A pharmacometric framework for norepinephrine transporter occupancy and dose equivalence across psychotropic medications

Abstract

Background: Norepinephrine transporter (NET) inhibition is a relevant mechanism across psychotropic medications, although prescribing classifications are largely based on drug class rather than quantitative target engagement. Aims: To facilitate cross-drug comparisons of noradrenergic activity, we developed a pharmacometric model to estimate NET occupancy for 26 psychotropic agents and their active metabolites. Methods: NET occupancy was estimated using National Institute of Mental Health Psychoactive Drug Screening Program Ki data, protein-binding-corrected plasma concentrations, a standard receptor occupancy model, and logit-derived ED50 values, and was compared with published positron emission tomography (PET) estimates. Results: After protein-binding correction, desipramine, milnacipran, and maprotiline showed very high NET occupancy (⩾90%), nortriptyline, doxepin, and norquetiapine showed high occupancy (70%–90%), and hydroxybupropion and duloxetine showed moderate occupancy (50%–70%). Clomipramine, atomoxetine, and reboxetine demonstrated moderate-low occupancy (30%–50%), whereas venlafaxine showed low occupancy (~28%). Hydroxybupropion exhibited substantially greater NET engagement (~68%) than bupropion (~2%), and most Selective serotonin reuptake inhibitors showed minimal occupancy (<10%). Estimated ED50 values ranged from 6.6 mg (desipramine) to ⩾63 mg (duloxetine), and predicted occupancies correlated moderately with PET data ( r = 0.76, p = 0.028, R² = 0.58). Conclusions: These findings suggest that variability in NET engagement across psychotropic medications may not be fully captured by conventional class-based classifications. The proposed framework offers a mechanism-informed approach to comparative pharmacological analysis and introduces a conceptual noradrenergic activity index. This approach may be useful for hypothesis generation in future studies integrating pharmacokinetic-pharmacodynamic modeling with in vivo imaging and clinical outcomes.