Bioequivalence of levothyroxine tablets administered to a target population in steady state

Two parallel trials were carried out with levothyroxine sodium salt in 50 a nd 100 mu g strengths, respectively, giving 100 mu g day(-1) (50 x 2 mu g d ay(-1) or 100 x 1 mu g day(-1)) in both trials in a repeated dose regimen. Twenty patients suffering from primary hypothyroidism under treatment with 100 mu g day(-1) of thyroxine sodium salt were enrolled in each trial. They were clinically and chemically euthyroid. Each trial lasted 114 days, with 57 days being devoted to the first treatment (test or reference) and 57 da ys to the other (reference or test), according to a two-period, two-sequenc e, two-formulation design in a steady state without wash-out. The test form ulation was prepared with a technological improvement and is being produced to replace that at present on the market. Serum concentrations of free and total levothyroxine, and free and total levotriiodothyronine were assayed repeatedly during the treatment and in timed samples after the last dose of each formulation, using radioimmunoassays. C-max and AUC(ss,tau) were cons idered to be target parameters for bioequivalence which was assessed throug h 90% confidence intervals in the 0.80-1.25 range, as required by EU and US FDA operating guidelines. The results have shown that of these hormones, t he free and total parent compound thyroxine is that which most clearly show ed a peak after dosing, whereas its metabolite, free and total triiodothyro nine, fluctuated around pre-dose concentrations. Bioequivalence was fully a ssessed with C-max and AUC(ss,tau) with all four hormones tested and at bot h strengths administered. The two test formulations in 50 and 100 mu g are thus bioequivalent with the two reference preparations. Tolerability was ve ry good in all cases. (C) 1999 The Italian Pharmacological Society.