The Use of Population Pharmacokinetic and Pharmacodynamic Modeling and Simulation in Anti-Osteoporotic Drug Development: A Perspective

摘要

Osteoporosis is a skeletal disorder characterized by compromised bone strength and increased risk of fracture. In postmenopausal osteoporosis, estrogen deficiency increases bone turnover with an imbalance between bone resorption and formation, resulting in low bone mass and subsequent increase in bone fragility. The fractures that result from osteoporosis are a major public health problem. Developing new anti-osteoporotic treatments is challenging, because clinical studies needed to establish the efficacy of osteoporosis prevention and treatment require a long follow-up duration. Population pharmacokinetic-pharmacodynamic (PK-PD) modeling is the standard approach to describe relationships between dose, dosing regimen, longitudinal concentration of targeted drug, and efficacy (or response) data including biomarkers, surrogate endpoints, and clinical endpoints obtained from particular groups of subjects. These relationships are believed to be useful in predicting an optimal dosing regimen and/or study duration. A number of examples utilizing the PK-PD modeling approach in clinical drag development have been reported. In the field of osteoporosis, several modeling examples have described a series of relationships between dose, PK, bone turnover markers, bone mineral density and fracture risk (clinical endpoint). Although there are relatively few reports in which PK-PD modeling is applied to clinical drag development in osteoporosis compared to other disease areas, the number of such reports has been increasing recently. The aim of this review is to provide a perspective on effective application of population PK-PD modeling in the clinical development of anti-osteoporotic drugs by revisiting the results of PK-PD modeling used in the field of osteoporosis.