A Physiologically-Based Pharmacokinetic Model to Characterize Dasotraline Pharmacokinetics and CYP-mediated Drug-Drug Interactions

Introduction: Dasotraline is an investigational inhibitor of dopamine and norepinephrine reuptake transporters that has completed pivotal studies in Attention Deficit and Hyperactivity Disorder (ADHD) and Binge Eating Disorder (BED). Preclinical studies show dasotraline is well absorbed, well distributed, and highly metabolized in animal models, though absorption is prolonged with slow overall elimination in humans. Dasotraline is a substrate of multiple Cytochrome P450s (CYP). The metabolism of dasotraline is largely determined by CYP2B6 (fraction of metabolism fm: 0.63) and, to a lesser extent, by CYP2D6 (fm: 0.12), CYP2C19 (fm: 0.11), and CYP3A4/5 (fm: 0.14). Dasotraline is not a CYP inducer but is an inhibitor of CYP2B6, CYP2C19, CYP2D6, and CYP3A4/5. Methods: A dasotraline PBPK model was established by a middle-out approach based on in vitro and clinical results. Simulations were performed to evaluate CYP-mediated drug-drug interactions (DDI) with dasotraline as a victim and perpetrator, the impact of polymorphic CYP2B6 on dasotraline PK, as well as the role CYP2B6 autoinhibition on dasotraline accumulation at steady state. Results: The PBPK model well described clinically observed PK not only after a single dose, but also predicted substantial accumulation of dasotraline due to auto-inhibition of CYP2B6-mediated clearance. In addition, the simulated CYP2B6-mediated DDI precisely depicted the clinically observed DDI. Although hepatic elimination of dasotraline is primarily mediated by CYP2B6, simulations suggest that the impact of CYP2B6 polymorphism on pharmacokinetics is minimal, likely due to compensatory auto-inhibition of the enzyme. As a result, dose adjustment based on CYP2B6 phenotype is likely unnecessary. Conclusion: The PBPK model developed via the middle-out approach provides a quantitative tool to predict CYP-mediated DDI with dasotraline as either a victim or a perpetrator and the impact of polymorphic CYP2B6 on dasotraline PK. This model may aid in optimizing dosing strategies to minimize the risks associated with CYP-mediated interactions and significant accumulation following repeated dosing.