Jan Berkhout (1,2) , Julie A. Stone (3), Katia M.C. Verhamme (1), Bruno H.C. Stricker (4,5), Miriam C.J.M. Sturkenboom (1), Meindert Danhof (2) and Teun M. Post (6)
(1) Department of Medical Informatics, Erasmus Medical Centre, Rotterdam, The Netherlands, (2) Leiden Academic Centre for Drug Research, Division of Pharmacology, Leiden, The Netherlands, (3) Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA, (4) Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands, (5) Drug Safety Unit, The Health Care Inspectorate, The Hague, The Netherlands, (6) Leiden experts on Advanced Pharmacokinetics and Pharmacodynamics (LAP&P), Leiden, The Netherlands
Objectives: A complete mechanism-based model describing osteoblast and osteoclast activity has been reduced in order to apply it in a population-approach. It was shown that the model reduction did not jeopardize the dynamical properties of the model. The reduced model was successfully applied to describe responses in treatment with various doses of tibolone and/or calcium in postmenopausal women. The objective of this study is to use the previously established systems pharmacology model to test whether it can also adequately describe the placebo and alendronate treatment response in BMD and other bone turnover markers in an external population of postmenopausal women.
Methods: Data were obtained from the Early Postmenopausal Intervention Cohort (EPIC) study, a 4-year clinical trial of oral alendronate in 1609 postmenopausal women randomly assigned in a double-blind manner to receive 2.5 or 5.0 mg alendronate once daily or placebo to evaluate the potential to prevent osteoporosis [1]. The model used is a mechanism-based disease systems model based on [2]. While maintaining the original model structure and system parameter values, we added the alendronate treatment function (as a disease independent proportional symptomatic effect) and updated the BMD dynamics equation (to an indirect-response model) of this model and implemented this in the population approach (NONMEM).
Results: The updated systems pharmacology model was shown to adequately describe the alendronate and treatment response. The final model yielded realistic parameter values that could be estimated with good precision. Visual predictive checks of the final model revealed that the dynamics of all biomarkers for all treatment arms could be described to very good approximation during the four study years. The final model allowed for simulations of the dynamics in BMD and biomarkers and revealed a symptomatic treatment effect for BSAP and a disease modifying effect for NTX and BMD.
Conclusions: We have successfully extended a mechanism-based osteoporosis model based on an external dataset with a different mechanism of action. Developing a robust model to describe the treatment response is of high importance to enable quantification of drug effects, and eventually to guide the design of clinical trials for osteoporosis treatment. Finally, this study shows the strength of a systems pharmacology approach, which could also be of great importance for other degenerative diseases.
References:
[1] Post et al., J Pharmacokinet Pharmacodyn. 2013;40:143–156
[2] Ravn et al., Ann Intern Med. 1999;131:935-942
Reference: PAGE 24 (2015) Abstr 3556 [www.page-meeting.org/?abstract=3556]
Poster: Drug/Disease modeling - Other topics