DISCUSSION
We examined chirality of the drugs withdrawn from the market over the last 70 years to uncover the potential reflections of such characteristic on major safety issues that outweigh its intended benefits. We observed that chiral status of withdrawn drug groups at ATC-1 level seem to exhibit subtle differences. On the other hand, assessment of ADRs by chiral category pointed out the tendency of racemic/non-racemic chiral mixtures towards hepatotoxicity and cardiovascular ADRs.
Drugs with a chiral characteristic, either in the form of racemic/non-racemic mixtures or pure enantiomers, constitute more than half (58%) of the drugs used . This figure appeared to show modest increments in favour of chiral drugs, as the annual new worldwide approval rates of chiral drugs were reported to range between 50% to 76% . In our study, 47.6% of the withdrawn drugs were of the chiral type, which seems to imply that the withdrawal risk of chiral drugs may be slightly less. Pure enantiomer drugs may offer advantage of less complex pharmacological profile with a greater therapeutic index . Nevertheless, our findings showed a comparable ratio of withdrawn chiral mixtures (58%) and pure enantiomers (42%), questioning the relative potential advantage of the latter on withdrawal. In fact, the predominant composition among chiral drugs is racemic mixtures . While scarce data was present in the literature, a recent nationwide study from Tanzania reported that 74% of all chiral drugs available on the market between 2003-2018 were racemates . On the other hand, the upward trend of chiral drugs appears to be mostly driven by up to 15-fold higher introduction of pure enantiomers over racemic mixtures between 2000-2008 . Therefore, the inverse association of chiral drugs to withdrawal might be partly attributed to the relatively higher share of pure enantiomers among newly approved drugs. This was further supported by our finding that those launched and withdrawn in the recent 20 years revealed a comparably lesser predominance of pure enantiomers (33.3%) over chiral mixtures (5.6%).
Chiral distribution of the withdrawn drug groups suggest that the overall pattern was preserved across many of the groups at ATC-1 level with several exceptions. One of these groups belonged to musculoskeletal system drugs, where the rate of withdrawal was higher for chiral mixtures (11.9%) than that in pure enantiomers (2.5%). Musculoskeletal system drugs include a substantial part of non-steroidal anti-inflammatory drugs (NSAIDs), whose majority is formed by racemates . In fact, NSAIDs have been well-recognized to be associated with important safety issues that may result in withdrawal. A study on withdrawn drugs between 1960-1999 reported that 13% of such drugs were NSAIDs . In fact, NSAIDs were among the most commonly utilized drug groups . This could suggest that putatively lower safety margin of chiral mixtures compared to pure enantiomer drugs may be associated with the emergence of important safety issues in frequently used medications. This might have been contributed by possible over-the-counter or non-prescription use of these drugs as self-medication since we did not identify such difference in cardiovascular drugs, commonly used prescription medicines. The top three best-selling drugs in the United States in 2009 were reported to belong to cardiovascular category and all were pure enantiomers . In addition, chirality-related pharmacodynamic and pharmacokinetic characteristics of cardiovascular drugs were also extensively reviewed in the literature . Nevertheless, our findings suggest that a potential relationship of chirality to withdrawal did not seem likely for cardiovascular mixed and pure enantiomers.
ADRs have a very wide range of potential causes, including chemical structure of the drugs, patient-related factors, concomitantly used drugs or medicinal products, etc. . Possible underlying causes trigger the incidence of drug-related problems of directly related tissues and organs. Hepatotoxicity, the most common type of ADR in our study, was the reason for withdrawal near 2.5-fold less likely in pure enantiomers (5.4%) than that in chiral mixtures (12.7%). As the major organ for drug biotransformation, the liver comprises majority of drug metabolizing enzymes, which are chiral molecules. Due to stereoselectivity, each drug enantiomer may be metabolized through different pathways at different rates by these chiral enzymes . As the metabolism of chiral mixtures may require different reactions for each of the individual isomers, this may raise the possibility of additional burden on the liver . Furthermore, one of the critical components of drug-induced liver injury has been reported as drug biotransformation . For instance, hepatotoxicity-related withdrawal of benoxaprofen, a racemic NSAID, was reported to be mediated by the formation of reactive acyl glucuronide metabolites . While our data was not empowered to infer a causal association between chiral mixtures and liver injury, the tendency of racemic/non-racemic mixture drugs towards hepatotoxicity-driven withdrawal seems to have biological plausibility. This warrants designation of further detailed studies with specific racemic drugs to investigate such causal relationship. Another common reason for withdrawal, cardiovascular ADRs were more frequently seen with chiral mixtures compared to that of achiral drugs, but similar to pure enantiomers. Though cardiovascular ADRs may also involve various mechanisms, a recent machine learning-based computational model study addressed biological binding and substructural chemical features of drugs in predicting cardiovascular ADRs . The relative complexity of chiral mixtures might have contributed to observed high share of cardiovascular ADRs as a reason for withdrawal in our study.
Since the 1950s, the production of synthetic drugs has become widespread and mostly racemates have been produced by this method . This might have paved the way for the withdrawal of chiral drugs introduced in 1960-2000 to be predominantly mixtures. On the contrary, the limited number of drugs withdrawn in the last 20 years are mostly pure enantiomers, which might be related to their increasing share among newly approved drugs . Additionally, drugs with different chiral characteristics in our study had similar durations till withdrawal, and this pattern was mostly maintained in sub-analyses based on the most common ADRs (only with one exception in dermatological reactions). These results suggest that both temporal parameters might be unrelated to chiral characteristics of the drugs.
The results of the study should be interpreted considering the limitations below. Chirality details of some drugs/medical products included in the publication, which was used to determine the drugs withdrawn between 1950 and 2014, could not be accessed. This resulted in a partial reduction in the number of products evaluated. In addition, ADRs that led to the withdrawal of the evaluated drugs were obtained directly from the sources used to identify the drugs, so these should not be considered as first-hand findings. Chiral characteristics-based design of the study should not suggest that examined drugs were withdrawn from the market solely due to their stereochemical properties. We aimed to point out the possible effect of chirality on the distribution of ADRs, which should be further addressed by detailed future studies.
In conclusion, this study revealed that the stereochemical properties of drugs are among the factors which should be considered for drug safety. The chiral distribution of the withdrawn drugs could differ according to the usage areas and the underlying reasons for withdrawal. While the share of racemic/non-racemic mixtures in drugs withdrawn from the market does not highly support the arguments in favour of them posing higher risk, tendency of these drugs towards hepatotoxicity and cardiovascular ADRs draws attention. The potential relationships between stereochemical properties of drugs and ADR mechanisms should be investigated with further experimental and epidemiological studies, which might eventually lead to improvements of safety standards in new drug development processes.