Patients’ Pharmacogenetic Characteristics and the Risk of Adverse Reactions to Non-steroidal Anti-inflammatory Drugs: Case Reports

• Published in: Bezopasnostʹ i risk farmakoterapii (Online) Vol. 12; no. 2; pp. 178 - 189
• Main Authors: Zhiryakova, A. S., Denisenko, N. P., Kryukov, A. V., Akmalova, K. A., Tuchkova, S. N., Mirzaev, K. B., Sychev, D. A.
• Format: Journal Article
• Language: English; Russian
• Published: Ministry of Health of the Russian Federation, Federal State Budgetary Institution «Scientific Centre for Expert Evaluation of Medicinal Products 01-07-2024
• Subjects: adverse drug reactions; case report; cyp2c9; gastrointestinal bleeding; ketorolac; nephrotoxicity; non-steroidal anti-inflammatory drugs; nsaid-induced gastrointestinal toxicity; pharmacogenetic testing; ptgs
• ISSN: 2312-7821; 2619-1164
• DOI: 10.30895/2312-7821-2024-409

INTRODUCTION.  The variability in patient response to non-steroidal anti-inflammatory drugs (NSAIDs) may be due to genetic polymorphisms. Decreased-function or non-functional  CYP2C9  alleles are known to be significant contributors to response variability, and research is being conducted on the potential contribution of polymorphisms in the  PTGS1  and  PTGS2  genes that encode for the NSAID targets, cyclooxygenases 1 and 2.
AIM.  This study aimed to demonstrate the contribution of pharmacogenetic characteristics to the development of adverse reactions to NSAIDs in clinical cases.
MATERIALS AND METHODS.  This study reports two clinical cases observed in a multidisciplinary hospital in Moscow. The first case report demonstrates a neurosurgical patient with spondylodiscitis who showed signs of renal failure associated with ketorolac administration during 13 days of inpatient treatment. The second case report presents a patient with gastrointestinal bleeding that developed after 3 weeks of ketorolac self-administration and ultimately required gastric resection surgery. According to real-time polymerase chain reaction results, these patients have single-nucleotide polymorphisms, including rs179985 ( CYP2C9*2 ) and rs1057910 ( CYP2C9*3 ) in the  CYP2C9  gene, rs10306135 and rs12353214 in the  PTGS1  gene, and rs20417 in the  PTGS2  gene.
RESULTS.  The described adverse reactions to ketorolac are attributable to the patients’ pharmacogenetic characteristics and other factors (exceeding the recommended duration of ketorolac therapy, concomitant conditions, drug interactions, and older age). In the case of nephrotoxicity, the patient has the  CYP2C9*1/*2  genotype, which is associated with decreased NSAID metabolism. Additionally, this patient has the  PTGS1  (C>T) rs12353214 genotype, which may be associated with variations in the activity of cyclooxygenase 1 and may lead to an increased risk of adverse reactions to NSAIDs. In the case of gastrointestinal bleeding, the patient also has genetic characteristics that affect the response to NSAIDs, as the  CYP2C9*1/*3  genotype is associated with significantly decreased NSAID metabolism. Patients with this genotype should take the lowest doses or switch to alternatively metabolised NSAIDs.
CONCLUSIONS.  To reduce the risk of nephrotoxicity and gastrointestinal bleeding in patients when prescribing ketorolac, healthcare providers should strictly follow the recommended dosing regimen and consider individual comorbidities and potential drug interactions that may potentiate adverse drug reactions. Additionally, patient risk management requires pharmacogenetic testing, including the determination of decreased-function or non-functional  CYP2C9  alleles and the rs12353214 polymorphism in the  PTGS1  gene.