The association of chiral characteristic with drug withdrawal due to
safety: a comparative analysis
Abstract
Aim: Chirality of drugs might be associated with safety issues through
pharmacokinetic or pharmacodynamic variations, interactions, or direct
toxicological responses. This study aimed to examine chiral status of
the drugs withdrawn from the market. Methods: We searched the literature
regarding withdrawn drugs between 1950-2020 due to safety-related issues
and identified 395 drugs. We examined their chirality and assigned into
one of three categories: achiral compound, chiral mixture, and pure
enantiomer. We compared their distribution at ATC-1 level, duration on
the market, and adverse drug reactions leading to their withdrawal.
Results: We identified that 52.4% (n=207) of withdrawn drugs were
achiral, whereas 27.6% (n=109) were chiral mixtures and 20.0% (n=79)
were pure enantiomers. The mean duration on the market was 24.6±27.5
years. The groups did not differ in terms of mean duration on the
market. Chiral mixtures were significantly more withdrawn than were
achirals in cardiovascular system drugs (17.4% vs. 7.7%, p=0.01). In
musculoskeletal system drugs, pure enantiomers were significantly less
withdrawn (2.5%) compared to achirals (12.6%, p=0.01) and chiral
mixtures (11.9%, p=0.03). Hepatotoxicity was significantly less common
in pure enantiomers (5.4%) compared to chiral mixtures (12.7%, p=0.04)
and achirals (17.0%, p<0.01). Cardiovascular toxicity was
significantly more common in chiral mixtures (14.5%) compared to that
in achiral drugs (7.5%, p=0.02). Conclusion: Our study showed slightly
higher representation of chiral mixtures among withdrawn drugs over pure
enantiomers. The assessment of withdrawal reasons further indicates
higher tendency of chiral mixtures towards hepatotoxicity and
cardiovascular toxicity.