GastroPlus™

PBPK modeling software – from discovery through
development…

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Additional Dosage Routes

What is the Additional Dosage Routes Module?

The Additional Dosage Routes Module in GastroPlus extends the program beyond the traditional oral and intravenous drug administration routes. With this module, you can simulate disposition through additional dosing sites – dermal (topical and subcutaneous), intraoral (oral cavity), pulmonary (intranasal and respiratory), ocular, and NEW! intramuscular. These models were all developed in collaboration with top 5 pharmaceutical companies and/or the U.S. FDA. The ability to predict concentration profiles in different regions of the skin, mouth, eye, lungs, nose, and muscle can help you:

  • Explore various formulation/drug delivery options to achieve desired therapeutic effects
  • Identify species-specific changes to estimate how a drug is handled in animals vs. humans

With the Additional Dosage Routes Module, simulating concentrations through these sites is managed through our easy-to-use interface. Mechanistic, physiologically-based models are provided for each tissue, for different species. You can also customize your own physiology by entering available information into the program. These models are linked with either compartmental or physiologically-based pharmacokinetics (PBPK) in GastroPlus, so you may predict your drug’s distribution and elimination once it enters into the systemic circulation.

For all of these PBPK delivery models, standard GastroPlus features, including the Population Simulator and Parameter Sensitivity Analysis, can be utilized. Plus, load measured in vivo PK data, for local tissues, to optimize and validate your models. And, finally, as with other GastroPlus modules, there is no equation or code writing required.

Dermal/Subcutaneous Model

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 transdermal & subcutaneous dosage forms, specified at different places on the body, including:

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

Some of the processes considered in the dermal/subcutaneous models include:

  • vehicle evaporation
  • absorption from the vehicle into the various tissue regions
  • nonlinear metabolism in any tissue region
  • systemic circulation and lymphatic absorption
  • drug partitioning and diffusion through different skin layers and compartments (stratum corneum, viable epidermis, dermis, sebum, hair)
  • built-in human physiologies for six (6) different locations: arm, leg, abdomen, back, face, and scalp (physiologies for additional regions or preclinical species may be created as user-defined options)
  • NEW! built-in physiology models for minipig (ear, snout, neck, back, flank, abdomen, and whole body), rat (whole body), and mouse (whole body)

Oral Cavity Delivery Model

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:

  • dissolution & precipitation in the saliva
  • diffusion through the oral mucosa
  • uptake into systemic circulation
  • swallowing of unabsorbed drug
  • physiological saliva flow and simulation of variety of study designs (normal swallowing, subjects asked to not swallow for certain period of time, etc…)
  • built-in physiologies for human, monkey, dog and rabbit (additional physiology models may be easily created as user-defined options)

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)

 

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

The pulmonary model includes the advanced ICRP 66 deposition model (Smith et al., 1999, LUDEP) 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

Ocular Delivery Model

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)

NEW! Intramuscular Injection Delivery Model

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).

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

  • Can be used for both small and large molecules (Biologics Module license required)
  • Linear metabolic clearance can be set up directly in the muscle tissue
  • Nonspecific binding can be incorporated
  • Effective depot volumes can be defined to specify the volume of muscle tissue into which the dose is injected
  • Predefined physiology models for human (deltoid, vastus lateralis, gluteus), rat (quadriceps), dog (quadriceps), monkey (quadriceps) – as with other routes, you can also create & save custom physiology models