Pharmacokinetics (PK) plays a crucial role in drug discovery and development by helping to describe and predict drug behavior in the body. Understanding PK — how a drug is absorbed, distributed, metabolized, and excreted (ADME) — allows researchers to optimize drug candidates for efficacy, safety, and optimal dosing. By assessing PK early, you can prioritize drug candidates with the best therapeutic potential, streamline the development process, and reduce the likelihood of costly late-stage failures. Ultimately, understanding PK is essential for ensuring that new drugs are both effective and safe for human use.

Why and how are pharmacokinetics evaluated during drug development?

Pharmacodynamics describes the interaction of a drug with its target and the relationship between its free concentration and the intended chemical/biological response. Promising pharmacodynamics properties of a candidate drug are, however, not sufficient for a successful drug development program. Another integral part is knowing the dose necessary to achieve a target drug concentration at the site of action (i.e., plasma or target tissue).

A mechanistic understanding of the PK properties of your drug will thus be important for a range of activities in both the non-clinical and clinical phases of drug development. The PK data necessary for this type of analysis typically comes from many sources, studies, in vitro assays, and species after administration via different administration routes and doses. The diverse data often makes a coherent comprehensive analysis complicated. A powerful tool to enable and simplify interpretation of this type of diverse data to perform rational translational and predictive analyses is physiologically-based pharmacokinetics (PBPK) modeling and simulation.

What is PBPK?

PBPK is revolutionizing drug development by offering a deeper understanding of how drugs behave within the human body. In short, it is a mathematical description of the body that is populated with all currently available knowledge of the physiology of the individual that you want to describe, and of your drug. This includes, for instance, sex-, body weight-, species-, and population-specific blood flows and organ volumes, as well as the abundance and distribution of metabolic enzymes and transport proteins involved in the biotransformation and distribution of your drug. The model is also informed by the physicochemical properties of your drug — which determines its passive membrane permeability and distribution — and by any in vitro and in vivo pharmacokinetic data available at the current stage of development. Quantitative in vitro studies generate data on, for instance, plasma protein binding, rate of enzymatic biotransformation, and active membrane transport. These affinities are in turn related to the abundance of the proteins involved in the species/population of interest. Lastly, observed animal and human PK data are used to optimize and to validate the PBPK model.

Nonclinical and clinical activities where PBPK can be used

There is a wide range of drug development activities that depend on early and reasonably accurate PK prediction of your development asset. By simulating real-world biological processes, PBPK allows for more accurate predictions of human ADME. Below, you find a few concrete activities where PBPK modeling and simulation can be used to make informed rational decisions:

• Candidate selection by identifying potential issues, such as poor bioavailability
• Guide formulation development to achieve optimal exposure levels
• Within and cross species PK translation — nonclinical to clinical
• Dose selection for nonclinical pharmacodynamic, PK and toxicology studies, and for First-in-Human clinical studies
• Predictions of drug exposure in special populations, such as those with varying genetic profiles, renal/hepatic impairment, and in elderly/infants
• Evaluation and prediction of metabolic and transporter-mediated drug-drug interactions (i.e., co-medications), and the impact of food and luminal pH on drug absorption
• Evaluation of population PK variability related to intrinsic and extrinsic factors
• Mechanistic analysis of metabolite formation and accumulation over time

Benefits of PBPK in drug development

With PBPK, you can rationalize candidate selection, optimize dosage, guide formulation development, anticipate drug-drug interactions, and assess the relationship between PK and safety & efficacy earlier in the development process — reducing risks and accelerating time-to-market. By moving beyond traditional testing and data evaluation, PBPK empowers you to make more informed decisions, minimize costly failures, and bring safe, effective treatments to patients faster. Incorporating PBPK modeling strategies at an early stage enables projection of investigational medicinal product needs, early cost-of-goods assessment, and dosage form strengths to be manufactured. Although PBPK is traditionally used for small molecules, Cytel has successfully used this technique also for siRNA products and biologics.

Interested in learning more? Watch our recent webinar, “Physiologically-Based Pharmacokinetics (PBPK) Modeling and Simulation: A Transformative Tool for Early-Stage Clinical Development”:

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