2015 usc gateway-mcnair scholars program research presentation
TRANSCRIPT
Integrated Model for Denosumab:Pharmacodynamics in
Postmenopausal Women
Diana Ramos, Mentor: Dr. D’ArgenioUniversity of Southern California, USC Viterbi School of Engineering
Department of Biomedical Engineering2015 USC Gateway/McNair Scholars Program
Osteoporosis• Bone disease• Affects 10 million Americans• 80% are women• Silent disease• 43.1 million have low bone
density
Healthy Bone OsteoporosisFigure 1
Specific Aims• Implement a computational model for the model-based
drug development that might improve the evaluation of osteoporosis therapies, leading to better treatment and prevention
• Investigate the effects of disease progression with a regimen of different doses of Denosumab, due to the up-regulation of RANKL on changes in bone mineral density
• Explore dose adjustments needed to compensate for the percent decrease in bone mineral density due to changes in RANKL
Materials and Methods
Figure 2: Bone homeostasis model
Results
0 200 400 600 800 1000 1200 1400 160094
96
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100
102
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Bone Mineral Density: multiple dosing of Denosumab
1ng30 ng
Time (days)
Chan
ge fr
om b
asel
ine
in lu
mba
r spi
ne B
MD
(%)
Figure 3
0 200 400 600 800 1000 1200 1400 1600949698
100102104106108110112
Disease Progression of Osteo-porosis
Klp = 0.3Klp=1.5Klp=2.0
Time(days)
Chan
ge fr
om b
asel
ine
in
lum
bar s
pine
BM
D (%
)
Results
Figure 4: Dose 1ng
% Increase in BMD= 5.18
0200
400600
8001000
12001400
1600949698
100102104106108110
Dose adjustments needed to compensate for decrease in BMD
Dose = 1ng, Klp= 2.0Dose = 4ng, Klp= 2.0
Time (days)
Chan
ge fr
om b
asel
ine
in lu
mba
r spi
ne
BMD
(%)
Figure 5
Conclusion
Future Work• Exploring the effects of a deficiency in Vitamin
D and/ or estrogen levels with a linked bone homeostasis model
• Model effectively predict changes in BMD for postmenopausal women
• Ability to identify clinical endpoints in the treatment of osteoporosis
• Provides a platform for testing various variables that regulate drug response and disease progression
Acknowledgements
This study was supported by Dr. D’Argenio, Professor of Biomedical Engineering at the University
of Southern California. I would also like to thank my 2014-2015 USC
McNair/Gateway Scholar Cohort.
References• Marathe, Anshu, Mark C. Peterson, and Donald E. Mager.
"Integrated Cellular Bone Homeostasis Model for Denosumab Pharmacodynamics in Multiple Myeloma Patients." The Journal of pharmacology and experimental therapeutics 326.2 (2008): 555-62. ProQuest. Web. 16 June 2015.
• Marathe, Dhananjay D., Anshu Marathe, and Donald E. Mager. "Integrated Model for Denosumab and Ibandronate Pharmacodynamics in Postmenopausal Women." Biopharmaceutics & drug disposition 32.8 (2011): 471-81. ProQuest. Web. 16 June 2015.
• Lemaire, Vincent, et al. "Modeling the Interactions between Osteoblast and Osteoclast Activities in Bone Remodeling." Journal of theoretical biology 229.3 (2004): 293-309. ProQuest. Web. 17 June 2015.