Contribution of the active metabolite M1 to the pharmacological activity of tesofensine in vivo:: a pharmacokinetic-pharmacodynamic modelling approach

Background and purpose: Tesofensine is a centrally acting drug under clinical development for Alzheimer's disease, Parkinson's disease and obesity. In vitro, the major metabolite of tesofensine (M1) displayed a slightly higher activity, which however has not been determined in vivo. The aims of this investigation were (i) to simultaneously accomplish a thorough characterization of the pharmacokinetic (PK) properties of tesofensine and M1 in mice and (ii) to evaluate the potency ( pharmacodynamics, PD) and concentration-time course of the active metabolite M1 relative to tesofensine and their impact in vivo using the PK/PD modelling approach. Experimental approach: Parent compound, metabolite and vehicle were separately administered intravenously and orally over a wide dose range (0.3-20mgkg(-1)) to 228 mice. Concentrations of tesofensine and M1 were measured; inhibition of the dopamine transporter was determined by co-administration of [H-3]WIN35,428 as the pharmacodynamic measure. Key results: Pharmacokinetics of tesofensine and M1 were best described by one-compartment models for both compounds. Nonlinear elimination and metabolism kinetics were observed with increasing dose. The PK/PD relationship was described by an extended E-max model. Effect compartments were used to resolve observed hysteresis. EC50 values of M1, as an inhibitor of the dopamine transporter, were 4-5-fold higher than those for tesofensine in mice. Conclusions and implications: The lower potency of M1 together with similar to 8-fold higher trough steady-state concentrations suggest that M1 did contribute to the overall activity of tesofensine in mice.