P.1.019 - Phenazepam's safety pharmacogenetic study results: influence of CYP2C9, CYP3A5, CYP2C19, ABCB1 and CYP3A4/5 isoenzymes' activity

Abstract

Introduction Bromdihydrochlorphenylbenzodiazepine (Phenazepam) is the Russian original benzodiazepine, which was widely prescribed in post-Soviet countries. The chemical structure is close to clonazepam [1]. Alcohol withdrawal syndrome is one from the most frequent indications for Phenazepam. However, an absence of pharmacogenetic studies on Phenazepam makes personalized treatment impossible. For the present study, several gene-candidates were chosen. CYP3A5, CYP2C9, CYP2C19 may affect the safety of Phenazepam [2,3]. ABCB1 (multidrug resistance gene 1 - MDR1) gene is the coding transport protein glycoprotein P. Glycoprotein P share its substrates with CYP3A4 isoenzyme. The CYP3A4 gene was not included in our panel, but the isoenzyme activity of CYP3A4/5 was phenotyped. Aim To investigate the influence of pharmacogenetic biomarkers CYP3A5*3, CYP2C9*2, *3, CYP2C19*2, *3 and *17, ABCB1 3435C>T and CYP3A4/5 activity on the safety of Phenazepam in patients with alcohol withdrawal syndrome. Materials and Methods 102 male patients with non-complicated AWS (F 10.3 by ICD-10) were involved in the study. During 6 days of dynamic observation, each participant was prescribed Phenazepam. The UKU Side Effects Rating Sale was used to measure safety on day 6. 5 ml of venous blood and 10 ml of urine were collected from each participant for genotyping and measuring CYP3A4/5 activity. 38 participants also received Pagluferal (contains phenobarbitalum, natrium coffeine-benzoate, bromisoval, papaverine) and/or Carbamazepine (Combined pharmacotherapy subgroup). Blood samples were analyzed to detect the CYP3A5*3, CYP2C9*2, *3, CYP2C19*2, *3, *17, ABCB1 3435C>T polymorphisms by PCR-RT. CYP3A4/5 activity was measured by 6-b-hydroxycortisol/cortisol ratio by fluid chromotography. Higher mean of this ratio is the sense of higher CYP3A4/5 activity. Sensitivity and specificity for each biomarker and UKU Scale items were calculated with Chi-square test (2x2 tables). Results There were few strong predictors of a lack of Phenazepam safety. CYP3A5*3 (GA heterozygous) was significantly associated with risk of higher overall adverse effects severity (sensitivity - 43.8%, specificity - 85.4%; OR - 2.79 (95%CI 1.26 - 6.22); p=0.031). CYP2C9*3 (AC+CC genotypes' carriers) raised the risk of duration of sleep (sensitivity - 32.5%, specificity - 91.7%; OR - 1.57 (95%CI 1.14 - 2.17); p=0.034). ABCB1 3435C>T (CC genotype) played a protective role: there was decreased severity of overall adverse effects in carriers of that genotype (sensitivity - 40%, specificity - 14.3%; OR=0,238 (95%CI 0,08 - 0,67); p=0,01). There was no significant odds ratio for CYP2C19 polymorphisms. According to 6-b-hydroxycortisol/cortisol ratio, CYP3A4/5 activity significantly decreased only in patients prescribed Phenazepam as monotherapy (n=64; 3.82±3.41 > 2.79±3.06; p=0.03). There was no substantial change in the overall group (n=102; 3.35±3.25 > 3.09±3.56; p=0.568) or in the Combined pharmacotherapy subgroup (n=38; 2.58±2.84 > 3.57±4.25; p=0.265). Correlational analasis did not find interrelationships of CYP3A4/5 activity and Phenazepam's safety (r=0,084; p=0,187). Conclusion Pharmacogenetic study of Russian original benzodiazepine Phenazepam confirmed the role of CYP3A5*3, CYP2C9*3 and ABCB1 3435C>T polymorphisms as biomarkers of safety. Carriers of current CYP polymorphisms had increased risk of unsafety of pharmacotherapy. CYP2C19*2, *3, *17 and CYP3A4/5 isoenzymes' activity had no significant contribution to the risk of Phenazepam's unsafety.