When people find out that you’re working to improve drug development for companion animals, you hear some colorful stories. The other day, one of my colleagues recounted to me the wild antics of Jinjer, her childhood dog. Jinjer was a 60 pound, fawn boxer, with a tiny stump of a tail, who loved everyone. This dog was also, it must be said, completely crazy. My colleague’s parents had to take Jinjer to the vet many times, for reasons ranging from her eating cactus to her jumping through a plate glass window not once, not twice, but three times. Jinjer also had a health problem that required giving her medication. Coincidentally, one of the family members also took the same medication. When Jinjer would occasionally run out of her meds, a family member would take a tablet of the human version, break it in half, and give it to her (disguised in peanut butter, of course).
Clearly, people want to provide top quality healthcare for their four-legged family members. These anecdotes got me thinking about the dramatic influence that modeling and simulation methods, including physiologically-based pharmacokinetic (PBPK) models, have had on helping develop safer, more effective medications for veterinary use. In this blog post, I’ll discuss our Cooperative Research and Development Agreement (CRADA) with the FDA to further develop the Simcyp Dog model for the evaluation of drug products for canines.
PBPK models: a systems biology approach
This approach can inform veterinary drug development in numerous ways. First, it provides a mechanism for combining physiological attributes, drug substance, formulation, and clinical variables into predictions of product performance across a patient population. Likewise, it helps identify the most influential variables in determining the dose-exposure-response relationship. Finally, it supports predicting potential consequences through the use of “what if” scenarios (eg, altered formulations, physiology and disease, drug-drug or drug-food interactions).
What variables can influence drug exposure and response?
When developing medications for veterinary uses, there are many variables to consider. These can be grouped into intrinsic and extrinsic factors. Some of the extrinsic factors include drug dosing, route of administration, drug formulation, diet, DDIs, the environment, and concurrent disease. Intrinsic factors encompass breed, genetics, age, gender, pregnancy, and lactation state. It seems to only make sense that a 5 pound chihuahua might need to be dosed differently than a 150 pound mastiff dog. In silico pharmacometric models can explore the potential influence of these variables on drug exposure.
Why develop in silico models of animals?
In addition to their importance as a companion animal species, dogs (primarily beagles & mongrels) are frequently used as a preclinical species to support human drug development or as a toxicological species when evaluating the human safety of drug residues in food-producing animal species. In both situations, in silico animal models can be invaluable for assessing the potential impact of differing drug formulations and enzyme polymorphisms on the interspecies extrapolation of the resulting study data. It is also a helpful tool in fulfilling the ethical obligation towards the refinement, replacement and reduction of in vivo studies in animals.
This five year project, in conjunction with the FDA’s Center for Veterinary Medicine (CVM), aims to deliver PBPK dog models that streamline veterinary drug product development and evaluation. Due to the inherent flexibility of PBPK models to separate extrinsic and intrinsic factors, this collaboration will investigate the effect of these factors in combination or independently on drug kinetics, such as effect of drug formulation and food on drug exposure in a Chihuahua or Mastiff. この評価を通して、動物安全性試験および臨床試験のデザインおよび考察に関連する複雑な問題に対応する目的で薬物動態の原則を活用することが促進され、適切な情報を伝える製品添付文書を作成するために、モデル予測を安全性および有効性に関する試験のデータと統合することが可能になります。
Last month, I attended the European Association for Veterinary Pharmacology and Toxicology (EAVPT) International Congress. Marilyn Martinez of the FDA’s Office of New Animal Drug Evaluation gave an insightful talk on how the agency is leveraging systems pharmacology, including PBPK, to develop safer medications for dogs. She was kind enough to let me share her slides with you.
Tools for human and veterinary drug development
The Simcyp Animal whole-body PBPK platform for beagle dog, Sprague Dawley rat, genetically modified mouse, and cynomolgus monkey (upcoming) can be used to:
- Assess PK properties of various drugs (small molecules) after intravenous or oral dosing
- Evaluate formulation and food effects on drug kinetics after oral drug administration
- Predict drug concentration-time profiles in plasma, different tissues and organs
- Predict the effect of knocking out or knocking in certain enzymes and transporters on pharmacokinetics of drugs
- Develop different breed populations to assess the impact of breed/species variability on drug pharmacokinetics.
- Assess the pharmacokinetics of large molecules (biologics) using the (under development) cynomolgus monkey model
PBPK simulations in combination with in vitro-in vivo extrapolation (IVIVE) using animal models, can help identify key data requirements, design subsequent experiments, and increase confidence before moving to a target veterinary species or ‘First-in-Human’ trial.
When used with the Simcyp Population-based Simulator, Simcyp Animal allows comparison of human and animal data without relying upon allometric scaling, which may not be a valid approach for some parameters.
Take a deeper dive into this topic
I’ve provided some resources for our readers who are interested in learning more about the research findings from our FDA CRADA and other animal models:
- My 2015 EAVPT poster, “Use of Physiologically Based Pharmacokinetic (PBPK) Models to Support Canine Drug Product Development“
- My 2014 AAPS poster, “A Physiologically-Based Pharmacokinetic Model to Predict the Disposition of Topotecan in Transporter Wild Type and Knock-Out Mice”
- My 2013 AAPS poster, (as a co-author) “Use of In Silico Physiologically Based Pharmacokinetic (PBPK) Models to Predict Food Effects in Dogs“
- My 2013 AAPS poster, “Prediction of Effective Regional Passive Intestinal Permeability in Mouse using ‘MechPeff’: A Mechanistic Model able to use only Drug Physicochemical Parameters as Inputs”
- My 2011 posters (AAPS & Animal Alternatives meetings) on Theophylline and Celecoxib Formulations in beagle dogs
- My 2015 AAPS Poster: In Silico Prediction of Regional Passive Intestinal Permeability in Cynomolgus Monkey using ‘MechPeff’: A Mechanistic Model with Drug Physicochemical and In Vitro Parameters as Inputs
- My 2015 AAPS Poster: Application of the ‘MechPeff’ Model to Predict Passive Regional Effective Intestinal Permeability in Rat Using Drug Physicochemical Parameters as Inputs
To learn more about how to recognize the many benefits of modeling and simulation technology for informing drug development and labeling, read our white paper, “Drug Label Optimization Using Proven Modeling and Simulation Methodology.”