COMPARISON OF ADINAZOLAM PHARMACOKINETICS AND EFFECTS IN HEALTHY AND CIRRHOTIC SUBJECTS

The pharmacokinetics and pharmacodynamics of adinazolam were investigated in six patients with cirrhosis and six sex-matched control subjects. These subjects received a single 30-mg oral dose of adinazolam mesylate. Serial blood samples were collected for 24 hours after drug administration. Plasma was assayed for adinazolam and mono-desmethyl-adinazolam (NDMAD) concentrations by a specific HPLC technique. Pharmacokinetic parameters were estimated by noncompartmental methods. Psychomotor effects of adinazolam were assessed using a digit-symbol substitution test (DSST) and aiming test (AIM). Memory effects were assessed by a modification of the Randt memory test (MEM); sedation was assessed using an observer-rated scale. Differences in pharmacokinetics of the parent drug were noted: adinazolam oral clearance was lower in patients with cirrhosis (35.0 +/- 27.9 L/hr) than in normal subjects (73.7 +/- 22.1 L/hr; P = .024); K(el) was significantly lower in patients with cirrhosis (.126 +/- .084 vs. .278 +/- .070; P = .007), whereas the mean t1/2 in patients with cirrhosis was 7.70 hours as compared with 2.67 hours in normal subjects. C(max) was higher in the group with cirrhosis (266 +/- 95.5 vs. 153 +/- 29.3 ng/mL; P = .019). For NDMAD, K(el) was lower in cirrhotic subjects and resulted in a prolonged t1/2 in cirrhotic subjects compared with normal subjects (6.70 vs. 3.79 hr; P = .0152). NDMAD AUC tended to be higher in cirrhotic subjects (1515 +/- 254 vs. 1162 +/- 254 ng . hr/mL; P = .064). No significant differences were noted in psychomotor performance, memory, or sedation. The large differences in adinazolam kinetics and small differences in NDMAD kinetics, and effects support previous reports that suggest that NDMAD is the major component responsible for responses that were assessed. These kinetic and side-effect data from this single-close study in a small population suggest that patients with cirrhosis may not be more sensitive to this benzodiazepine, but that accumulation of drug and metabolite may lead to greater effects in patients with cirrhosis during multiple-dose therapy.