Model-based drug development: the road to quantitative pharmacology.

High development costs and low success rates in bringing new medicines to the market demand more efficient and effective approaches. Identified by the FDA as a valuable prognostic tool for fulfilling such a demand, model-based drug development is a mathematical and statistical approach that constructs, validates, and utilizes disease models, drug exposure-response models, and pharmacometric models to facilitate drug development. Quantitative pharmacology is a discipline that learns and confirms the key characteristics of new molecular entities in a quantitative manner, with goal of providing explicit, reproducible, and predictive evidence for optimizing drug development plans and enabling critical decision making. Model-based drug development serves as an integral part of quantitative pharmacology. This work reviews the general concept, basic elements, and evolving role of model-based drug development in quantitative pharmacology. Two case studies are presented to illustrate how the model-based drug development approach can facilitate knowledge management and decision making during drug development. The case studies also highlight the organizational learning that comes through implementation of quantitative pharmacology as a discipline. Finally, the prospects of quantitative pharmacology as an emerging discipline are discussed. Advances in this discipline will require continued collaboration between academia, industry and regulatory agencies.

Population dose-response model for tadalafil in the treatment of male erectile dysfunction.

PURPOSE: To determine the population dose-response relationship for tadalafil during on-demand (as-needed) administration for treatment of erectile dysfunction (ED). METHODS: A total of 212 male patients with mild, moderate, or severe ED participated in a multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Patients were randomized to receive placebo or 2, 5, 10, or 25 mg tadalafil, taken on demand over an 8-week period. Efficacy was assessed on the basis of questions 2 and 3 of the Sexual Encounter Profile (SEP) and questions 3 and 4 of the International Index of Erectile Function (IIEF) questionaires. These scores were modeled using logistic regression. A fifth patient response, the IIEF EF (erectile function) domain score, was modeled as a continuous variable. RESULTS: The dose-response relationship for each efficacy variable was best described with an Emax model, in which maximum effect increased with ED severity at baseline. Response scores increased substantially between 10 and 25 mg tadalafil doses, and the dose-response parameter estimates suggested possibly higher responses at even higher doses. CONCLUSIONS: Population dose-response modeling of all five oucome measures indicated that efficacy in all ED severity groups in the studied population generally increased across the 2 to 25 mg tadalafil dose range. Estimates of maximal improvement (Emax) in the IIEF EF domain score were 7.5, 11.4, and 16.3 points for patients with mild, moderate, and severe ED, respectively. Corresponding tadalafil doses to attain half-maximal improvement (ED50 estimates) were 4.7 mg, 7.1 mg, and 10.1 mg.