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.

Benefit-risk assessment of raloxifene in postmenopausal osteoporosis.

Raloxifene, a nonsteroidal benzothiophene, is a second-generation selective estrogen receptor modulator (SERM) that is an antiresorptive agent. Raloxifene is a non-hormonal agent that binds to the estrogen receptor and results in estrogen agonist effects on bone and the cardiovascular system and estrogen antagonist effects on endometrial and breast tissue. Raloxifene has diverse pharmacodynamic properties due to its differential interactions with the estrogen receptor and tissue selectivity. Raloxifene was the first SERM to be approved for the prevention and treatment of postmenopausal osteoporosis. In this review, we conducted a systematic search of the literature for trials that evaluated the following outcomes: bone density, fractures, quality of life, cardiovascular outcomes, safety and adverse events. Raloxifene at the approved dosage of 60 mg/day increased lumbar spine bone density by 2.5% relative to control after 2 years of therapy. A large fracture prevention trial confirmed that treatment with raloxifene 60 mg/day for 3 years decreased the relative risk of incident vertebral fractures by 30-50% in women with prevalent fractures or osteoporosis. Extraskeletal effects of raloxifene include a reduction in total cholesterol and low density lipoprotein cholesterol levels. Assessment of the safety profile revealed that raloxifene was not associated with endometrial hyperplasia and that there was a 72% reduction in the incidence of invasive breast cancer in raloxifene-treated postmenopausal women with osteoporosis. Adverse events associated with raloxifene included an increase in the absolute risk of venous thromboembolism and an increase in the risk of hot flashes and leg cramps. In comparison to other osteoporosis therapies, raloxifene has a lesser impact on bone mineral density, a similar effect on the occurrence of vertebral fractures, but no effect on the frequency of non-vertebral fractures. Raloxifene can be recommended for the prevention of vertebral fractures in women with osteopenia/osteoporosis who are not at high risk of non-vertebral fractures and who do not have a past history of venous thromboembolism.