PI-111 - DEVELOPMENT OF A QUANTITATIVE SYSTEMS PHARMACOLOGY MODEL TO CHARACTERIZE THE EFFECTS OF INHALED CORTICOSTEROIDS ON PEDIATRIC BONE HEALTH.

T. Nguyen¹, V. Gershuny², J. Momper³, J. Bai², S. Schmidt⁴, G. Burckart², G. Abulwerdi²; ¹U.S. Food and Drug Administration/University of California, San Diego, San Diego, CA, Unites States, ²U.S. Food and Drug Administration, Silver Spring, MD, United States, ³University of California, San Diego, San Diego, CA, United States, ⁴University of Florida, Orlando, FL, United States.

Background: The chronic use of high doses of corticosteroids have well established adverse effects on bone health. Children with persistent asthma are commonly treated with inhaled corticosteroids (ICS) and are particularly vulnerable to increased risk of osteoporosis, fracture incidence, and growth retardation. For this reason, the U.S Food and Drug Administration prescribing information for ICS such as budesonide provides a precaution for potential effects on growth. The bone turnover process occurs throughout an individual’s life and is tightly regulated by bone forming cells (osteoblasts) and bone resorbing cells (osteoclasts). During childhood and adolescence, cartilage cells (chondrocytes) play a central role in driving linear growth. The objective of this study was to predict ICS toxicity on bone health in children using a quantitative systems pharmacology (QSP) model.

Methods: Ordinary differential equations of a previously developed bone turnover model were amended to capture the effects of ICS treatment on cells responsible for bone turnover: (A) osteoblasts, (B) osteoclasts; and linear growth: (C) chondrocytes (Figure 1). The primary ICS effects incorporated into the model are direct inhibition and increased apoptosis of osteoblasts, increased osteoclastogenesis and survival of osteoclasts, and decreased proliferation, hypertrophy, and cartilage-matrix deposition of chondrocytes. Bone and chondrocyte cells were not directly measured, so the model included the following biomarkers that were used to elucidate changes in these cell counts: bone-specific alkaline phosphatase (BSAP), C-telopeptide of type 1 collagen (CTX), cartilage, lumbar spine and total hip bone mineral density (LSBMD and THBMD).

Results: The model predictions were compared to data from the Childhood Asthma Management Program. The analysis focused on LSBMD levels over time in 311 children aged 5-12 years who received 200 mcg budesonide twice daily for 4-6 years and 418 children who received placebo.

Conclusion: The developed QSP model was able to quantitatively describe the effects of ICS on bone health in pediatric patients with asthma treated with budesonide. The mechanistic model will allow us to flag doses and exposures of ICS that may cause serious side effects such as growth retardation or bone fractures in growing children and adolescents.