Study summary · research use only
Contribution of the active metabolite M1 to the pharmacological activity of tesofensine in vivo: a pharmacokinetic-pharmacodynamic modelling approach
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
In this mouse pharmacokinetic-pharmacodynamic study, the authors characterized tesofensine and its metabolite M1. Parent compound, metabolite, and vehicle were given intravenously and orally over a dose range of 0.3-20 mg/kg to 228 mice. Concentrations were measured, and dopamine transporter inhibition (via co-administered [3H]WIN35,428) served as the pharmacodynamic measure. Pharmacokinetics of both were best described by one-compartment models, with nonlinear elimination and metabolism at increasing dose. The PK/PD relationship was described by an extended Emax model, with effect compartments used to resolve hysteresis. The abstract reports that EC50 values of M1 as a dopamine transporter inhibitor were 4-5-fold higher than those of tesofensine in mice. The authors conclude the lower potency of M1, with roughly 8-fold higher steady-state concentrations, suggests M1 contributed to overall tesofensine activity in mice.
Abstract
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. 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. 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. The lower potency of M1 together with approximately 8-fold higher through steady-state concentrations suggest that M1 did contribute to the overall activity of tesofensine in mice.
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