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

Abstract

Aims: To develop a population model that can describe the pharmacokinetic profile 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 profile 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 KIR and KSR, rate constants for immediate-release and sustained-release, respectively, with first-order elimination (Ke; 1.05 h-1). The surface, unencapsulated drug was immediately absorbed into the central compartment with first-order absorption (KIR; 0.0312 h-1), while the microencapsulated drug was first released in a zero-order fashion into a depot before being absorbed into the central compartment with first-order absorption (KSR; 0.00469 h-1) during a period of tau (1680 h). Body weight and gender were important covariates for the apparent volume of distribution. The type of formulation was an important covariate for KIR but had no effect on KSR. An inhibitory Emax 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 significant covariate for the baseline effect (E0). A relationship between GH concentration and octreotide concentration was not established.

Conclusions: The pharmacokinetic profile 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.

Figure 1

Pharmacokinetic model describing serum octreotide concentration-time profiles.

Figure 2

Correlation between baseline effect (E₀) vs observed baseline IGF-1 concentration (a; 63 treatments); Bayesian estimated IGF-1 vs observed IGF-1 () (b; r² = 0.72; 469 observations/63 treatments). — line of identity.

Figure 3

Population predicted (—) and individual serum IGF-1 concentrations (expressed as percent baseline) vs simultaneously measured serum octreotide concentrations (469 observations/63 treatments).

Figure 4

Individual serum octreotide concentration-time plots (a: 0–2 days; b: 2–112 days; 3927 observations/110 treatments). (study 1); B (study 2); C (study 2); B (study 2).

Figure 5

Bayesian absorption rate constants for unencapsulated octreotide vs actual doses administered (110 treatments). A (study 1); C (study 2); B (studies 1 and 2).

Figure 6

Bayesian estimated vs observed octreotide concentrations (a; r² = 0.59; 3927 observations/110 treatments). C (study 2); B (study 2); A (study 1); (study 1); line of identity; Weighted residuals vs population predicted octreotide concentrations based on population parameter estimates (Model 5) (b; 3927 observations/110 treatments).

Figure 7

Individual serum octreotide concentration vs time profiles and population predicted profile () for a typical female subject with body weight of 78 kg and receiving 30 mg C intramuscularly (a: 0—2 days; b: 2—112 days; 3927 observations).

Figure 8

At various estimated effective concentrations (EC) from 50% to 95%, the percentage of the population at steady state exceeding the specified EC vs frequency of dosing. Based on the population pharmacokinetic parameters for a healthy female subject with body weight of 78 kg.

Figure 9

Relationship between serum IGF-1 and IGFBP3 concentrations (388 observations/51 treatments).