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Drug-induced Vascular Injury (DIVI): An Often Complicated Issue

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Drug-induced vascular injury (DIVI) is a major concern for development of new and novel therapies.  Efforts to identify biomarkers consistent with DIVI have not been successful, largely attributed to the complex nature of the vascular responses to injury and a lack of understanding of the mechanisms controlling these responses.  Recent publications on biomarkers of DIVI highlight some of the pitfalls in these efforts1,2,3.

The causes of vascular injury are wide ranging from alterations in hemodynamics to targeted toxicity on components of the vasculature (e.g. endothelial and smooth muscle cells) and to inflammatory and immune-mediated alterations, leading to secondary effects on the vasculature.  The characterization of the vascular findings are still considered essential in determining their relationship to treatment and to understanding their potential mechanism.  Hemodynamically active compounds typically target the smooth muscle cell of the media.

The distribution and morphology of the vascular findings associated with vasoactive-induced arterial lesions in association with vasodilator and/or positive inotrope-induced lesions are well recognized.  These vasoactive-induced arterial lesions generally involve the coronary arteries and are associated with significant medial necrosis and hemorrhage.  Likewise, vasoconstrictor-induced vascular lesions primarily affect smaller caliber arteries in multiple tissues and are also characterized by medial necrosis and hemorrhage.  Vascular injury secondary to inflammation or immune reactions often involve the formation of immune complexes that can directly or indirectly damage the vasculature.

Understanding the temporal pattern of vascular injury is also useful as most mechanisms of vascular injury eventually result in vascular inflammation.  Inflammation and immune-mediated mechanisms present the greatest challenge in determining the underlying mechanism and the relevance to humans.  In the absence of predictive or signature biomarkers for underlying mechanisms of DIVI an accurate and thorough characterization of the lesions over time is still considered a key first step in determining the importance of the finding in preclinical assessments.

 

References

  1. Biomarkers and mechanisms of drug-induced vascular injury in non-rodents. Louden C, Brott D, Katein A, Kelly T, et al, Toxicol Pathol 34:19-26, 2006.
  2. Translation strategy for the quantification of drug-induced vascular injury biomarkers. Bendjama K, Gounaud S, Aras G, et al, Toxicol Pathol 42:658-671, 2014.
  3. Nonclinical safety biomarkers of drug-induced vascular injury: Current status and blueprint for the future.  Mikaelian I, Cameron M, Dalmas DA, et al, Toxicol Pathol 42:635-657, 2014.
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