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

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.

Effect of genotype on individual response to the pharmacological treatment of glaucoma: a systematic review and meta-analysis

“…Twenty-six records remained to be examined and were sought for retrieval. The full text was not available for the following 3 articles: Campos-Mollo et al [ 44 ], Lei et al [ 45 ], Moshetova et al [ 46 ]. The report by Kirilenko et al [ 47 ] was excluded because the article was written in Russian.…”

Prospects for the development of pharmacogenetics in Russia for the personalization of pharmacotherapy

“…Выбор биомаркера для последующего изучения в фармакогенетических исследованиях может быть основан на «ген-кандидат» подходе, когда отбор осуществляется, исходя из генов, кодирующих ключевые молекулы на путях всасывания, распределения, метаболизма и выведения препарата, а также механизмов и мишеней его действия. Так, на основе «ген-кандидат» подхода удалось спрогнозировать системные нежелательные реакции со стороны сердечно-сосудистой системы при применении тимолола малеата при глаукоме, поражение печени при использовании ремдесивира у больных новой коронавирусной инфекцией, развитие сухого кашля при применении ингибиторов ангиотензинпревращающего фермента, различных нежелательных реакций при проведении радиойодтерапии [5][6][7][8]. Альтернативным методом для выявления кандидатных полиморфизмов генов выступают полногеномные ассоциативные исследования с дальнейшей проверкой валидности обнаруженных маркеров в проспективных клинических исследованиях.…”