Development and Evaluation of a Population PK/PD Model for Fc-OPG in Healthy Postmenopausal Women
Matthew L. Zierhut(1), Mark C. Peterson(2), Marc R. Gastonguay(3), Steven W. Martin(2), Paolo Vicini(1), Pirow J. Bekker(2), Donna Holloway(2), Philip T. Leese(4)
(1) Department of Bioengineering, University of Washington Box 352255, Seattle, WA, 98195-2255; (2) Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA, 91320; (3) Gastonguay Consulting LLC, Simsbury, CT, USA; (4) Quintiles, Lenexa, Kansas, USA
Osteoporosis is a disease characterized by low bone mass and deterioration of bone tissue. This leads to increased bone fragility and risk of fracture, particularly of the hip, spine and wrist. Osteoprotegrin (OPG) is a promising alternative medication for osteoporosis. It is a member of the tumor necrosis factor (TNF) family, and works to decrease bone resorption by inhibiting osteoclast differentiation through the RANKL/RANK/OPG pathway. We describe the development of a PK-PD model for the fusion protein, Fc-osteoprotegrin (Fc-OPG), in healthy postmenopausal women. The model describes data from 8 cohorts (n = 13 subjects/cohort; OPG:placebo = 10:3) classified by dose level (0.1, 0.3, 1.0, or 3.0 mg/kg) and route of administration (intravenous (IV) or subcutaneous (SC) injection). OPG serum concentrations following IV or SC administration and urinary N-telopeptide (NTX) levels were available. The model was developed in a stepwise fashion and results in an adequate fit to the data with physiologically plausible parameter estimates. Model robustness was tested via a posterior predictive check with the model performing well in almost all cases. Clinical trial simulations with the model clearly showed that 2 weeks after a single 3 mg/kg SC dose, Fc-OPG produces a median urinary NTX percent change (w.r.t. baseline) of 45% (with a 95% confidence interval ranging from 34 to 60%). Simulations were evaluated using local and global sensitivity analysis methods. The model selection and simulation strategies we applied are rigorous, useful, and easily generalizable.