Effect of CYP2D6*4, CYP2D6*10 polymorphisms on the safety of treatment with timolol maleate in patients with glaucoma

Larisa K. Moshetova; Maria M. Soshina; Ksenia I. Turkina; Elena A. Grishina; Zhannet A. Sozaeva; Anastasia A. Kachanova; Kristina A. Akmalova; Dmitriy V. Ivashchenko; Mikhail S. Zastrozhin; Vladimir P. Fisenko; Dmitry A. Sychev

doi:10.1515/dmpt-2022-0117

Article

Effect of CYP2D64, CYP2D610 polymorphisms on the safety of treatment with timolol maleate in patients with glaucoma

Larisa K. Moshetova , Maria M. Soshina , Ksenia I. Turkina , Elena A. Grishina , Zhannet A. Sozaeva , Anastasia A. Kachanova , Kristina A. Akmalova , Dmitriy V. Ivashchenko , Mikhail S. Zastrozhin , Vladimir P. Fisenko and Dmitry A. Sychev

Published/Copyright: August 24, 2022

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From the journal Drug Metabolism and Personalized Therapy Volume 38 Issue 2

Abstract

Objectives

Timolol maleate is used for the treatment of glaucoma and metabolized by cytochrome CYP2D6 in the liver. The aim of this study was the evaluation of the influence of CYP2D6*4 and CYP2D6*10 gene polymorphisms on the safety of medications containing 0.5% of timolol maleate as glaucoma treatment in patients with primary open-angle glaucoma (POAG).

Methods

105 patients with POAG were prescribed glaucoma medications, containing 0.5% timolol maleate. The safety of glaucoma treatment was determined by electrocardiography (ECG) (to assess heart rate (HR) and PQ interval) and blood pressure (BP) measurements. The real-time polymerase chain reaction method was used for the detection of single nucleotide polymorphisms (SNP).

Results

The risk of adverse drug reactions was higher in patients with the CYP2D6*4 GA genotype compared with GG: mean HR change at 1 month (2.88 ± 4.68 and 6.44 ± 5.57, p<0.001) and 6 months (5.14 ± 8.93 and 7.88 ± 5.65, p<0.001), mean PQ interval change at 1 (0.01 ± 0.031 and 0.02 ± 0.022, p=0.003) and 6 months (0.01 ± 0.032 and 0.02 ± 0.024, p=0.003). The risk of adverse drug reactions was higher in patients with the CYP2D6*10 CT genotype compared with CC: mean HR change at 1 month (2.94 ± 4.65 and 6.34 ± 5.66, p<0.001) and 6 months (5.20 ± 8.90 and 7.78 ± 5.75, p<0.001), mean PQ interval change at 1 (0.01 ± 0.032 and 0.02 ± 0.021, p=0.014) and 6 months (0.01 ± 0.033 and 0.02 ± 0.022, p=0.014).

Conclusions

CYP2D6*4 and CYP2D6*10 gene polymorphisms may affect a higher risk of timolol-induced bradycardia and increased PQ interval of treatment medications containing 0.5% of timolol maleate in patients with POAG.

Keywords: CYP2D6; glaucoma; ophthalmic timolol; pharmacogenetics; polymorphism

Corresponding author: Maria M. Soshina, Researcher, Department of Ophthalmology, Russian Medical Academy of Continuing Professional Education, 2/1-1 Barrikadnaya str., 125993 Moscow, Russian Federation, Phone: +7 (925) 888-03-97, E-mail: greenmaha@yandex.ru

Funding source: The Ministry of Health of the Russian Federation for the Russian Medical Academy of Continuing Professional Education of the Ministry of Health of Russia for 2022–2024

Award Identifier / Grant number: (No. 121110800062–6)

Acknowledgments

Special thanks to Anastasia Samoilova, the student of New York University, for help in translating the article.

Research funding: This study was carried out within the framework of the state task of the Ministry of Health of the Russian Federation for the Russian Medical Academy of Continuing Professional Education of the Ministry of Health of Russia for 2022–2024 (No. 121110800062–6).
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Competing interest: Authors state no conflict of interest.
Conflict of interest statement: The authors declare no conflicts of interest regarding this article.
Informed consent: Informed consent was obtained from all individuals included in this study.
Ethical approval: The protocol of this study was reviewed and approved by the local Ethics Committee of the Russian Medical Academy of Postgraduate Education (Act No 12, date of act 08.11.2016).

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Received: 2022-03-08

Accepted: 2022-05-30

Published Online: 2022-08-24

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Articles in the same Issue

https://doi.org/10.1515/dmpt-2022-0117

Keywords for this article

CYP2D6; glaucoma; ophthalmic timolol; pharmacogenetics; polymorphism