The Transdermal Compartmental Absorption & Transit (TCAT™) model represents the skin as a collection of the following compartments: stratum corneum, viable epidermis, dermis, sebum, hair lipid, and hair core. The PBPK model diagram is shown in the figure provided.

The model can simulate a variety of transdermal dosage forms, specified at different places on the body, including:

• liquid formulations (solutions, lotions, suspensions)
• semi-solid formations (gels, creams, lotions, pastes)

Some of the processes considered in the dermal models include:

The Transdermal Compartmental Absorption & Transit (TCAT™) model represents the skin as a collection of the following compartments: stratum corneum, viable epidermis, dermis, subcutaneous tissue, sebum, hair lipid, and hair core. The subcutaneous tissue is also considered. The PBPK model diagram is shown in the figure provided.

The model can simulate a variety of subcutaneous dosage forms, specified at different places on the body, including:

• subcutaneous injections
• default in vitrotransdermal permeability (skin penetration) assay models to allow for easy analysis of data and translation to in vivo performance

Some of the processes considered in the subcutaneous models include:

The Oral Cavity Compartmental Absorption & Transit (OCCAT™) model represents the oral cavity (mouth) as a collection of the following compartments: buccal, gingival, palate, top of the tongue, bottom of the tongue, and mouth floor. The PBPK model diagram is shown in the figure provided.

The model can simulate a variety of dosage forms including:

• sublingual solutions & tablets
• lingual sprays and supralingual tablets
• controlled release buccal patches

Some of the processes considered in the oral cavity models include:

Pulmonary (Intranasal/Respiratory) Model

The Pulmonary Compartmental Absorption & Transit (PCAT™) model represents the lung/nose as a collection of the following compartments: an optional nose (containing the anterior nasal passages), extra-thoracic (naso- and oro-pharynx and the larynx), thoracic (trachea and bronchi), bronchiolar (bronchioles and terminal bronchioles) and alveolar-interstitial (respiratory bronchioles, alveolar ducts and sacs and interstitial connective tissue). The PBPK model diagram is shown in the figure provided.

The pulmonary model provides dosing via the intranasal or respiratory route as an:

• Immediate release or infusion solutions
• Immediate release or infusion powders
• Intratracheal administration
• Nasal sprays (solution or powder)
• Finlay deposition models

Some of the processes considered in the pulmonary (inhaled) models include:

The pulmonary model includes the advanced ICRP 66 (Smith et al., 1999, LUDEP) and Finlay deposition models for calculating deposition fractions in each compartment of both API and carrier particles. Additionally, you may account for the following processes in your simulations:

• Mucociliary transit
• Linear mucus and tissue binding
• Lymphatic transport & systemic absorption
• Nonlinear metabolism or transport in any lung tissue compartment
• Built-in physiology models for human, rat, NEW! dog, NEW! mouse
• Age-dependent scaling of the human pulmonary physiology

The Ocular Compartmental Absorption & Transit (OCAT™) model represents the eye as a collection of the following compartments: pre-cornea, cornea, conjunctiva, aqueous humor, anterior sclera, posterior sclera, iris-ciliary body, choroid-RPE (a combination of choroid and the retinal pigment epithelium), retina, anterior and posterior vitreous humor. The PBPK model diagram is shown in the figure provided.

The ocular model provides dosing as:

• Eye drop (topical solution or suspension)
• IVT (intravitreal injection)
• Intravitreal or subconjunctival implants

Some of the processes considered in the ocular models include:

• Nonlinear metabolism or transport in any eye tissue
• Two-site melanin binding options
• Convective flow incorporated into the ocular disposition model
• Predefined physiology models (human, rabbit, NEW! monkey)
• model structure modifications and updates to initial estimates for tissue permeability and systemic rates

The intramuscular (IM) drug delivery model represents the site of injection as a single compartment. Within this compartment, drug can be bound, and local clearance can take place. Drug can also be transported into the lymph or systemic circulation.

GastroPlus now provides two intramuscular (IM) dosage forms, both of which assume that drug is injected into the muscle tissue. One of these is an immediate release (IR) dosage form, with the other treated as controlled release (CR).

Suspension dosage forms and precipitation kinetics with solution injections!

Some of the processes considered in the IM injection models include:

Understanding the knee joint physiology and its impact on drug PK after intraarticular (IA) injection is critical for developing new drugs aiming to cure rheumatoid arthritis (RA) and other specific diseases affecting human joints.

 The developed IA injection model in GastroPlus® represents knee articulation as a collection of compartments, including synovial fluid, cartilage, and synovium, subdivided into intimal and subintimal layers. Once the drug is present in the systemic circulation, its distribution and clearance can be described either by a mechanistic PBPK model or a conventional compartmental approach. All physiological parameters were directly extracted or derived from information available in literature, and validation of our methods has been published (Development of PBPK model for intra-articular injection in human: methotrexate solution and rheumatoid arthritis case study). As with other models in the Additional Dosage Routes Module, all GastroPlus functionality, including Optimization, Population Simulator, and Parameter Sensitivity Analysis, can drive efficient IA injection model development activities.

 Mechanistic PBPK models describing the joint tissue concentration time course following IA administration of a drug molecule in GastroPlus is a powerful tool to facilitate the development of new therapeutics and improve current practices by better understanding the impact of disease on drug distribution within the joint.