Pharmacokinetics, pharmacodynamics, and safety of microencapsulated octreotide acetate in healthy subjects.
The pharmacokinetics, pharmacodynamics, and safety of the marketed formulation of microencapsulated octreotide acetate were evaluated in an open-label study in 22 healthy cholecystectomized subjects. Each subject received a single 30 mg dose of microencapsulated octreotide acetate intramuscularly (i.m.). Concentrations of octreotide, growth hormone (GH), insulin-like growth factor binding protein 3 (IGFBP-3), and insulin-like growth factor 1 (IGF-1) as well as clinical safety were evaluated over a period of 112 days (16 weeks). After the injection, mean serum octreotide concentration initially increased rapidly, reached the maximum (Cmax, day 1 = 0.96 +/- 0.25 ng/ml) approximately 1.5 hours after dosing, and declined thereafter until 24 hours postdose (Cmin, 24 h = 0.088 +/- 0.093 ng/ml). The octreotide concentration then increased and started a sustained release from day 7 onward. Plateau concentrations were maintained through day 70 and gradually declined to below the lower limit of quantification (LLOQ) by day 112. The plateau height (Cplateau (2-112d, 60%)) was 1.68 +/- 0.88 ng/ml, and the duration (delta plateau, 60%) was 30.2 +/- 15.7 days. The integrated concentration-time curve, AUC0-112d, was 2819 +/- 782 (ng.h/ml), and the apparent half-life (t1/2) was 169 hours. To assess the variability, the drug concentrations were determined hourly for 8 hours on day 28, and the mean octreotide concentration, Cavg, day 28' was 1.55 +/- 1.26 ng/ml. The suppression of IGF-1 was statistically significant compared to the baseline (p < 0.05) through day 63; however, there were no appreciable changes in GH and IGFBP-3 concentrations after a single injection of microencapsulated octreotide acetate. Simulation of a 28-day dose schedule suggested that steady-state octreotide concentrations would be reached by the third injection with steady-state concentrations about twofold greater than the first injection. There were no serious adverse events or clinically meaningful changes in vital signs, ECGs, or laboratory evaluations observed in this study, indicating that the 30 mg i.m. dose of microencapsulated octreotide acetate was well tolerated in this population.
Chen
T
T
Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936, USA.
Miller
T F
TF
Prasad
P
P
Lee
J
J
Krauss
J
J
Miscik
K
K
Kalafsky
G
G
McLeod
J F
JF
D015746:Abdominal Pain / Q000139:chemically induced; D000328:Adult; D019540:Area Under Curve; D003692:Delayed-Action Preparations; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D005260:Female; D006261:Headache / Q000139:chemically induced; D006728:Hormones / Q000009:adverse effects / Q000493:pharmacokinetics*; D019382:Human Growth Hormone / Q000097:blood; D006801:Humans; D007273:Injections, Intramuscular; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D015282:Octreotide / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
D003692:Delayed-Action Preparations; D006728:Hormones; D018972:Insulin-Like Growth Factor Binding Protein 3; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D015282:Octreotide