Uninvited guest
When a drug enters the body, it operates through the same intracellular signaling pathways. However, since individuals have different metabolic capacities and conditions in their metabolic organs, the dosage and dosing intervals for each patient may need to be adjusted to maximize the drug's effectiveness in the safest way possible. The fact that chiral drugs are often synthesized as racemic mixtures can be compared to inviting someone for help, only for that guest to bring an uninvited companion without my consent. If I cannot predict how this unexpected guest will affect me, it might be best to avoid allowing them in from the start. This uncomfortable situation is particularly undesirable for those who want to minimize their medication intake, especially for drugs that need to be taken consistently over the long term.
Fortunately, recent guidelines from the FDA and the European Medicines Agency (EMA) regarding chiral drugs, as well as current trends in drug development, indicate that most new drugs being developed are now single enantiomers, known as enantiopure drugs.
Therapeutic Drug Monitoring (TDM)
Therapeutic drug monitoring (TDM) is a branch of clinical pharmacology that measures the levels of specific drugs in the blood to ensure that the dosage being taken is safe and effective. Some medications have a narrow therapeutic range, meaning that if the dosage is too low, the therapeutic effect may diminish or tolerance may develop. Conversely, if the dosage is too high, toxicity or tissue damage can occur. TDM is conducted to optimize the concentrations of such challenging drugs on an individual basis. This includes certain chemotherapy agents, anticonvulsants, and immunosuppressants.
To determine the optimal drug concentration for each patient, various data are collected, including changes in health status, other medications being taken, and factors such as age. The increasing interest in TDM is partly due to the reality that, while average life expectancy has risen, more people are living with multiple medications simultaneously. Additionally, significant advancements in relevant medical technologies have positively contributed to the accessibility and cost-effectiveness of these monitoring practices.
The principles of toxicology were established by the Swiss physician Paracelsus, who famously stated, "All things are poison, and nothing is without poison; only the dose makes a thing not a poison." This means that even the best medications can become toxic if taken in excessive amounts, and every drug inherently carries a risk of toxicity. The way drugs work is by modulating or interfering with specific pathways in the body, but this process can unintentionally have negative effects on surrounding targets. The liver must work harder to metabolize and process these chemical substances, and if drugs accumulate in the body, they may lead to hepatotoxicity. Furthermore, multiple drugs can interact negatively, leading to adverse synergistic effects or interference with each other. Therefore, it is ideal to maximize therapeutic effects while minimizing dosages to the necessary minimum. Ultimately, drugs are not natural substances for our bodies.
I believe that the fact that chiral drugs are often synthesized as racemic mixtures containing both enantiomers is significant in this context. If a drug were made solely from the enantiomer with a therapeutic effect that is several times stronger, it would be possible to achieve the desired effects with a significantly lower dosage. The inactive distomer, which is absorbed alongside the eutomer, can waste the therapeutic potential of the eutomer and, while not contributing to therapeutic effects, may unnecessarily remain in the body, leading to side effects or putting strain on the liver and kidneys.
Unnecessary distomers can react with biomolecules other than the intended targets, causing unintended physiological responses or side effects (off-target effects). Therefore, the use of more selective single enantiomers aligns with therapeutic drug monitoring (TDM) by defining a dosage range that enables safe and effective treatment while minimizing side effects. I often boast that I don’t want to live a long life by taking a bunch of medications at every meal, but honestly, how can I be sure that won’t be my reality?
Trends in new drug manufacturing
Optically pure drugs, or single enantiomer drugs, rather than racemic mixtures, account for more than half of all Investigational New Drug Applications (INDs) approved by the U.S. Food and Drug Administration (FDA) since 1999. Additionally, reports indicated that eight out of the top ten drugs sold in the U.S. in 2010 were chiral drugs.[1] This underscores the overwhelming prevalence of mirror-image isomers in the pharmaceutical field and demonstrates the pharmaceutical industry's direction toward maximizing therapeutic effects and minimizing side effects by developing drugs based on single enantiomers.
In fact, in 1992, the FDA emphasized the importance of considering stereochemical properties in drug development by releasing documents that provide regulatory and scientific guidelines related to the development of chiral compounds.[2] Through this document, the FDA stated that when both enantiomers have pharmacological activity but show significant differences in efficacy, specificity, and maximum effect, it is crucial to evaluate each clinically and develop only the more suitable enantiomer. This policy adopts a somewhat stringent approach to chiral drugs, providing detailed guidelines for their evaluation and emphasizing the desirability of developing single mirror-image enantiomer drugs. Thus, this guideline is considered a significant turning point in the field of chiral pharmacology.
Approval of new drugs
The FDA classifies drugs that contain previously unapproved active ingredients as either New Molecular Entities (NME) or New Biological Entities (NBE). Meanwhile, the European Medicines Agency (EMA) uses the term New Active Substance (NAS) for new drugs. NAS refers to drugs that contain new active ingredients that have not been previously approved, including chemicals that have never been authorized in the European Union or modified forms of existing chemicals (e.g., isomers, derivatives) that exhibit distinguishing characteristics in terms of safety and efficacy compared to existing substances.[3]
If a single enantiomer, enantiopure drug, is demonstrated to have pharmacological properties that distinguish it from its racemic counterpart, it may be considered either an NME or an NAS.
Trends in FDA approval of new drugs
I looked for data on the proportion of single enantiomers among newly approved drugs and found a very well-organized report titled "Chirality of New Drug Approvals (2013–2022): Trends and Perspectives." [4] By examining the FDA's data alongside the figures from this report, we can better understand the trends.
The first graph presents the FDA's data for new drug approvals over the past ten years as of 2022. On average, approximately 43 new drugs were approved each year. After cross-checking this data with the report, I extracted only the data from the three-year period between 2020 and 2022 for a more detailed comparison. New drugs are categorized into two groups: New Molecular Entities (NME) and New Biological Entities (NBE). The NME category can be further subdivided into three groups according to chirality: achiral small molecule drugs, single enantiomer(enantiopure drugs), and racemic small molecule drugs. In the rightmost graph below, we can observe a significant difference between enantiopure drugs and racemic mixture drugs among chiral drugs.
From the data over the three-year period, it can be observed that chiral drugs are either more numerous than or nearly equal to achiral drugs. Furthermore, among the chiral drugs, racemic compounds are quite rare. The graph below, which shows the distribution of small molecules NME excluding NBE from 2002 to 2022, also indicates that chiral drugs significantly outnumber achiral drugs. Additionally, it is evident that newly developed enantiopure drugs account for a larger proportion than racemic new drugs.
According to the graph below, out of a total of 278 small molecules NME approved from 2013 to 2022, only 10 were racemic mixtures. In contrast, during the previous decade from 2003 to 2012, there were 23 racemic drugs among a total of 211 NME small molecules, indicating a decrease of approximately threefold. The approvals of achiral drugs and enantiopure drugs have shown a consistent increase over time.
Trends in new drug approvals by the European EMA
What are the trends in new drug development in Europe? Looking at the data on New Active Substances (NAS) approved by the EMA from 2013 to 2022, a total of 163 NAS were approved in the first five years, followed by 206 new drugs in the next five years. In Europe, the approval of biological medicines has significantly increased, while the approval of small molecule NAS drugs has remained steady.
It is worth noting that, in the FDA data mentioned above, biological medicines extracted, manufactured, or semi-synthesized from biological raw materials such as vaccines, blood, and somatic tissues are excluded from the statistics. In this discussion, I want to emphasize my interest in comparing chiral and achiral small molecule drugs, as well as enantiopure drugs and racemic compounds among small molecule new drugs. The graph on the bottom right compares the small molecule NAS by categorizing them into three types for each year.
A notable point is that there have been no drugs approved as racemic mixtures since 2017. It also appears that chiral drugs hold a greater proportion than achiral drugs in Europe. In conclusion, the data indicates that, at least over the past 20 years, the proportion of chiral drugs has increased in both the United States and Europe. However, the number of racemic mixture drugs has rapidly declined, while the number of single enantiomer drugs has steadily increased.
Currently, both the FDA and EMA prefer the development of pure enantiomer compounds from the outset rather than creating new drugs through chiral switching by isolating active ingredients from already registered racemic mixture drugs. The chiral switch strategy was prominent between 1994 and 2011, but it has been used less frequently in the past decade.[5]
I hope for a world where the focus shifts from the profits of pharmaceutical companies to maximizing therapeutic effects and minimizing side effects for patients. As someone who remains vigilant and critical of the pharmaceutical industry, I felt a sense of relief knowing that fewer than 50 new drugs are approved each year. This suggests that extensive research, evaluation, and testing are conducted over a long period, rather than rushing the process.
[References]
[1] A review of recent advances in mass spectrometric methods for gas-phase chiral analysis of pharmaceutical and biological compounds
https://doi.org/10.1016/j.jpba.2012.04.022
[2] Development of New Stereoisomeric Drugs
[3] New Active Substance categorization and Orphan Similarity
[4] Chirality of New Drug Approvals (2013–2022): Trends and Perspectives
https://pmc.ncbi.nlm.nih.gov/articles/PMC10895675/
[5] Chiral Switch: Between Therapeutical Benefits and Marketing Strategy
https://doi.org/10.3390/ph15020240
