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

98

100

102

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106

108

110

112

Bone Mineral Density: multiple dosing of Denosumab

1ng30 ng

Time (days)

Chan

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in lu

mba

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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

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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.