Magazine Article | August 1, 2012

The Impact Of DMPK Clinical Failures

By John James Vrbanac, MPI Research

According to the Pharmaceutical Research and Manufacturers of America (PhRMA), out of 10,000 compounds that begin the drug discovery process, a mere 250 make it to the preclinical stage, only five will enter the clinic, and just one will land on the shelves of pharmacists. It is a process that takes up to 15 years or more and costs more than $1 billion.

These exorbitant attrition rates, often associated with pharmacokinetic issues (PK), are blowing holes in drug development pipelines. That’s tragic for patients and for drug developers. Given that attrition rates as high as 40% have been attributed to PK issues, drug developers need to carefully evaluate the quality of the Drug Metabolism and Pharmacokinetic (DMPK) studies conducted on their behalf. Not doing so can cause a company to potentially spend millions of dollars unnecessarily, if an unqualified candidate is moved along the drug development pathway or if a qualified candidate is “killed” too early in the process.

Fortunately, companies can avoid these unnecessary costs by integrating DMPK studies early in the drug development process and by incorporating new technologies. These steps allow more accurate allometric scaling to man and better prediction of therapeutic index, factors that can cause attrition to significantly decrease. 

Biopharma and biotech companies are finding that paying early attention to the quality of the DMPK program with which they are pacing their studies is a good investment. In fact, doing so can reduce clinical failure rates to as little as 10%. Whether the research is done within their own companies or  with CROs, a top quality DMPK program is supported by the scientific expertise necessary to assure successful IND (investigational new drug) submission and clinical  success.

Bringing a safe and effective compound through the pipeline successfully requires specific expertise in many areas of the IND-enablement process, but it is particularly essential to consider four categories into which all DMPK data falls. Ensuring expert knowledge in each of these areas allows drug developers to significantly improve their chances of bringing the best drugs to market. Your DMPK team should address these four categories by considering the following questions:

  1. What are the physiochemical properties of the drug molecule? 
  2. What are the kinetics of movement of the drug (metabolite) through tissues and fluids (concentration-time data)?
  3. What are the dynamics of interaction of the drug with proteins, nucleic acids, etc., that influence PK (drug-drug interaction, etc.)?
  4. How has the body changed the drug; what is the metabolism of the drug qualitatively and quantitatively?

Some of these studies are simple, off-of-the-shelf, box-checking protocols, and it likely does not matter where you place these studies. Other areas, such as quickly identifying MIST (Metabolites in Safety Testing) liability issues, production of reactive metabolites, full metabolite structure ID, and covalent binding of metabolites, require special expertise that is essential to maximize the financial gains of lowering attrition rates.

Successful drug developers know that applying high DMPK standards early in the development process by considering these four dimensions will allow them to better identify the most promising compounds as well as those that will fail early-on. By identifying these candidates early in the process, unnecessary development costs are avoided, and failure in the clinic is minimized. A comprehensive, timely, and multidimensional approach to DMPK research helps to identify failure, so the chances of successfully bringing a safe and effective compound to market are maximized.

John James “Jim” Vrbanac, Jr., Ph.D., is director of absorption, distribution, metabolism, and excretion (ADME) and senior study director at MPI Research. He is responsible for overseeing the ADME department by providing leadership for business development, scientific advancements, and high-quality performance of the ADME team, as well as managing the overall planning and conduct of nonclinical investigations.