Heart breaker

January 25, 2019

Small molecule chemcal antibiotics are among the most prescribed drugs in the world, and few individuals in the first world can say they have never taken at least one course of these drugs.  For a variety of economic reasons, antibiotic drug discovery is increasingly the realm of startups and biotech, rather than Big Pharma.  That makes the concern of drug attrition or post-marketing warnings more acute for drug development in this arena, as a single unexpected adverse effect could doom the only lifeline of an entire company.

That’s what makes the business impact of a recent FDA warning noteworthy.  The FDA recently warned that one of the flagship classes of antibiotics, fluoroquinolones, increase the risk of aortic rupture or dissection.  This is a devastating event in which the main outflow artery of the heart basically breaks, which is largely not surviveable.

 

Fluoroquinolones are a more recent class of antibiotics that work by targeting DNA gyrase and topoisomerase, two enzymes critical for untangling DNA during replication in rapidly dividing cells. Infectious bacteria exhibit less resistance to these than the old classics of the penicillin and cephalosporin class.  The most commonly prescribed and oldest fluoroquinolone is ciprofloxacin (“cipro”), and indeed, cipro was the focus of the recent warning.

 

The FDA came to its determination epidemiologically, namely by studying their own drug adverse events database and correlating their finding with published reports by independent researchers around the world. However, although their findings were associative, fluoroquinolones were already known to have tissue-specific adverse effects, namely tendon rupture.  If tendon rupture sounds distressingly similar to aortic rupture, just a different tissue, you are not alone. Thus, it wouldn’t be a stretch to conclude that fluoroquinolones have a mechanistic tissue-specific adverse effect, specifically targeting tissues that need to remodel frequently in response to pressure, forces and tension . . . like bones and skin in addition to muscles and arteries!  And, as we have been saying for quite some time, by taking polypharmacology and tissue specific expression of small molecule drugs into account, such mechanistic tissue-specific adverse events might be predicted up front.

 

Accordingly, developers and marketers of similar drugs would be wise to go beyond the FDA and warn or stratify for any individual with any weaknesses in such tissues.  The FDA warned with a particular eye towards those with genetic defects in these tissues such as Marfan and Ehler-Danlos Syndromes, but the most concerning are the many individuals with idiopathic weaknesses or aneurysms in their aortas.  Nevertheless, screening broadly for such tissue specific vulnerabilities could preemptively save the approval of a drug by carrying the warning through the trial with its testing.

 

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