Steady-state plasma bromdihydrochlorophenylbenzodiazepine concentrations in men with alcohol withdrawal syndrome: impact on safety

Background: Bromdihydrochlorophenylbenzodiazepine is a domestic benzodiazepine tranquilizer used in the treatment of alcohol withdrawal syndrome (AWS). Therapeutic drug monitoring (TDM) of bromdihydrochlorophenylbenzodiazepine has not been sufficiently studied.

Objective: Analysis of the associations of phenazepam and oxyphenazepam TDM parameters with the development of adverse reactions (ARs) during the treatment of AWS in men, taking into account pharmacogenetic and clinical factors.

Materials and methods: The study included 102 male patients diagnosed with AWS (F10.30 according to ICD-10). All patients were prescribed bromdihydrochlorophenylbenzodiazepine. On the 6th day, the presence of ARs was assessed using the UKU Side-Effects Rating Scale. Venous blood samples were obtained from each patient for TDM and pharmacogenetic testing of polymorphic variants of CYP3A5*3, CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3 and CYP2C19*17.

Results: The mean age of 100 participants (2 samples spoiled) was 41.42±8.5 years. The mean concentrations of bromdihydrochlorophenylbenzodiazepine (216.04±144.68 ng/ml) and oxybromdihydrochlorophenylbenzodiazepine (59.34±42.98 ng/ml) were determined among patients. The dose-normalized concentrations were 38.15±28.44 ng/ml for bromdihydrochlorophenylbenzodiazepine and 10.47±34.11 ng/ml for the metabolite, respectively. The concentration of bromdihydrochlorophenylbenzodiazepine was significantly higher in patients with the AR “Constipation” (72.5 [37.75; 154.5] versus 34 [16.25; 46] ng/ml; p=0.034). The presence of the ARs “Asthenia/lethargy/fatigue” and “Constipation” was associated with a higher concentration of oxybromdihydrochlorophenylbenzodiazepine (10 [7; 14] vs. 8 [5; 11] ng/ml; p=0.013 and (27 [9.25; 43.25] vs. 9 [6, 12] ng/ml; p=0.03), respectively. The AR “Depression”, on the contrary, was more often observed among patients with a lower concentration of bromdihydrochlorophenylbenzodiazepine (27 [12; 34] vs. 38 [23; 47.5] ng/ml; p=0.023). No associations were found between polymorphic variants of CYP3A5*3, CYP2C9*2, *3, CYP2C19*2, *3, *17 and TDM data of phenazepam.

Conclusion: In this study, the blood bromdihydrochlorophenylbenzodiazepine and oxybromdihydrochlorophenylbenzodiazepine concentrations in patients with AWS was determined for the first time. Increased plasma concentration of oxybromdihydrochlorophenylbenzodiazepine was associated with an increase in the frequency of any adverse reactions (subjectively and objectively), separately the frequencies of the adverse reactions «Asthenia / lethargy / increased fatigue» and «Constipation». In patients with complaints of depression, a lower concentration of bromdihydrochlorophenylbenzodiazepine was noted.