Transforming Bioequivalence Assessment with the Finite Absorption Time Concept

Bioequivalence studies play a big role in the pharmaceutical industry because it make sure that generic drugs work just as well as their brand-name counterparts. To do this, researchers focus on two key things: how much of the drug is absorbed (usually measured by the area under the curve, or AUC) and how fast it’s absorbed (often based on the peak concentration, known as C_max​ . These methods have been around for a long time, but they’re not perfect. In fact, more and more evidence is showing that C_max​ ​ doesn’t do a great job of capturing the full picture of how drugs are absorbed. This raises serious questions about whether the current ways of measuring bioequivalence are as reliable as we’ve thought. The process of absorbing drugs in the body is far from simple. It’s influenced by things like how quickly the stomach empties, how the intestines move, and how long the drug stays in the digestive tract. Older models assume drug absorption happens continuously and follows a smooth, predictable curve. But here’s the catch: these assumptions don’t always match what actually happens in the body. New research shows that drug absorption tends to follow a more structured pattern, always happening within a set time period and under specific conditions, like when there’s a strong concentration gradient driving the process. These gaps in the traditional models create some big challenges. If we can’t accurately measure how fast a drug is absorbed, we risk making the inaccurate determination on whether a generic drug is truly equivalent to its branded version. That’s a problem for patient safety and treatment effectiveness. Additionally, the current methods, which mostly rely on comparing C_max​  and AUC, don’t take into account the real physiological processes that vary between different formulations. This has left the pharmaceutical industry searching for a better, more reliable way to assess bioequivalence. That’s where this new study comes in. Published in Pharmaceutical Research Journal, Professors Athanasios Tsekouras and Panos Macheras from the National and Kapodistrian University of Athens proposed a new method called the Finite Absorption Time (F.A.T.) concept. This approach shifts the focus to what’s really happening in the body, providing a framework that matches how drugs are actually absorbed over time.

The authors started by building simulations based on physiologically-based finite-time pharmacokinetic (PBFTPK) models. These models were designed to mimic drug absorption under a range of conditions, including different rates and durations of absorption. By factoring in one- and two-compartment kinetics and testing various drug scenarios, the researchers could assess how well the F.A.T. concept captured the real-world dynamics of drug absorption. The results were impressive. The rate of absorption was consistently represented by the slope of the percent absorbed versus time curve—a much more sensitive and realistic measure compared to the traditional C_max​​. As for the extent of absorption, they found it could be reliably determined by the plateau in the ratio of cumulative absorption between test and reference formulations, offering a clear and stable way to assess bioavailability. To put their findings to the test in the real world, the team turned to existing data from bioequivalence studies on carbamazepine, a drug known for its tricky absorption patterns. They digitized the data and applied their F.A.T.-based models to reanalyze the drug’s pharmacokinetics. What they found was revealing: the time it took for the drug to be absorbed varied widely between formulations, from 16 to 33 hours. This variability underscored the limitations of using C_max​ ​ as a rate metric. Their models showed that carbamazepine followed zero-order kinetics during these absorption periods, which directly contradicted the long-standing assumption of exponential absorption. By focusing on the slope of the initial absorption phase, they created a rate metric that accurately reflected the true input rate of the drug, solving many of the ambiguities associated with C_max​ ​. Meanwhile, their method for measuring the extent of absorption matched up well with the traditional AUC values but added more detail and clarity, especially in cases where absorption was prolonged.

Professors Tsekouras and Macheras have introduced a fresh and innovative way to approach bioequivalence testing, and it could have a huge impact on the pharmaceutical world and the way regulators work. The new method shifts the focus to a more accurate and realistic way of evaluating how much and how fast drugs are absorbed, with the potential to make generic drug approvals more reliable and, ultimately, keep patients safer. What makes this study stand out is how it ties drug absorption metrics to actual biological processes. The F.A.T. concept recognizes that drug absorption doesn’t go on indefinitely. It happens over a limited time, shaped by factors like how long a drug stays in the gastrointestinal tract. Traditional models assume absorption is continuous and exponential, which doesn’t really match what happens in real life. By bringing this more realistic perspective into bioequivalence testing, the study gives us a clearer and more scientifically sound basis for making regulatory decisions.

This isn’t just theoretical either—it has real-world implications. Agencies like the FDA and EMA could easily adopt this F.A.T.-based approach to update their guidelines. The study introduces a new way of measuring absorption rate, using the slope of the absorption curve rather than C_max​. It’s a smarter, more reliable way to assess how drugs behave in the body and avoids the pitfalls of older methods that sometimes lead to misleading results. This could make a big difference in ensuring that generic drugs truly match their branded counterparts in therapeutic effect. From a patient’s perspective, this research is a game-changer. By improving how we measure and compare drug absorption, we can ensure people get the same therapeutic benefits from generic drugs as they do from the originals. This is especially important for medications with narrow safety margins or complicated absorption processes, where even small differences can have serious effects. In the bigger picture, this study challenges outdated ideas and offers a practical, science-backed solution for improving bioequivalence testing. It has the potential to raise the bar for how we evaluate generic drugs, making the whole system more precise and reliable. At the end of the day, that means better-quality medications and safer outcomes for patients everywhere.

Note from the authors:

This work, nicely summarized above, is part of a five-year-long research that has uprooted firmly held notions in oral drug absorption and pharmacokinetics. The “new” concept is the obvious fact that drugs have finite time to pass from the gastrointestinal tract to the blood stream, rather than infinite time. That has changed the way several quantities related to the process need to be determined, measured or calculated. A list of relevant publications can be found in http://jupiter.chem.uoa.gr/pchem/lab/fat/, which also contains contact information.