SINGLE AND MULTIPLE-DOSE PHARMACOKINETICS OF TENIDAP SODIUM IN HEALTHY-SUBJECTS

1 The absorption, protein binding, clearance and absolute bioavailabil ity of tenidap sodium were studied after single and multiple dosing. 2 Thirteen healthy male volunteers received a single 120 mg oral dose o f tenidap sodium and a 20 mg intravenous infusion of deuterated tenida p ([D-3]-tenidap) on day 1. This was followed by a 6-day washout perio d (days 2-7) and then further daily doses of oral tenidap sodium 120 m g for 21 consecutive days (days 8-28) with an additional 20 mg intrave nous infusion of [D-3]-tenidap on day 28. Twelve subjects were eligibl e for pharmacokinetic evaluation. 3 Following multiple oral doses, the half-life of tenidap is approximately 23 h. 4 Following single and mu ltiple dose administration, the absolute bioavailability is 85% 5 Syst emic clearance of [D-3]-tenidap was 29% greater on day 28 than on day 1 indicating a significant increase in intrinsic clearance (CL(int)) o f tenidap since protein binding of tenidap in plasma did not change du ring the study. Consistent with the increase in systemic clearance, th e half-life of [D-3]-tenidap decreased and the ratio of AUC(0,24h) day 28/AUG day 1 following oral dosing was less than one. Tenidap is subj ect to extensive hepatic metabolism, so the increase in CL(int) may in dicate that tenidap induces its own metabolism. 6 Steady-state was ach ieved by the eleventh day of dosing. Since numerous studies in patient s with rheumatoid arthritis have shown that multiple dosing with tenid ap is clinically efficacious, this suggests that the pharmacokinetic d ifferences observed between the first and twenty-first day of multiple tenidap dosing do not influence the clinical response.