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 (0.3–20 mg kg −1 ) to 228 mice. Concentrations of tesofensine and M1 were measured; inhibition of the dopamine transporter was determined by co‐administration of [ 3 H]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. EC 50 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 ∼8‐fold higher trough steady‐state concentrations suggest that M1 did contribute to the overall activity of tesofensine in mice. British Journal of Pharmacology (2008) 153 , 164–174; doi: 10.1038/sj.bjp.0707539 ; published online 5 November 2007