In the pharmaceutical development pipeline today, increasing numbers of molecules present sub-optimal pharmacokinetic (PK) data, such as poor exposure, large variability, short half-life, or Cmax-related adverse events (AEs).
At Quotient Sciences, we support our biotech and pharma customers in the development and optimization of drug products. Our chemists and formulation scientists review the properties of each drug candidate and use their expertise to develop formulations that improve the exposure profile of the compound. To embark on formulation optimization, it is key that we understand the biopharmaceutic properties of the compound, as that will guide the formulation strategy and technology selection.
Biopharmaceutics is a scientific discipline that examines the interrelationship of the physicochemical properties of the drug, the dosage form in which the drug is given, and the route of administration on the rate and extent of systemic drug absorption (Applied Biopharmaceutics and Pharmacokinetics, Shargel, Wu-Pong and Yu, 5th Edition).
In order to deliver the right amount of drug at the right time with the correct concentration within the body to exert a therapeutic effect, our formulators need to understand systemic exposure of the drug. For an orally administered drug, that means understanding the process of absorption and then teasing apart the rate-limiting steps in the process.
Biopharmaceutics allows you to understand the solubility, dissolution, and permeability of a compound, and from this, we can then assess the potential fraction absorbed. Our formulators are often able to directly impact the amount of drug absorbed through formulation optimization and improve exposure.
Understanding the biopharmaceutic properties of your compound can help us identify a formulation strategy that overcomes the challenges the compound faces or can assess the potential for the specific compound to meet the target product profile (TPP).
At Quotient Sciences, we have a number of tools within our biopharmaceutics toolbox to predict human exposure and drive formulation strategies:
Poorly soluble molecules are increasingly prevalent in early development, requiring enhanced formulation technologies to achieve therapeutic outcomes. The DCS, developed by Dressman and Butler, is a system used to classify the developability potential of compounds based on solubility and permeability. The DCS classifies compounds into four categories: Class I (high solubility, high permeability), Class II (low solubility, high permeability), Class III (high solubility, low permeability), and Class IV (low solubility, low permeability). Most new molecules fall into Class II, which is sub-divided into Class IIa (dissolution limited) and Class IIb (solubility limited). For Class IIa compounds, formulation strategies to improve exposure focus on particle size reduction, such as nanomillling and micronization. For Class IIb compounds, solubility-enhancement strategies such as spray-dried dispersions (SDDs) and lipids may be used.
At Quotient Sciences, we use the DCS to help drive formulation strategies for our clients. We can either take your existing data and assign a DCS classification or measure solubility and calculate a predicted human effective permeability (Peff) using GastroPlus® ADMET predictor, which is done by our modeling and simulation group based on the compound structure.
Traditional drug development programs rely heavily on using pre-clinical models to predict exposure in humans. This can be risky and inefficient, given the poor correlation of exposure between pre-clinical species and humans.
At Quotient Sciences, our unique Translational Pharmaceutics® platform integrates drug substance, drug product development, real-time adaptive Good Manufacturing Practice (GMP) manufacturing, and clinical testing activities under a single organization. We use biopharmaceutics information along with the DCS to select a formulation strategy, and then within a clinical study use rapid ‘make-test’ cycles to select and optimize formulations in real time based on arising clinical data. This innovative approach reduces development risks, maximizes the probability of clinical success, and saves time and costs for our customers.
Translational Pharmaceutics® has now been used by pharma and biotech companies on over 500 drug programs. The financial benefits and time savings were quantified in a publication by the Tufts Center for the Study of Drug Development (CSDD).
Nominated candidates entering clinical development often have sub-optimal physicochemical, biopharmaceutic, or drug metabolism and pharmacokinetics (DMPK) properties for oral delivery.
Development teams are challenged with how to understand the properties of new drug candidates, how to design the appropriate formulation strategy, and how to move quickly and successfully into early-phase clinical trials. Along the way, it is important to identify developability risks and take steps to mitigate these factors, balanced carefully against time and cost investments.
Join Chris Roe, Principal Research Fellow at Quotient Sciences, as he discusses effective strategies to overcome biopharmaceutic challenges for small molecules and alternative approaches for accelerating your early development plan. Chris presents case studies related to poorly soluble molecules, drugs with short half-lives, and pre-clinical to clinical translation.