Physiologically Based Pharmacokinetic Modeling of Transdermal Selegiline and Its Metabolites for the Evaluation of Disposition Differences between Healthy and Special Populations.

Santosh Kumar Puttrevu,Sebastian Polak,Sumit Arora,Nikunj Kumar Patel

doi:10.3390/pharmaceutics12100942

Santosh Kumar Puttrevu, Sebastian Polak + Show 2 more

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https://doi.org/10.3390/pharmaceutics12100942

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Journal: Pharmaceutics	Publication Date: Sep 30, 2020
Citations: 21	License type: CC BY 4.0

Affiliation: Simcyp (United Kingdom), Jagiellonian University

Abstract

A physiologically based pharmacokinetic (PBPK) model of selegiline (SEL), and its metabolites, was developed in silico to evaluate the disposition differences between healthy and special populations. SEL is metabolized to methamphetamine (MAP) and desmethyl selegiline (DMS) by several CYP enzymes. CYP2D6 metabolizes the conversion of MAP to amphetamine (AMP), while CYP2B6 and CYP3A4 predominantly mediate the conversion of DMS to AMP. The overall prediction error in simulated PK, using the developed PBPK model, was within 0.5–1.5-fold after intravenous and transdermal dosing in healthy and elderly populations. Simulation results generated in the special populations demonstrated that a decrease in cardiac output is a potential covariate that affects the SEL exposure in renally impaired (RI) and hepatic impaired (HI) subjects. A decrease in CYP2D6 levels increased the systemic exposure of MAP. DMS exposure increased due to a reduction in the abundance of CYP2B6 and CYP3A4 in RI and HI subjects. In addition, an increase in the exposure of the primary metabolites decreased the exposure of AMP. No significant difference between the adult and adolescent populations, in terms of PK, were observed. The current PBPK model predictions indicate that subjects with HI or RI may require closer clinical monitoring to identify any untoward effects associated with the administration of transdermal SEL patch.

Highlights

R-(−) Selegiline (SEL) is a selective irreversible mono amine oxidase-B (MAO-B) inhibitor approved for the treatment of major depressive disorder (MDD), it is used in oral adjunct therapy with Levodopa for the treatment of late-stage Parkinson disease [1,2]
The outcomes of the present study indicated that a reduction in cardiac output is a potential covariate that affected the pharmacokinetics of SEL, which was reflected in terms of area under curve (AUC) and Cmax estimates of healthy and severe renally impaired (SRI) subjects (Figure 6)
The model was further extrapolated to three special population groups, renally impaired, hepatic impaired, and adolescent subjects

Summary

Introduction

R-(−) Selegiline (SEL) is a selective irreversible mono amine oxidase-B (MAO-B) inhibitor approved for the treatment of major depressive disorder (MDD), it is used in oral adjunct therapy with Levodopa for the treatment of late-stage Parkinson disease [1,2]. Administered SEL undergoes extensive first pass metabolism (4% oral bioavailability) [3], which led to the development of the selegiline transdermal patch system (STS). Suicidality is the major risk factor associated with the administration of anti-depressant drugs such as SEL; patients undergoing MDD therapy must balance this therapeutic risk against the benefits [5]. Patients of all age groups, who are under chronic repetitive anti-depressant therapy, should undergo closer clinical monitoring for their suicidal tendencies [5]

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