Comparative bioavailability of two oral L-thyroxine formulations after multiple dose administration in patients with hypothyroidism and its relation with therapeutic endpoints and dissolution profiles

The aim of the present study was to evaluate the bioequivalence and therape utic equivalence of the two most commonly prescribed L-thyroxine (monsodium L-thyroxine hydrate, CAS 25416-65-3) formulations in Brazil in patients tr eated for hypothyroidism. Twenty-four patients received 100 pg L-thyroxine daily of either Puran T4 (R) (test) or the Brazilian reference formulation (reference) during 42 days, in a two-period crossover design. Serum samples obtained over a 24-h interval were analyzed for their total T4 concentrati on by a chemiluminescent immunoassay. Content and uniformity of the tablets and dissolution studies were also assessed according to USP 24 monograph u sing an isocratic HPLC-W system and a rotating-paddle method. The mean phar macokinetic parameters for total T4, expressed as geometric means (CV), for the test and reference were, respectively: C-max (mug/dl) 9.8 (14.3 %) and 10.8 (14.9 %); AUC(0-24) h (mug/dl.h) 206.8 (13.9 % and 230.4 (14.9 %). Me dian values (90 % CI) for T-max (h) were 3 (2-3) and 2 (2-4) for the test a nd reference, respectively. 90 % CI for ratios of LogC(max) and LogAUC(0-24 h) were 86.6-94.9 and 86.3-93.4, respectively. Although the test exhibited values of C-max and AUC(0-24) h around 10 % lower than the reference, thes e formulations must be considered bioequivalent since the 90 % CI for both C-max and AUC(0-24) h mean ratio were within the 80-125 % interval as propo sed by the US Food and Drug Administration and the Brazilian legislation. T SH dosages within the normal range further support therapeutic equivalence between the two formulations. Dissolution data were roughly in agreement wi th in vivo results since both formulations comply with the USP dissolution criteria although the test tablets had a slower dissolution rate than the r eference tablets. As a conclusion, the two oral formulations of L-thyroxine are both bioequivalent and therapeutically equivalent although presenting a small difference in their extent of absorption. Noteworthy, the dissoluti on profiles of the tablets correlate well with their bioavailability in the present experimental conditions.