When is an Effect Adverse?

//When is an Effect Adverse?

When is an Effect Adverse?

by Adam Aulbach, DVM, DACVP
Director, Clinical Pathology

The answer is, whenever it isn’t.

I could stop there, and this would be the shortest blog outside of Twitter. It also wouldn’t be particularly helpful. Like most things in science, the details matter. As a clinical pathologist, I find those details to be most effective in quality hematologic evaluations.

As I explained at the Society of Toxicology annual meeting in San Antonio recently, evaluating blood toxicity gives critical insight of adverse effects in preclinical safety studies. Quality hematologic evaluations are important for several reasons:

They’re required by regulatory agencies, among them the U.S. Food and Drug Administration, the European Medicines Agency, the international Organization for Economic Cooperation and Development, and Japan’s Ministry of Health, Labor and Welfare. The guidelines for each may vary, but there is much overlap, and most use panels that represent a consensus within the global scientific community.

Hematotoxicity in preclinical studies reflect what comes out of human clinical trials about 91 percent of the time, making this evaluation predictive of a candidate drug’s safety.

While a standard definition for an adverse effect remains fuzzy, even mild changes in blood measures can be considered adverse.

Blood serves as a good biomarker that is sensitive and available in-life.

When MPI Research conducts a hematologic evaluation, we consider a number of variables that can impact results. For example, stress from handling, dosing or noise can influence epinephrine and glucocorticoid levels in an animal model, which in turn affect a number of hematology measures. Reduced food consumption during a study – not the same as fasting, which would be part of the study design – also has an effect, especially in rodents. Finally, the study procedures themselves can have a bearing hematology values, from blood loss and anesthesia use in surgery, infusion and catheterization, blood draws and even vehicles used in drug delivery.

Factoring in those variables, we apply specific parameters in hematologic evaluations.

Erythroid parameters involve the study of erythrocytes, or red blood cells – specifically, red cell mass (e.g., red blood cell count, hemoglobin, hemocrit) and red cell indices (mean corpuscular volume, mean corpuscular hemoglobin/hemoglobin concentration). Mass increases are linked to dehydration and elevated hemoconcentration, use of erythropoietin-like compounds, pulmonary pathology or a hemoglobin defect. On the other hand, decreases may be due to blood loss, cell destruction or reduced production from toxicity, suppression or anemia caused by inflammation.

The questions we strive to answer when we see these results are:

1) Is there a regenerative effect? And, 2) Is the problem linked to the marrow?

Myeloid parameters refer to leukocytes or white blood cells, produced in the marrow. Increases or decreases in white cells can indicate a direct or an indirect effect from a test compound, the latter including inflammation, marrow suppression, stress, and lymphoid organ toxicity or depletion. It also can relate to any combination of physiological responses that require expert insight to trace the root causes. For example, our team can distinguish between these effects, including eliminating stress as a factor, by focusing on specific eosinophil and lymphocyte measures. Likewise, we can determine when it makes sense to evaluate the marrow directly – typically when results unexpectedly exceed certain data points.

So if, as I said earlier, the details matter, where do they lead? They point out the complexity and precision of hematologic evaluations – not just how they are done but what they mean. From decades of collective experience, our team at MPI Research has compiled a rich set of guidelines, both objective and subjective, to determine when an effect really is adverse and what the next steps should be.

Precision and accuracy – understood and meaningfully applied – are at the heart of preclinical studies that increase our understanding of the effects and safety of a candidate drug.

By |2017-07-04T10:28:17+00:00June 4th, 2013|Blog|Comments Off on When is an Effect Adverse?

About the Author:

MPI Research, with global headquarters in Mattawan, Mich., provides safety evaluation, discovery, bioanalytical and analytical services to the biopharmaceutical, medical device, animal health, and chemical industries. The company offers comprehensive imaging solutions including preclinical imaging, radiochemistry, and data analysis. Scientific knowledge and experience, responsiveness, integrity, trust, teamwork, and dedication to strong and enduring Sponsor relationships are the defining attributes that characterize MPI Research as a high-performance, high-quality organization that is committed to bringing safer and more effective products to the world.