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| By Jim Schmidt Sr. Scientific Advisor ABC Laboratories www.abclabs.com |
I performed metabolite profiling of one kind or another for most
of my nearly thirty-year career at the bench; even though I’m not in the lab,
presently, it’s still a passion and interest, and with good reason: metabolite
profiling is a very intellectually satisfying exercise, owing in no small part
to its interdisciplinary nature. The “detective work” of metabolite profiling
contributes to medicinal chemistry, enzymology, pharmacology, toxicology,
mechanistic chemistry, analytical chemistry, and many other fields. Among the
more satisfying and exciting results of metabolite profiling is the discovery
of novel and/or unexpected metabolites.
Apart from the satisfying “detective work,” there are some
other very important and practical reasons for performing metabolite profiling
early and often, including but not limited to:
Drug Attrition - The most practical reason for pursuing
metabolite profiling efforts as early and as diligently as possible is to
mitigate attrition in the drug discovery process. Owing in no small part to
an increased focus on metabolite profiling in drug design, attrition attributed
to poor pharmacokinetic (PK) behavior decreased
from 40% in the early 1990s to <10% in 2000 (in one recent study, poor PK
behavior represented as little as 3% of drug failures in preclinical
evaluation). In fact, metabolite profiling can support troubleshooting of other
aspects of drug attrition and should not be limited simply to improving PK
behavior.
The Law - The aphorism applied to highway speed limits and (cheekily) applied
to gravity—“It’s Not Just a Good Idea. It’s the Law”—can also be applied to metabolite
profiling. Guidance documents, including—but not limited to—those from the US
Food and Drug Administration (FDA) and the European Medicines Agency (EMA)/ICH,
have formalized the regulatory framework and decision-making of metabolite
profiling.
Due Diligence - Another important rationale is the due diligence process that is associated
with the process of acquisition of intellectual property and/or drug portfolios.
While limited funding may result in a temptation to delay or minimize metabolite
profiling efforts, that temptation should be ignored: scientific due diligence
is every bit as essential as financial analysis and important questions about
metabolites and pathways help minimize poor choices in investment decisions;
likewise, groups should be prepared to answer these questions to improve chances
for desired investment.
Stay tuned to this blog for more thoughts on metabolite
profiling.
What are you doing to pay more (and earlier) attention
to metabolites in the drug discovery and development process?
