BioWorld Perspectives Contributing Writer

Editor's note: Chris Bode, PhD, is vice president, corporate development, at Absorption Systems LP. Prior to joining Absorption Systems, Bode was vice president of operations for Tissue Transformation Technologies.

In the drug development stage of pharmaceutical research, many companies give little or no thought to in vitro studies — but they should. The FDA allows sponsors to avoid certain clinical trials based on appropriate in vitro data, so why not take advantage of this cost-effective approach? The intent of the FDA's Critical Path Initiative has been to modernize and accelerate the drug development process by making it less empirical, more scientific and rational. While much of the focus of the initiative has been on clinical trials, including validation of biomarkers and surrogate endpoints, in vitro models can have a significant impact on clinical testing.

In Vitro ADME Models Can Accelerate and Improve the Drug Development Process
In the early 1990s, about 40 percent of drug candidates failed in clinical trials due to poor absorption, distribution, metabolism and elimination (ADME) properties. Fifteen years later, that number is around 10 percent. Why? The main reason is that in vitro testing, some of which is now required by the FDA, identifies potential problems long before a compound reaches the clinic. Today, toxicity and poor efficacy result in most clinical trial failures. This is largely due to the fact that it remains difficult to predict clinical efficacy and toxicity based on preclinical models, either in vitro or in vivo. Again, this emphasizes the value of reliable, predictive in vitro model systems.

By 1997, when the FDA mandated the use of human in vitro models to test for potential metabolism-based drug interactions, the pharmaceutical industry already was on board. A 1999 FDA guidance on in vivo drug metabolism and drug interaction studies, as well as an update that was published in draft form in 2006, specified the clinical consequences of in vitro drug interaction findings: A positive result requires a follow-up clinical drug interaction trial, but a negative result in vitro is sufficiently definitive on its own.

Predicting Absorption and the Role of Transporters
In addition to drug metabolism, absorption also can be predicted in vitro. Caco-2 cell monolayers were first characterized as an in vitro model for predicting intestinal drug absorption by Hidalgo, Raub and Borchardt in 1989 and eventually became the de facto standard for that purpose in the pharmaceutical industry. The correlation between apparent permeability across a Caco-2 monolayer in vitro and absorption of orally administered drugs in vivo is well established and responsible, in part, for the aforementioned decrease in the number of clinical drug failures attributable to poor ADME properties. Sponsors of new chemical entities (NCEs) can now select, for clinical development, those drug candidates with desirable ADME properties, based on in vitro testing.

One aspect of the distribution and elimination of drugs is their interaction with membrane proteins called transporters. Uptake transporters are required for the uptake of some drugs into cells, whereas efflux transporters are responsible for pumping some drugs out of cells or preventing them from ever getting in. Interactions with transporters, or lack thereof, can account for many differences between drugs in terms of systemic bioavailability (via intestinal absorption or uptake and subsequent metabolism in the liver), side effects (e.g., via efflux transporters in the blood-brain barrier), toxicity (e.g., via placental efflux transporters), efficacy (e.g., via efflux transporters expressed in cancer cells), and biliary or renal excretion (via uptake and efflux transporters in the liver and kidneys). Transporters also can be involved in drug-drug interactions, a fact recognized by the FDA in its 2006 draft guidance on drug interaction studies. Through the use of a variety of in vitro models, we now understand the basis for a number of clinical drug interactions (e.g., the increase in bioavailability of digoxin, a P-glycoprotein substrate, seen with co-administered quinidine, an inhibitor of the same transporter). Increasingly, we now can predict, at least qualitatively, such interactions.

The FDA now expects, and will soon require, in vitro testing for interactions with drug transporters. The results of such testing will inform the design of clinical trials in the same way as in vitro testing for metabolism-based drug-drug interactions.

In Vitro Models and Use for Generics
In vitro models such as the Caco-2 monolayer have had an equally dramatic impact on the development of generic drugs. The 2000 FDA guidance on the Biopharmaceutics Classification System (BCS) established a mechanism by which a generic drug developer could obtain a "biowaiver" based on in vitro data. A biowaiver means that a clinical bioequivalence study need not be carried out — another example where appropriate in vitro data, obtained with a properly validated system, can substitute for an otherwise necessary clinical trial, thereby saving several months and hundreds of thousands of dollars. A BCS biowaiver also can apply to new drug development, where an average of four to six clinical bioequivalence studies are performed (e.g., following a change in formulation or manufacturing process) during the development of a typical NCE.

The Future of Clinical Failure Prevention
It has taken the industry a while to catch on to the benefits of the BCS. For example, Absorption Systems performed more than 50 such studies between 2001 and 2007, more than half of them in 2007 alone. BCS classification is now a routine part of the drug development process for many pharmaceutical companies, both for generics and NCEs.

Drugs may fail in clinical development or post-marketing for a variety of reasons: They may simply not be as effective as anticipated; poor pharmacokinetic properties may prevent them from reaching their intended target in therapeutic doses; or they are proven unsafe.

Regardless the reason, late-stage drug failures are costly — wasting time, resources and manpower — and have contributed significantly to the declining overall productivity in the pharmaceutical industry in recent years. In vitro models — not only before, but during the clinical trial process — can help mitigate against these failures.

Published: August 13, 2009