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

Abstract

The aim of the present study was to evaluate the bioequivalence and therapeutic equivalence of the two most commonly prescribed L-thyroxine (monsodium L-thyroxine hydrate, CAS 25416-65-3) formulations in Brazil in patients treated for hypothyroidism. Twenty-four patients received 100 micrograms L-thyroxine daily of either Puran T4 (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 concentration by a chemiluminescent immunoassay. Content and uniformity of the tablets and dissolution studies were also assessed according to USP 24 monograph using an isocratic HPLC-UV system and a rotating-paddle method. The mean pharmacokinetic parameters for total T4, expressed as geometric means (CV), for the test and reference were, respectively: Cmax (microgram/dl) 9.8 (14.3%) and 10.8 (14.9%); AUC0-24 h (microgram/dl.h) 206.8 (13.9%) and 230.4 (14.9%). Median values (90% CI) for Tmax (h) were 3 (2-3) and 2 (2-4) for the test and reference, respectively. 90% CI for ratios of LogCmax and LogAUC0-24 h were 86.6-94.9 and 86.3-93.4, respectively. Although the test exhibited values of Cmax and AUC0-24 h around 10% lower than the reference, these formulations must be considered bioequivalent since the 90% CI for both Cmax and AUC0-24 h mean ratio were within the 80-125% interval as proposed by the US Food and Drug Administration and the Brazilian legislation. TSH dosages within the normal range further support therapeutic equivalence between the two formulations. Dissolution data were roughly in agreement with in vivo results since both formulations comply with the USP dissolution criteria although the test tablets had a slower dissolution rate than the reference 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 dissolution profiles of the tablets correlate well with their bioavailability in the present experimental conditions.

Oral and intravenous thyroxine (T4) achieve comparable serum levels for hormonal resuscitation protocol in organ donors: a randomized double-blinded study

“…4 These findings are consistent with previous studies of T4 pharmacokinetics studied in healthy volunteers and other patient populations. [4][5][6] Therefore, the oral form of thyroxine is a suitable route of administration in this patient population. The hemodynamic responses following T4 administration were also similar between groups; however, since a control group (no thyroxine administration) was not used in this study, we cannot exclude the possibility that hemodynamics improved simply with time from the sympathetic storm usually seen at time of brain death and that the administration of thyroxine has no effect.…”

“…The target sample size for the study was 34 patients, which was based on the sizes of previous studies of thyroxine pharamcokinetics. [4][5][6] No formal sample size calculation was performed. The study drug was administered once consent for organ donation was received, and this point in time was designated as time zero.…”

Levothyroxine: Conventional and Novel Drug Delivery Formulations

“…The tablet form is the predominant preparation of LT4, accounting for more than 95% of LT4 prescriptions ( 43 ). Generally, a dose of LT4 of 1.6 to 1.8 µg/kg body weight is sufficient for the normalization of thyroid function ( 44 ).…”

A derivative UV spectrophotometric method for the determination of levothyroxine sodium in tablets

“…Since commercially available products of L-T 4 usually consist in scored tablets, it is a very common practice to break them in order to obtain the required treatment dose, but jeopardizing the uniformity of the administered units [13]. Thus, another goal of the present study was to assess the effect of the breaking process in the uniformity of dosage units.…”

“…Most of the analytical literature methods are HPLC methods [6][7][8][9]. Other methods include electrospray ionization tandem mass spectrometry (ESI-MS/MS) [10] and inductively coupled plasma mass spectrometry [11].…”