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We examined chirality of the drugs withdrawn from the market over the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 We observed that chiral status of withdrawn drug groups at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 In our study, 47.6% of the withdrawn drugs were of the chiral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Nevertheless, our findings showed a comparable ratio of withdrawn chiral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by our finding that those launched and withdrawn in the recent 20 years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Chiral distribution of the withdrawn drug groups suggest that the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.