What is modeling and simulation, and why is it important in drug development?
Modeling and simulation (M&S) is a proven scientific approach used to inform key drug development decisions, and it can be employed throughout the development lifecycle of a drug. Physiologically based pharmacokinetic (PBPK) modeling integrates knowledge of a drug’s characteristics with physiological information to provide important insights into how new drugs and formulations will behave in vivo, allowing informed decisions around product development to be made confidently.
How is PBPK M&S used as molecules enter clinical research?
PBPK modeling can be used to risk assess a compound prior to it entering the clinic, in order to generate information to guide formulation strategies. By understanding the solubility and permeability of a compound, coupled with an estimation of intended dose range, M&S can enable rational decisions to be made, for example:
- “Could micronization of my active pharmaceutical ingredient (API) help increase Cmax/exposure?”
- “Is precipitation a risk for my compound?”
- “Will I need to use an enabled formulation to get the exposure I need?”
Early in development, some data may not yet exist. However, only limited information is needed for an initial risk assessment. For example, M&S can use in-silico predictions (from chemical structure) to assess small intestinal permeability.
How can PBPK M&S help me to develop my product?
During clinical and product development, M&S can be used to provide insights into many key questions, such as:
- “Can I change my API particle size without impacting on pharmacokinetic (PK) parameters (Cmax and AUC) significantly?”
- “Will my drug’s PK parameters change (and, if so, by how much) if my drug is taken with a meal?”
- “What dose can I give to an older person/child etc. to obtain equivalent exposure to a healthy adult?”
These are difficult questions to answer without doing a formal clinical study, but M&S can provide valuable information to help guide the development strategy before the drug has even been dosed to a human.
Although it is possible under certain circumstances to use M&S data to secure biowaivers in lieu of clinical studies, in most cases M&S is not a replacement for a clinical trial. Instead, it maximizes the use of data from in-vitro, clinical, and pre-clinical studies to aid the understanding of a drug in the human body, which can then be used to inform formulation design and development strategies. In later-stage development, PBPK modeling is increasingly used to support chemistry, manufacturing, and controls (CMC) aspects of regulatory applications, such as dissolution or particle size specifications.
Tell me more about the M&S team at Quotient Sciences
Our growing M&S team consists of talented scientists whose backgrounds include biochemistry, chemistry, physiology, drug metabolism, pharmaceutical science, biopharmaceutics, mathematics, coding, and pharmacokinetics. M&S involves integrating information from many scientific disciplines, so a large knowledge base is required. In addition, the M&S team is part of the larger Scientific Consulting department, providing further access to a wealth of scientific knowledge built up within Quotient Sciences over many years of developing and testing drug products in a clinical setting.
What software does Quotient Sciences use for M&S?
Most of the modeling work performed at Quotient Sciences uses the software tool GastroPlus™ to build virtual PBPK models to describe mechanistically the behavior of a drug in the body. In-vivo disposition is mainly governed by a drug’s physicochemical properties, such as lipophilicity, molecular weight, and ionization potential, along with their affinity for enzymes and transporters. For example, a basic drug will likely be ionized at low (stomach) pH and is more likely to dissolve in this environment than an acidic (unionized) drug. In contrast, an acidic drug is more likely to dissolve in the intestinal pH of 6-7, whereas a basic drug may not dissolve well here. PBPK modeling allows integration of the knowledge around a potential drug using the GastroPlus™ software to produce accurate predictions of in-vivo performance in an almost limitless range of scenarios, e.g. fed state, pediatric physiology, elderly physiology, renally impaired, and co-administration with acid-reducing agents.
PBPK M&S mechanistically describes not only drug dissolution (location, rate, and precipitation potential) but also drug absorption (rate, intestinal location, and affinity for metabolic gut enzymes and transporters), tissue and blood distribution, and finally excretion (metabolic and/or renal clearance/other mechanism). By accurately understanding all these processes and using GastroPlus™, the plasma concentration of a drug at any given time after administration of a particular dose/regimen/formulation can be accurately predicted.
Do you do any other types of M&S work other than PBPK modeling?
The M&S group is also experienced in developing numerical (empirical rather than mechanistic modeling) in-vitro/in-vivo correlations (IVIVCs), which allow a relationship between in-vitro performance (dissolution) and in-vivo outcome (PK parameters Cmax and AUC) to be developed. A successful Level A IVIVC can be used to inform drug product development or used as part of a regulatory submission.
How does Quotient Sciences work with customers for M&S programs?
The M&S team supports customers who are performing full development programs at Quotient Sciences, as well as customers that need to perform a discrete, standalone M&S project. We are a customer-focused team with dedicated scientists, aided by project managers who work closely in a collaborative manner to efficiently meet customer needs. All of our programs start with a scientific peer discussion with our customers to understand their development project and the types of questions they need M&S to help answer.