tesofensine and Alzheimer-Disease

Tesofensine (TE) is a norepinephrine, dopamine, and serotonin reuptake inhibitor. We conducted a meta-analysis of TE's effect on body weight in trials investigating its potential for treatment of Parkinson's or Alzheimer's disease.. Four randomized, double-blind, multicenter trials compared TE (n = 740) and placebo (n = 228), two in each disease. Patients received oral TE or placebo once daily for 14 weeks without any weight loss program. Results were adjusted for baseline values, age, and study.. In the placebo group, 14% were obese and 21% were in the TE group. In the total cohort, weight change after 14 weeks was +0.5, -0.5, -0.9, -1.8, -2.8% in the placebo, 0.125, 0.25, 0.5 and 1.0 mg in the TE groups, respectively (P = 0.015 for dose effect). In the obese subgroup, weight changes were -0.2, -1.7, -1.6, -1.5, -3.7%, and 2.1, 8.2, 14.1, 20.9, 32.1% of the obese patients achieved > or = 5% weight loss (P < 0.001 for 0.25, 0.5, and 1.0 mg vs. placebo for both end points). Changes in heart rate were -0.4, 2.1, 4.2, 6.0, and 6.8 bpm after 14 weeks (TE vs. placebo: P < 0.001 from 0.25 mg), but no effect on blood pressure was observed.. TE produced a placebo-subtracted weight loss of approximately 4% for >14 weeks without any diet and lifestyle therapy, which is similar to that of sibutramine, but with no effect on blood pressure. On the basis of these results, TE is now being developed for obesity management.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Biogenic Monoamines; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Dose-Response Relationship, Drug; Double-Blind Method; Female; Heart Rate; Humans; Male; Middle Aged; Multicenter Studies as Topic; Obesity; Parkinson Disease; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors; Weight Loss

Effective therapeutic options for Alzheimer's disease (AD) are limited and much research is currently ongoing. The high attrition rate in drug development is a critical issue. Here, the quantitative pharmacology approach (QP-A) and model-based drug development (MBDD) provide a valuable opportunity to support early selection of the most promising compound and facilitate a fast, efficient, and rational drug development process. The aim of this analysis was to exemplify the QP-A by eventually predicting the clinical outcome of a proof-of-concept (PoC) trial of tesofensine in AD patients from two small phase IIa trials. Retrospective population pharmacokinetic/pharmacodynamic (PK/PD) modeling of tesofensine, its metabolite M1, and assessment scale-cognitive subscale data from two 4-week placebo-controlled studies in 62 mild AD patients was performed using non-linear mixed effects modeling. The final PK/PD model was used to predict data of a negative 14-week phase IIb PoC trial (430 AD patients). For the PK, one-compartment models for tesofensine and M1 with first-order absorption and elimination were sufficient. An extended Emax model including disease progression best described the PK/PD relationship using effect compartments. The placebo effect was also implemented in the final PK/PD model based on a published placebo model developed in a large AD cohort. Various internal evaluation techniques confirmed the reliability and predictive performance of the PK/PD model, which also successfully predicted the 14-week PoC data. For tesofensine, the dose concentration-effect relationship has successfully been described in mild AD patients demonstrating the supportive value of PK/PD models in QP-A/MBDD in early phases of clinical development for decision-making.

Topics: Algorithms; Alzheimer Disease; Biogenic Monoamines; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Cognition; Computer Simulation; Databases, Factual; Disease Progression; Dose-Response Relationship, Drug; Double-Blind Method; Forecasting; Humans; Models, Statistical; Neuropsychological Tests; Nonlinear Dynamics; Population; Treatment Outcome

To develop a population pharmacokinetic model for NS2330 and its major metabolite M1 based on data from a 14 week proof of concept study in patients with Alzheimer's disease, and to identify covariates that might influence the pharmacokinetic characteristics of the drug and/or its metabolite.. Plasma data from 320 subjects undergoing multiple oral dosing, and consisting of 1969 NS2330 and 1714 metabolite concentrations were fitted simultaneously using NONMEM.. Plasma concentration-time profiles of NS2330 and M1 were best described by one-compartment models with first-order elimination for both compounds. Absorption of NS2330 was best modelled by a first-order process. Low apparent clearances together with large apparent volumes of distribution resulted in long half-lives of 234 h (NS2330) and 374 h (M1). The covariate analysis identified weight, sex, CL(CR), BMI and age as influencing the pharmacokinetics of NS2330 and/or M1. However, simulations performed revealed that only CL(CR) and sex had a significant effect on the steady-state plasma concentration-time profiles. Females with a creatinine clearance of 35.6 ml min(-1) showed a 62% increased exposure compared with males without renal impairment. The robustness and accuracy of the model were demonstrated by the successful predictivity of an external dataset.. A descriptive, robust and predictive model for NS2330 and its M1 metabolite was developed. Important covariates influencing pharmacokinetics were identified, which might guide the further development of NS2330 and optimize its long-term use in the treatment of Alzheimer's disease.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials, Phase II as Topic; Creatinine; Double-Blind Method; Female; Humans; Male; Middle Aged; Models, Biological; Sex Factors