Pharmacokinetic-pharmacodynamic comparison of a novel multiligand somatostatin analog, SOM230, with octreotide in patients with acromegaly.
OBJECTIVE
Acromegaly is a serious hormonal disorder resulting from a pituitary adenoma causing excess growth hormone (GH) production. Somatostatin analogs such as octreotide have been the medical treatment of choice. SOM230, a novel somatostatin analog, was compared with octreotide with respect to pharmacokinetic (PK) profiles and inhibition of GH secretion in acromegalic patients.


METHODS
In a double-blind, 3-period, crossover, proof-of-concept study, 12 patients with active acromegaly were randomized to single subcutaneous doses of SOM230 (100 and 250 microg) and octreotide (100 microg). Concentrations of SOM230, octreotide, and GH were determined at designated times after dosing and at baseline. The PK properties of SOM230 and octreotide and the relationship of PK with GH were investigated by a nonlinear mixed-effects modeling analysis.


RESULTS
The apparent clearance for SOM230 is approximately half of that for octreotide (8.0 L/h versus 15.8 L/h). The elimination half-life for SOM230 is about 5 times longer than that for octreotide (11.8 hours versus 2.3 hours). The relationship between GH levels and plasma concentrations of SOM230 and octreotide is well described by a direct inhibitory model. The test drug concentration level at which half of the maximum drug effect is observed (EC50) is 46 and 553 pg/mL for octreotide and SOM230, respectively, with large interpatient variability (coefficients of variation, 164% and 65%, respectively), mainly attributable to the heterogeneous responses among patients.


CONCLUSIONS
SOM230 demonstrates a lower clearance and longer half-life than octreotide, which compensates for the lower potency in GH inhibition. As a result of the lower interpatient variability for EC50 , SOM230 is expected to have a more uniform clinical GH inhibition than octreotide for acromegalic patients at a clinically effective dosing regimen.
Ma
Peiming
P
Novartis Pharma KK, Tokyo 106-8618, Japan. peiming.ma@novartis.com
Wang
Yanfeng
Y
van der Hoek
Joost
J
Nedelman
Jerry
J
Schran
Horst
H
Tran
Ly-Le
LL
Lamberts
Steven W J
SW
D000172:Acromegaly / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D000328:Adult; D000367:Age Factors; D000465:Algorithms; D001835:Body Weight; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D019382:Human Growth Hormone / Q000037:antagonists & inhibitors / Q000097:blood; D006801:Humans; D007279:Injections, Subcutaneous; D008163:Luminescent Measurements; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D015282:Octreotide / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D012737:Sex Factors; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use
D019382:Human Growth Hormone; D013004:Somatostatin; C517782:pasireotide; D015282:Octreotide