A double-blind, randomized, dose-response study investigating the pharmacodynamic and pharmacokinetic properties of the long-acting insulin analog detemir.
OBJECTIVE
To investigate the pharmacodynamic profile and duration of action for five subcutaneous doses of insulin detemir (0.1, 0.2, 0.4, 0.8, and 1.6 units/kg; 1 unit = 24 nmol) and one subcutaneous dose of NPH insulin (0.3 IU/kg; 1 IU = 6 nmol).


METHODS
This single-center, randomized, double-blind, six-period, crossover study was carried out as a 24-h isoglycemic clamp (7.2 mmol/l) in 12 type 1 diabetic patients.


RESULTS
Duration of action for insulin detemir was dose dependent and varied from 5.7, to 12.1, to 19.9, to 22.7, to 23.2 h for 0.1, 0.2, 0.4, 0.8, and 1.6 units/kg, respectively. Interpolation of the dose-response relationships for AUC(GIR) (area under the glucose infusion rate curve) revealed that a detemir dose of 0.29 units/kg would provide the same effect as 0.3 IU/kg NPH but has a longer duration of action (16.9 vs. 12.7 h, respectively). Lower between-subject variability was observed for insulin detemir on duration of action (0.4 units/kg insulin detemir vs. 0.3 IU/kg NPH, P < 0.05) and GIR(max) (maximal glucose infusion rate) (0.2 and 0.4 units/kg insulin detemir vs. 0.3 IU/kg NPH, both P < 0.05). Assessment of endogenous glucose production (EGP) and peripheral glucose uptake (PGU) resulted in an AOC(EGP) (area over the EGP curve) of 636 mg/kg (95% CI 279-879) vs. 584 (323-846) and an AUC(PGU) (area under the PGU curve) of 173 (47-316) vs. 328 (39-617) for 0.29 units/kg detemir vs. 0.3 IU/kg NPH, respectively.


CONCLUSIONS
This study shows that insulin detemir provides a flat and protracted pharmacodynamic profile.
Plank
Johannes
J
Department of Internal Medicine, Medical University Graz, Auenbruggerplatz 15, A-8036 Graz, Austria.
Bodenlenz
Manfred
M
Sinner
Frank
F
Magnes
Christoph
C
Görzer
Evelyn
E
Regittnig
Werner
W
Endahl
Lars A
LA
Draeger
Eberhard
E
Zdravkovic
Milan
M
Pieber
Thomas R
TR
D000293:Adolescent; D000328:Adult; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D018592:Cross-Over Studies; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy*; D004311:Double-Blind Method; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005947:Glucose / Q000493:pharmacokinetics; D015309:Glucose Clamp Technique; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D007279:Injections, Subcutaneous; D007328:Insulin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D000069057:Insulin Detemir; D007336:Insulin, Isophane / Q000008:administration & dosage / Q000493:pharmacokinetics; D049528:Insulin, Long-Acting; D008297:Male
D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; D049528:Insulin, Long-Acting; D000069057:Insulin Detemir; D007336:Insulin, Isophane; D005947:Glucose