• Aaps J · Jun 2010

    Randomized Controlled Trial

    Quantitative pharmacology approach in Alzheimer's disease: efficacy modeling of early clinical data to predict clinical outcome of tesofensine.

    • Thorsten Lehr, Alexander Staab, Dirk Trommeshauser, Hans Guenter Schaefer, and Charlotte Kloft.
    • Institute of Pharmacy, Department of Clinical Pharmacy, Martin-Luther-Universitaet Halle-Wittenberg, 06120 Halle, Germany.
    • Aaps J. 2010 Jun 1;12(2):117-29.

    AbstractEffective 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.

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