Pharmacokinetics and pharmacodynamics of insulin lispro protamine suspension compared with insulin glargine and insulin detemir in type 2 diabetes.
OBJECTIVE
The primary aim was to evaluate duration of action of a single 0.8 U/kg dose of insulin lispro protamine suspension (ILPS) in type 2 diabetes (T2DM) patients; secondarily to compare onset and duration of action of ILPS, glargine (G), and detemir (D) (0.8 U/kg) and evaluate pharmacokinetic (PK) and pharmacodynamic (PD) dose responses of ILPS.


METHODS
In a single-center, double-blind, five-arm crossover study, 34 patients were randomized to a treatment sequence which included a single subcutaneous 0.8 U/kg dose of G and D and three doses of ILPS (0.4 U/kg, 0.8 U/kg, and 1.2 U/kg) and were studied using 24-hour euglycemic glucose clamps.


METHODS
Duration of action was determined as the time to the last measurable glucose infusion rate (tR(last)) during glucose clamps.


RESULTS
The duration of insulin action (tR(last)) for ILPS at 0.8 U/kg was >23 hours and was similar to G (p = 0.114) and D (p = 0.570). Post-hoc analysis demonstrated the probability of achieving 24 hours of glucose-lowering activity after a 0.8 U/kg dose: 48% (ILPS), 43% (G), and 26% (D). G(tot) and R(max) were significantly greater for ILPS versus G or D. The median ILPS time-dependent values demonstrated a significantly earlier maximum PD response (tR(max) and early 50% tR(max)) versus either G or D. ILPS demonstrated dose-dependent increases in PK and PD measures across the dose range.


CONCLUSIONS
Following a single 0.8 U/kg dose in T2DM patients, ILPS, G, and D demonstrated similar durations of glucose-lowering activity and ILPS demonstrated significantly greater glucose-lowering activity (R(max) and G(tot)) and earlier maximum PD response. These results potentially support once-daily dosing of ILPS in T2DM.


CONCLUSIONS
The observed number of 24-hour censored observations was higher than expected and the wash-out period for basal insulin treated patients may have been too short to definitively rule out a carry-over effect; however, such an effect, if present, would potentially only affect onset of action and not the primary outcome measure.
Hompesch
Marcus
M
Profil Institute for Clinical Research, Inc., San Diego, CA, USA.
Ocheltree
Scott M
SM
Wondmagegnehu
Eshetu T
ET
Morrow
Linda A
LA
Kollmeier
Alexa P
AP
Campaigne
Barbara N
BN
Jacober
Scott J
SJ
D000328:Adult; D000368:Aged; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D007328:Insulin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000069057:Insulin Detemir; D000069036:Insulin Glargine; D061268:Insulin Lispro; D049528:Insulin, Long-Acting; D008297:Male; D008875:Middle Aged; D011479:Protamines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D013535:Suspensions
D007004:Hypoglycemic Agents; D007328:Insulin; D061268:Insulin Lispro; D049528:Insulin, Long-Acting; D011479:Protamines; D013535:Suspensions; D000069036:Insulin Glargine; D000069057:Insulin Detemir