in situations where greater initial glucose control is required.