The pharmacokinetics and pharmacodynamics of adinazolam: multi-ethnic comparisons

Abstract

The pharmacokinetics and pharmacodynamics of adinazolam and N-demethyladinazolam (NDMAD), its major active metabolite, were compared in 39 healthy male volunteers (13 Asian, 12 Caucasian and 14 African-American). In a four-way, double-blind crossover design, subjects were administered (1) 30 mg oral adinazolam mesylate SR tablets, (2) 10 mg parenteral (i.v.) adinazolam mesylate, (3) 30 mg i.v. NDMAD and (4) placebo. Venous blood samples were collected at specific time intervals after drug administration and assayed for adinazolam and NDMAD concentrations. Sedation was rated at the time of each blood draw according to the Nurse-Rated Sedation Scale, and the digit-symbol substitution test was administered to evaluate psychomotor performance. After i.v. administration of adinazolam, Asians manifested significantly higher Cmax, larger AUC and lower CL of both adinazolam and NDMAD than their Caucasian and African-American counterparts. Likewise, after i.v. NDMAD Asians had significantly higher NDMAD Cmax and AUC than Caucasians and African-Americans. Most of these differences remained statistically significant after controlling for body surface area. With PO adinazolam, Asians also manifested substantially higher Cmax, larger AUC and lower CL for both adinazolam and NDMAD; however, with the exception of Cmax, these differences did not reach statistical significance. These results are in accordance with previous observations for ethnic-related differences in drug pharmacokinetics. In contrast, pharmacodynamic differences were not noted among the three study groups.

Kinetics and Dynamics of Intravenous Adinazolam, N‐Desmethyl Adinazolam, and Alprazolam in Healthy Volunteers

“…Therefore, intestinal metabolism of adinazolam substantially contributes to incomplete adinazolam oral bioavailability. Previous studies demonstrated that pharmacokinetic parameters for adinazolam and NDMAD can vary with age and across ethnic groups 6,35 . In this study, we demonstrated that pharmacokinetic parameters for adinazolam, NDAMD, and alprazolam in healthy male subjects are similar to those published previously 9–11 …”

A Review and Assessment of Potential Sources of Ethnic Differences in Drug Responsiveness

“…Another study compared adinazolam in Asians (Japanese, Chinese, Filipinos) versus Caucasians and African Americans after both oral and IV administration. 122 This study was well conducted and showed greater exposure of adinazolam in Asians, but no pharmacodynamic differences were seen (using observer sedation scores and the digit symbol substitu-tion test). Finally, nitrazepam was compared in Caucasians and Japanese.…”

“…This study was rather small ( n = 8 in each group) and revealed no pharmacodynamic differences, although a higher C max was observed in Asians. Another study compared adinazolam in Asians (Japanese, Chinese, Filipinos) versus Caucasians and African Americans after both oral and IV administration 122 . This study was well conducted and showed greater exposure of adinazolam in Asians, but no pharmacodynamic differences were seen (using observer sedation scores and the digit symbol substitution test).…”

Association between high cumulative dose of benzodiazepine in Chinese patients and risk of dementia: a preliminary retrospective case–control study

“…Benzodiazepine metabolism was shown to be different in Asian and Caucasian patients. Asian patients have a higher maximum plasma concentration, a larger area under the plasma concentration–time curve, and lower systemic clearance . One study did not show any significant difference, possibly because of its smaller sample size .…”