Population pharmacodynamic analysis of octreotide in acromegalic patients.
BACKGROUND
Octreotide is an octapeptide analog of somatostatin used to normalize growth hormone levels in acromegaly. This article presents a population analysis of the relationship between octreotide and growth hormone concentrations in 94 patients with acromegaly, including 10 patients responding incompletely to subcutaneous treatment (poor responders).


METHODS
Growth hormone and octreotide concentrations were recorded hourly over 12-hour time periods during long-term subcutaneous treatment. Twelve-hour profiles were also collected on different days up to 2 months after intramuscular injection of the long-acting formulation. We modeled the inhibition of growth hormone secretion by octreotide with a direct maximum inhibition model. A joint analysis of both formulations was performed with NONMEM (GloboMax, LLC, Hanover, Md). During model building, we examined the relationships between parameters and demographic covariates or formulations with the use of likelihood ratio tests.


RESULTS
The baseline growth hormone level was higher in poor responders and was best described by a bimodal distribution. The maximum inhibition was common to both formulations and had a mean of 90%, with low interindividual variability. Sensitivity to octreotide (50% inhibitory concentration) was found to be slightly lower on average with intramuscular administration than with subcutaneous administration.


CONCLUSIONS
Given adequate doses of octreotide, in 72% of 94 patients, growth hormone would decrease to levels below 2.5 ng. mL(-1), considered to be a desirable target concentration in acromegaly. This study provides a way to identify poor responders during subcutaneous treatment, allowing an early clinical decision to be made to switch nonresponders to alternative therapies.
Comets
Emmanuelle
E
Unité 436 of the Institut National de la Santé et de la Recherche Médicale, Groupe Hospitalier Bichat-Claude Bernard, Paris, France. emmanuelle.coats@bch.ap=hop-paris.fr
Mentré
France
F
Grass
Peter
P
Kawai
Ryosei
R
Marbach
Peter
P
Vonderscher
Jacky
J
D000172:Acromegaly / Q000097:blood* / Q000188:drug therapy; D000328:Adult; D000368:Aged; D001499:Bayes Theorem; D002986:Clinical Trials as Topic; D005260:Female; D013006:Growth Hormone / Q000097:blood*; D006728:Hormones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D020128:Inhibitory Concentration 50; D007273:Injections, Intramuscular; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D015282:Octreotide / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D006728:Hormones; D013006:Growth Hormone; D015282:Octreotide