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Article

Population Pharmacokinetic Modelling of the Complex Release Kinetics of Octreotide LAR: Defining Sub-Populations by Cluster Analysis

1
Laboratory of Biopharmaceutics-Pharmacokinetics, Department of Pharmacy, National and Kapodistrian University of Athens, 15771 Athens, Greece
2
Athena Research and Innovation Center in Information, Communication and Knowledge Technologies, 15125 Athens, Greece
*
Author to whom correspondence should be addressed.
Academic Editors: Dong Hyun Kim and Ulrika Simonsson
Pharmaceutics 2021, 13(10), 1578; https://doi.org/10.3390/pharmaceutics13101578
Received: 29 July 2021 / Revised: 24 September 2021 / Accepted: 25 September 2021 / Published: 28 September 2021
(This article belongs to the Special Issue Artificial Intelligence Enabled Pharmacometrics)
The aim of the study is to develop a population pharmacokinetic (PPK) model, of Octreotide long acting repeatable (LAR) formulation in healthy volunteers, which describes the highly variable, multiple peak absorption pattern of the pharmacokinetics of the drug, in individual and population levels. An empirical absorption model, coupled with a one-compartment distribution model with linear elimination was found to describe the data well. Absorption was modelled as a weighted sum of a first order and three transit compartment absorption processes, with delays and appropriately constrained model parameters. Identifiability analysis verified that all twelve parameters of the structural model are identifiable. A machine learning method, i.e., cluster analysis, was performed as pre-processing of the PK profiles, to define subpopulations, before PPK modelling. It revealed that 13% of the patients deviated considerably from the typical absorption pattern and allowed better characterization of the observed heterogeneity and variability of the study, while the approach may have wider applicability in building PPK models. The final model was evaluated by goodness of fit plots, Visual Predictive Check plots and bootstrap. The present model is the first to describe the multiple-peak absorption pattern observed after octreotide LAR administration and may be useful to provide insights and validate hypotheses regarding release from PLGA-based formulations. View Full-Text
Keywords: population pharmacokinetics; octreotide; long acting injectables; machine learning population pharmacokinetics; octreotide; long acting injectables; machine learning
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MDPI and ACS Style

Kapralos, I.; Dokoumetzidis, A. Population Pharmacokinetic Modelling of the Complex Release Kinetics of Octreotide LAR: Defining Sub-Populations by Cluster Analysis. Pharmaceutics 2021, 13, 1578. https://doi.org/10.3390/pharmaceutics13101578

AMA Style

Kapralos I, Dokoumetzidis A. Population Pharmacokinetic Modelling of the Complex Release Kinetics of Octreotide LAR: Defining Sub-Populations by Cluster Analysis. Pharmaceutics. 2021; 13(10):1578. https://doi.org/10.3390/pharmaceutics13101578

Chicago/Turabian Style

Kapralos, Iasonas, and Aristides Dokoumetzidis. 2021. "Population Pharmacokinetic Modelling of the Complex Release Kinetics of Octreotide LAR: Defining Sub-Populations by Cluster Analysis" Pharmaceutics 13, no. 10: 1578. https://doi.org/10.3390/pharmaceutics13101578

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