Population PK and PK/PD modelling of microencapsulated octreotide acetate in healthy subjects

Abstract

AimsTo develop a population model that can describe the pharmacokinetic pro®le of microencapsulated octreotide acetate in healthy cholecystectomized subjects. To investigate the correlation between serum IGF-1 and octreotide concentration. Methods A population pharmacokinetic analysis was performed on octreotide data obtained following a single dose of 30 mg microencapsulated octreotide acetate intramuscularly. The relationship between serum IGF-1 concentration and octreotide concentration was effectively described by a population pharmacokinetic/pharmacodynamic model. Results The pharmacokinetic pro®le of octreotide was characterized by an initial peak of octreotide followed by a sustained-release of drug. Plateau concentration were sustained up to day 70, and gradually declined to below the detection limit by day 112. A one-compartment linear model was constructed which consisted of two absorption processes, characterized by K IR and K SR , rate constants for immediate-release and sustained-release, respectively, with ®rst-order elimination (K e ; 1.05 h x1 ). The surface, unencapsulated drug was immediately absorbed into the central compartment with ®rst-order absorption (K IR ; 0.0312 h x1 ), while the microencapsulated drug was ®rst released in a zero-order fashion into a depot before being absorbed into the central compartment with ®rst-order absorption (K SR ; 0.00469 h x1 ) during a period of t (1680 h). Body weight and gender were important covariates for the apparent volume of distribution. The type of formulation was an important covariate for K IR but had no effect on K SR . An inhibitory E max population pharmacokinetic/pharmacodynamic model could adequately describe the relationship between IGF-1 (expressed as percent baseline) and octreotide concentration. Baseline IGF-1 concentration was found to be a signi®cant covariate for the baseline effect (E 0 ). A relationship between GH concentration and octreotide concentration was not established. Conclusions The pharmacokinetic pro®le of microencapsulated octreotide acetate was effectively described by the derived population model. The relationship between IGF-1 and drug concentration could be used to guide optimization of therapeutic octreotide dosage regimens.

Pharmacodynamic Modeling of the Effects of Lanreotide Autogel on Growth Hormone and Insulin‐Like Growth Factor 1

“…However, because of the sparse sampling design in the current study, C max or AUC could not be explored. The time course of IGF‐1 after a single intramuscular administration of microencapsulated octreotide in healthy volunteers was described using an indirect response model 10 . Levels of IGF‐1 at baseline between healthy volunteers and patients with acromegaly are very different: 110 ng/mL 10 vs 795/617 ng/mL (not previously treated patients/previously treated patients in current study).…”

“…The time course of IGF‐1 after a single intramuscular administration of microencapsulated octreotide in healthy volunteers was described using an indirect response model 10 . Levels of IGF‐1 at baseline between healthy volunteers and patients with acromegaly are very different: 110 ng/mL 10 vs 795/617 ng/mL (not previously treated patients/previously treated patients in current study). Our model presents some additional limitations: (1) the pulsatile release of GH was not considered, (2) the effect of time from diagnosis and duration of the various interventions were not explored, and (3) it does not allow linking the surrogate responses analyzed (GH and IGF‐1) with the clinical end point (bone growth).…”

“…Despite the increasing role of population pharmacodynamic modeling as a tool to quantitatively characterize drug action, the relationship between C P and GH has been reported only once for lanreotide 8 and octreotide 9 . As for the relation between C P and IGF‐1, it has been reported for octreotide in healthy volunteers only and under non‐steady‐state conditions 10 . Furthermore and to our knowledge, there have been no attempts to relate C P simultaneously with GH and the latter with IGF‐1 for any SSA.…”

Pharmacokinetic-pharmacodynamic comparison of a novel multiligand somatostatin analog, SOM230, with octreotide in patients with acromegaly

“…Results regarding the effects of demographic covariates should, therefore, be understood in such a context. It is perhaps of interest to note that identifying such a PK‐GH relationship in healthy volunteers has not always been possible, 20 , 21 because of the low basal GH concentration in healthy subjects and the low sampling frequency in such clinical studies. The discrepancy in identifying a PK‐GH relationship between acromegalic patients and healthy subjects is perhaps also attributed to the different neurohormonal mechanisms governing the GH dynamics 18 …”

Pharmacokinetics and population pharmacodynamic analysis of lanreotide Autogel

“…The model and model estimates are similar to those published previously for the somatostatin analog octreotide, whose pharmacodynamics properties were also described by an inhibitory E max model. An incomplete reduction of GH was also found, as was a high interpatient variability of the estimates [12,13].…”