01. Discover
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 mechanistic absorption and disposition through dermal (topical and subcutaneous), intraoral (oral cavity), pulmonary (respiratory), ocular, intramuscular, and intraarticular routes. The long-acting injectable models can be utilized for subcutaneous, intramuscular, and NEW! intraarticular routes. These models were all developed in collaboration with the 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

 

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An infographic titled "Trust Our Gut... and Model Everywhere!" showcases the applications of Simulations Plus, Inc's GastroPlus platform, featuring a translucent human body to highlight various drug administration routes—ocular, oral cavity, topical dermal, intramuscular, pulmonary, subcutaneous, and intraarticular —and detailing the "Explore," "Translate," and "Support" aspects of our comprehensive offerings.
Easy-to-use interface

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) & physiologically based biopharmaceutics modeling (PBBM)  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.

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02. Explore

Explore Additional Dosage Routes

  • Topical Dermal Model

    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)

     

    A screenshot of the GastroPlus Transdermal Compartmental Absorption & Transit (TCAT) model

    Some of the processes considered in the dermal 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)
    • built-in physiology models for minipig (ear, snout, neck, back, flank, abdomen, and whole body), rat (whole body), and mouse (whole body)
  • 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 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

    A screenshot of the GastroPlus Transdermal Compartmental Absorption & Transit (TCAT) model

    Some of the processes considered in the 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)
    • 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

    A screenshot of the GastroPlus Oral Cavity Compartmental Absorption & Transit (OCAT) model

    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 Model

    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

    A screenshot of the GastroPlus nasal pulmonary drug delivery model

    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
  • 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)
    • model structure modifications and updates to initial estimates for tissue permeability and systemic rates
  • 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).

    Suspension dosage forms and precipitation kinetics with solution injections!

    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
  • Intraarticular Model

    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.

03. Resources
Additional Dosage Routes Resources
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Fluorometholone Ocular Suspension PBPK Simulations Using the OCAT™ Model in GastroPlus™

Development of generic formulations of ophthalmic corticosteroids and regulatory acceptance of bioequivalence can be facilitated by analysis of the mechanisms of ocular dissolution, absorption...

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Physiologically-Based Pharmacokinetic (PBPK) Model for Prediction of Tobramycin Pulmonary Absorption and Pharmacokinetics in Children

To fit an absorption-pharmacokinetic model for simulation of tobramycin in adult and pediatric populations. Tobramycin pulmonary absorption and pharmacokinetics were simulated using GastroPlus™.

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Physiologically-Based Pharmacokinetic (PBPK) Model for Prediction of Midazolam Pharmacokinetics After Intranasal Administration in Children

To predict midazolam absorption and pharmacokinetics (PK) after intranasal (i.n.) administration in young children. The absorption and PK of midazolam were simulated using GastroPlus™. The program’s…

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Development of a Novel Oral Cavity Compartmental Absorption and Transit Model for Sublingual Administration: Illustration with Zolpidem

Intraoral (IO) delivery is an alternative administration route to deliver a drug substance via the mouth that provides several advantages over conventional oral dosage forms.

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Physiologically Based Pharmacokinetic (PBPK) Model to Describe Absorption and Disposition of Inhaled Capreomycin

The current work describes the simulation of capreomycin pharmacokinetics (PK) after IV and pulmonary administration. Capreomycin is an antibiotic used to treat tuberculosis. It is eliminated mainly by...

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