Open Access Research Article

PBPK Models of Two CNS Stimulants, Amphetamine and Methylphenidate, for Clinical Dosing Regimen Optimizations

Jingchen Zhai, Shuhan Liu, Beihong Ji, Yuzhao Zhang and Junmei Wang*

Department of Pharmaceutical Science, University of Pittsburgh, USA

Corresponding Author

Received Date:February 01, 2020;  Published Date: February 19, 2020

Abstract

Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disease. Amphetamine (AMP) based and methylphenidate (MPH)- based agents are the first-line medications that are used as the treatment for ADHD. In this study, we successfully constructed and validated Physiologically based Pharmacokinetic (PBPK) models for AMP of oral extended-release formation and MPH of oral immediate-release formulation and predicted the toxic and lethal doses for these two medications using our PBPK models. To create the models, we utilized drug-related parameters and system-related parameters that are obtained from database, ADMET Predictor, Simcyp built-in predictor and literature. Overall, the predicted AMP concentration in plasma was slightly underestimated but is still located within the confidence interval, while our PBPK model for MPH can predict the PK profiles very well according to the clinical data, indicating the credibility of our model. We also stated that with the application of our PBPK models, we can effectively design more rational drug regimen and estimate the toxic risk under different doses. In terms of our simulation results, we also concluded that the toxic dose of sustained-release AMP is approximately 100-400mg, and the dose over 400mg may even cause death. The dosage that is over 300mg is strongly not recommended. As for immediate-release oral MPH, the maximal recommended dose is also 100mg.

Keywords: PBPK model; ADHD; Dosing regimen; PK modeling; Stimulant; Drug abuse; Toxicity; Lethal dose

Keywords: ACAT: Advanced Compartmental Absorption and Transit; ADAM: Advanced Dissolution Absorption and Metabolism; ADHD: Attention Deficit/Hyperactivity Disorder; ADME: Absorption Distribution Metabolism and Elimination; AMP: Amphetamine; AUC: Area Under Curve; B/P: Blood-to- Plasma Partition Ratio; CLpo: In Vivo Clearance Rate; fa: Fraction available from dosage form; fu: Fraction of unbound drug in plasma; MPH: Methylphenidate; MW: Molecular Weight; NE: Norepinephrine; PBPK: Physiologically-Based Pharmacokinetic; Peff: Human Jejunum Effective Permeability; MCS: Maximum Common Substructure-based; Vss: Steady State Volume of Distribution

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