ORLANDO – Diagnostics is both growing broader – through new techniques and systems – and at the same time narrower – through more individualized assessment.

These were just two conclusions that could be drawn from the session titled “Experiences with an Active Therapeutic Drug Management Practice,” during a Mayo Clinic Reference Services (Rochester, Minnesota) conference held just prior to the recent joint conference of the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC; Milan, Italy) and the American Association for Clinical Chemistry (AACC; Washington).

Loralie Langman, PhD, a consultant in clinical biochemistry and immunology for the Mayo Clinic College of Medicine (Rochester, Minnesota), said that the “old” definition of therapeutic drug monitoring is “quantitative measurement of drugs in plasma in order to assist a care provider to ensure that a patient is treated with optimal concentration [and] doses” of drugs.

The “new” definition of therapeutic drug management is the “measurement [and] detection of drugs, physiological responses and genetic factors in order to deliver optimal patient care.”

“So, really, we’re talking about individual drug management,” she told the audience at the Rosen Centre Hotel.

Drug management can be done via blood/serum, cerebrospinal fluid, urine and saliva samples, among others, to determine drug response or toxicity.

Langman said “traditional” drug concentration monitoring should be done “when there’s serious toxicity” combined with a “poorly defined or difficult-to-detect clinical endpoint, or when there is a steep dose-response curve for which a small increase in dose “can result in a marked increased in desired or undesired response.”

It should also be done when it involves drugs with a narrow therapeutic range, or to assess medication compliance.

With drug analysis, there can be “marked inter-individual pharmacokinetic variability,” including differences in absorption, distribution, metabolism and excretion. It also is possible to have disease-based variation, resulting in gastro-intestinal, hepatic, cardiovascular or renal differences, such as when “elimination is altered,” she said.

There are various ways to “look at drug monitoring,” including liquid chromatography mass spectrometry (MS) – which she said can “achieve high levels of specificity”; ion trap MS; and matrix-assisted desorption ionization – time-of-flight MS (MALDI-TOF), which she called much more expensive than other options.

As for the pharmacodynamics of drug monitoring, Langman said the “dosage adjustments or treatment can be made based on the physiological or biochemical response of the drug’s target.”

The techniques for pharmacodynamics include 2-D gel electrophoresis and protein microarrays. Electrophoresis is used to study proteins, a point when you have to “start talking about dollars and cents” and the impact of cost on the bottom line of the lab.

Langman termed LC-MS/MS/, MALDI-TOF and prote-omic assays “high-cost systems.”

In drug monitoring, labs are focusing more on pharmacogenetics. “[This] usually refers to genetic mutations vs. pharmacogenomics,” which means how genetics works together, Langman told her audience.

There “has been a lot of literature coming out of basic research that indicates differential metabolism, differential response, efficacy or toxicity which has a genetic basis,” she said. For example, “If you new a patient couldn’t handle certain metabolites, you would give them a lower dose or a different drug.”

Using genetic analysis could potentially avoid adverse reactions, optimize dose before the initial administration of a drug or enable a more effective drug selection by eliminating drugs that may be toxic or ineffective.

Many labs also have incorporated DNA testing into their offerings, she said, to detect, as just one example, inherited diseases.

And Langman discussed the fact that the FDA is beginning programs to encourage drug companies and diagnostics companies to develop “companion diagnostics” – tests in tandem to assess an individual’s response to that particular drug.

The FDA is doing this in two ways, she said. First, the agency is offering federal matching funds to joint ventures between pharmaceutical and diagnostic companies, as well as extending “the exclusivity incentives of the Orphan Drug Act to certain drugs linked with companion diagnostics or pharmacogenomic assays.”

But there are barriers to the development of companion diagnostics, or what is called “theranostics.” For example, she noted the a lack of capital to maintain “innovative diagnostic development.” Additionally, she said that drug companies may be reluctant to forfeit some of their potential income in the event a test could prove that certain people would either not benefit or would be adversely affected by taking a particular drug.

Langman also discussed another factor that she said will affect the immunoassays that the diagnostic industry – and she said she was “using this word globally” – will develop, that is testing for regulated drugs.

She noted that “all sorts of safety [sensitive] industries” were looking at new ways to test for drugs of abuse, including alcohol. Many industries, such as the chemical, transportation and nuclear industries, already have such programs in place.

Of the 320,000 tests performed in 2004 at the Mayo Clinic Drug Lab, only 18,000 samples were for drugs of abuse, she said.

“We’re a small drop in the bucket,” she said, compared to others.

No Comments