THE PHARMACOKINETICS OF TENILOXAZINE IN HEALTHY-SUBJECTS AND PATIENTSWITH HEPATIC CIRRHOSIS

The single-dose and steady-state pharmacokinetics of teniloxazine, an investigational drug with antidepressant and anti-anoxic properties, w ere compared in 12 healthy volunteers and 12 cirrhotic patients, follo wing oral administration of 80 mg teniloxazine maleate every 12 h for 7 days. In healthy volunteers, an increase in oral clearance, CL, (fro m a mean (s.d.) value of 14.6 (3.9) to 18.0 (6.6) ml min(-1) kg(-1); m ean % ratio between the two values (95% CI), 123 (94-151)) and a signi ficant shortening of t(1/2) (from 6.2 (2.7) to 4.8 (1.4) h; mean % rat io (95% CI), 78 (58-98)) were observed upon repeated administration, s uggesting autoinduction of teniloxazine metabolism. In cirrhotic patie nts, the pharmacokinetic parameters of teniloxazine remained essential ly invariant with time. Compared with normal subjects, CL(0) was about halved in cirrhotic patients, whereas t(1/2) was more than doubled. A s a consequence of these modifications, the multiple-dose regimen resu lted in a two-fold mean drug accumulation in cirrhotic patients, compa red 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.