CFDRC is developing multiscale modeling tools, “Leonardo” for integrated “top-down” whole body physiology based pharmacokinetics (PK, PBPK) and “bottom-up” systems biology based pharmacodynamics (PD) and toxicology. The whole body physiology PBPK module includes the blood circulation, respiration, metabolism, autoregulation, and other physiological components while the PK module takes into account various modes for drug administration, distribution, absorption, metabolism, and excretion. The PD module, coupled to pathology and systems biology (SB), simulates the modulation of the cell biology (e.g. metabolic/signaling pathways and toxicology) by the drug action as well as the physiological parameters of the PBPK model (e.g. regulation of vascular tone and resultant blood flow redistribution). We integrate these modules and customize for specific diseases.

To the best of our knowledge, Leonardo is the first ever coupled PB-PK-PD modeling framework. Unlike conventional compartmental PK/PD models, which treat organs as “well stirred reactors” and assume constant blood flow distribution among organs, in the Leonardo some organs can be treated as classical compartments, spatially distributed compartments, or full 3D geometrically resolved organs with vasculature.

The systems physiology and pathology modules are described separately. In the PBPK models the hemodynamics model is tightly coupled to the volume kinetics model which calculates the fluid, solute, and ionic shifts between plasma, tissue, and cellular compartments as a result of change in the hydrostatic pressure (e.g. hemorrhage, resuscitation, dialysis), osmotic pressure due to water or solute intake, or other physiological, pathological, nutritional, or other events.

The pharmacokinetics module in Leonardo is solving drug and metabolites blood transport, distribution among various organs, and partitioning into tissue interstitium and cellular spaces. Several routes of administration are enabled including intravenous, oral, subcutaneous, transdermal, and pulmonary inhalation. The drug can be passively or controlled released from various vehicles including tablets, micelles, polymers, patches, etc. Biochemical reaction mechanisms can be constructed to simulate drug interaction with plasma proteins, drug binding to plasma cells, endothelial cells, as well as passive and facilitated transport across the endothelial and epithelial barriers. A customized module has been established to simulate gastrointestinal (GIT) administration, that accounts for spatio-temporal tablet transport in he GIT track, tablet dissolution and drug release, and drug absorption into the vascular and lymphatic system. The PK module provides the initial conditions for the PD module.

The pharmacodynamics module is essentially a cellular systems biology model that simulates the drug interaction with intracellular signaling and metabolic pathways. The PD model interacts with the PK model calculating the drug metabolism rates, production of additional metabolic species, and with the physiology model by changing the membrane and tissue physical properties (e.g. vasodilation, permeability, tissue proliferation, apoptosis, etc.), and physiological properties e.g. heart rate or other autoregulation responses.

Examples:

• PBPK of cyclosporine,
• Estradiol PBPK model for rats, pigs, and humans
• Ototoxicity of gentamicin and otoprotection
• Genetic screening of antimalarials – mefloquine
• Neural protectants against organophosphorus compound toxicity
• Multiscale modeling of paclitaxel drug eluting stents,
• Blood coagulation cascade – pathophysiology and pharmacology,
• MMP targeted contrast agent delivery kinetics in the coronary artery,
• Model based pharmaco-therapeutics of diabetes
• Chemotherapy and antiangiogenic cancer treatment
• Drug delivery and treatment planning of brain tumors,