Bioequivalence of levothyroxine tablets administered to a target population in steady state.
Two parallel trials were carried out with levothyroxine sodium salt in 50 and 100 microg strengths, respectively, giving 100 microg day-1(50x2 microg day-1 or 100x1 microg day-1) in both trials in a repeated dose regimen. Twenty patients suffering from primary hypothyroidism under treatment with 100 microg 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 days to the other (reference or test), according to a two-period, two-sequence, two-formulation design in a steady state without wash-out. The test formulation 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. Cmax and AUCss,tau were considered to be target parameters for bioequivalence which was assessed through 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, the free and total parent compound thyroxine is that which most clearly showed a peak after dosing, whereas its metabolite, free and total triiodothyronine, fluctuated around pre-dose concentrations. Bioequivalence was fully assessed with Cmax and AUCss,tau, with all four hormones tested and at both strengths administered. The two test formulations in 50 and 100 microg are thus bioequivalent with the two reference preparations. Tolerability was very good in all cases.
Cerutti
R
R
Direzione Medica Etici, Bracco S.p.A., Via Egidio Folli 50, Milan, 20134, Italy.
Rivolta
G
G
Cavalieri
L
L
Di Giulio
C
C
Grossi
E
E
Vago
T
T
Baldi
G
G
Righini
V
V
Marzo
A
A
D000328:Adult; D000704:Analysis of Variance; D005260:Female; D006801:Humans; D007037:Hypothyroidism / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D013607:Tablets; D013810:Therapeutic Equivalency; D013974:Thyroxine / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
D013607:Tablets; D013974:Thyroxine