A physiologically based pharmacokinetic model for strontium exposure in rat

Area of Science:

• Pharmacokinetics and Pharmacodynamics
• Translational Medicine
• Bone Biology

Background:

• Osteoporosis affects post-menopausal women, with strontium (approved as strontium ranelate) being a bone-seeking agent for treatment.
• Understanding strontium's disposition is crucial for optimizing its therapeutic use and developing new bone-seeking agents.
• Physiologically based pharmacokinetic (PBPK) models offer a powerful tool for describing drug behavior in the body.

Purpose of the Study:

• To develop a PBPK model to characterize the disposition of strontium, a bone-seeking agent.
• To utilize preclinical data from ovariectomized (OVX) rats, a model for post-menopausal osteoporosis, for model development.

Main Methods:

• A PBPK model was constructed using plasma and bone exposure data from OVX rats.
• The model incorporated literature elements describing bone tissue heterogeneity and remodeling processes.
• Model fitting to exposure data was performed using nonlinear regression in MATLAB.

Main Results:

• The developed PBPK model successfully described strontium's plasma and bone exposure in OVX rats.
• Estimated model parameters and observed behavior align with known strontium distribution and bone incorporation.
• The model provides a physiologically rationalized description of strontium exposure.

Conclusions:

• The PBPK model effectively describes strontium exposure in a physiologically meaningful way.
• This model has potential for future applications in pharmacokinetic-pharmacodynamic (PK-PD) modeling of strontium and other bone-seeking agents.
• The model can be scaled for predicting human strontium bone exposure.