(P-489) Evaluation of Chirality for Withdrawn Drugs

Background: It has been suggested that chiral properties might affect drugs in terms of safety. Due to potential safety issues, guidelines published regulatory agencies around the world tend to promote the development of new pure enantiomeric drugs instead of racemates.

Objectives: To evaluate the details of chiral properties of drugs which were withdrawn due to safety issues.

Methods: We analyzed the drugs withdrawn from the market between 1950-2020 due to safety issues. These drugs were classified according to the first level of Anatomic Therapeutic Chemical (ATC-1) classification, and the main causes leading to withdrawal. “Chiral/achiral” distribution of these drugs and "racemate/non-racemic mixture/pure enantiomer" distribution of chiral ones was determined.

Results: In a total of 395 withdrawn medicinal products, the most common drug groups were “N-nervous system” (20.5%), “A-alimentary tract and metabolism” (11.6%), and “C-Cardiovascular system” (9.1%). We found that 188 drugs (47.6%) were chiral. Chiral/achiral distribution of “M-musculoskeletal system” and “N” groups were similar to overall results (46.7% and 48.1% chiral, respectively). Chiral drug predominance was observed in “G-genitourinary system and sex hormones” (66.7%), “C” (61.1%), and “A” (56.5%) groups of drugs. The half (50.0%) of chiral drugs were racemates and 42.0% were pure enantiomers. Among chiral withdrawn drugs, preponderance of the racemates in “M” and “N” groups were remarkable (76.9% and 66.7%, respectively), as opposed to pure enantiomer predominance in “J-anti-infectives for systemic use” (75.0%), “G” (71.4%) and “A” (50.0%) groups. When medications are classified based on the reasons for withdrawal, chiral drugs were more prominent in “abuse” (68.6%), “cardiovascular adverse drug reactions (ADR)” (61.7%), “respiratory ADRs” (60.0%) and “psychiatric ADRs” groups (52.9%), as opposed to their underrepresentation in “hepatotoxicity” (34.2%), “carcinogenicity” (36.4%) and “hematological ADRs” (38.8%). Racemates were more common in “dermatological ADRs” (81.8%), “genitourinary ADRs” (61.5%) and “hepatotoxicity” (59.3%), whereas pure enantiomers were more prevalent in “hematologic ADRs” (57.9%), “carcinogenicity” (56.3%), and “neurologic ADRs” (52.2%).

Conclusions: It appears that withdrawn drugs might show different chiral characteristics according to their usage areas and reasons for withdrawal. These findings about stereochemical differences could make chirality a feature that should be taken into consideration more during drug safety studies.