Comparative pharmacokinetics and glucodynamics of two human insulin mixtures. 70/30 and 50/50 insulin mixtures.
OBJECTIVE
To compare and contrast the pharmacokinetics and glucodynamics of two insulin mixtures, one of 50% NPH human insulin and 50% Regular human insulin (50/50) and one of 70% NPH human insulin and 30% Regular human insulin (70/30), in healthy male volunteers after subcutaneous administrations of 0.3 U/kg.


METHODS
We administered single doses of 50/50 and 70/30 insulins to 18 volunteers in a randomized crossover fashion. All subjects received 0.3 U/kg of each mixture separated by at least 7 days. Each dose was given after an overnight fast and during a glucose clamp to maintain a euglycemic state. We measured serum insulin and C-peptide concentrations through frequent blood sampling after each treatment. Pharmacokinetic measurements were calculated from insulin data corrected for C-peptide, including maximum insulin concentration (Cmax), time to maximum insulin concentration (tmax), terminal rate constant (beta), area under the curve from 0 to infinity (AUCinfinity0), and mean residence time (MRT). Pharmacodynamic measurements were summarized from C-peptide concentrations (minimum C-peptide concentration [Cmin], time to minimum C-peptide concentration [tmin], area between the C-peptide baseline and the C-peptide suppression curve [AOCc], absolute maximal difference from baseline [Sdiff] and glucose clamp measurements. The glucose clamp measurements included maximum infusion rates (Rmax) and time to Rmax (TRmax) from glucose infusion rate (GIR) documentation, as well as cumulative glucose infused during the first 4 h ((0)4Gtot) and total glucose infused (Gtot) during the study.


RESULTS
For the pharmacokinetic assessment, statistically greater values of insulin Cmax and beta were found for the 50/50 mixture, whereas the 70/30 mixture had a greater MRT. Statistical differences were also detected in glucodynamics, with greater values of Rmax and (0)4Gtot found with the 50/50 mixture. Notably, differences were not detected for insulin AUCinfinity0 and Gtot values.


CONCLUSIONS
Higher insulin concentrations and a greater initial response were present with the 50/50 mixture, 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.
Woodworth
J R
JR
Lilly Laboratory for Clinical Research, Eli Lilly and Company, Wishard Memorial Hospital, Indianapolis, Indiana 46202.
Howey
D C
DC
Bowsher
R R
RR
Brunelle
R L
RL
Rowe
H M
HM
Compton
J
J
Cerimele
B
B
D000328:Adult; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D002096:C-Peptide / Q000097:blood; D004347:Drug Interactions; D006801:Humans; D007328:Insulin / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007336:Insulin, Isophane / Q000097:blood / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D011863:Radioimmunoassay; D011994:Recombinant Proteins / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D013997:Time Factors
D001786:Blood Glucose; D002096:C-Peptide; D007328:Insulin; D011994:Recombinant Proteins; D007336:Insulin, Isophane