THE PHARMACOKINETICS OF TENILOXAZINE IN HEALTHY-SUBJECTS AND PATIENTS WITH HEPATIC CIRRHOSIS

The single-dose and steady-state pharmacokinetics of teniloxazine, an investigational drug with antidepressant and anti-anoxic properties, were compared in 12 healthy volunteers and 12 cirrhotic patients, following oral administration of 80 mg teniloxazine maleate every 12 h for 7 days. In healthy volunteers, an increase in oral clearance, CL, (from a mean (s.d.) value of 14.6 (3.9) to 18.0 (6.6) ml min(-1) kg(-1); mean % ratio between the two values (95% CI), 123 (94-151)) and a significant shortening of t(1/2) (from 6.2 (2.7) to 4.8 (1.4) h; mean % ratio (95% CI), 78 (58-98)) were observed upon repeated administration, suggesting autoinduction of teniloxazine metabolism. In cirrhotic patients, the pharmacokinetic parameters of teniloxazine remained essentially invariant with time. Compared with normal subjects, CL(0) was about halved in cirrhotic patients, whereas t(1/2) was more than doubled. As a consequence of these modifications, the multiple-dose regimen resulted in a two-fold mean drug accumulation in cirrhotic patients, compared with virtually no accumulation in healthy volunteers. Although no adverse events were noted in either study group, it is suggested that maintenance doses for patients with liver dysfunction should initially be at the lower end of the therapeutic range.