2019 PharmSci 360
Selegiline (SEL) transdermal patch has been approved for the treatment of major depressive disorder for patients above 12 years. The behavioural untoward effects of SEL are due to its metabolites, methamphetamine (MAP) and amphetamine (AMP). These effects are well correlated with their systemic exposure. The objective of the study was to evaluate the differences in pharmacokinetics of SEL and its metabolites in hepatic and renally impaired versus healthy populations to minimize the therapeutic risk.
Previously undocumented, comprehensive PBPK model capturing the parent (SEL), primary metabolites (MAP and DMS) and AMP (secondary metabolite) was developed and verified at SEL different transdermal doses.
Renal impairment (RI) patients had greater systemic exposure of MAP (>1.5 fold), due to lesser liver CYP2D6 enzyme expression. Two fold increase in unbound SEL concentrations hepatic impaired (HI) populations lead to decrease in AMP levels. The RI and HI populations require a closer clinical monitoring for untoward effects.