A bioequivalence study of Levothyroxine tablets versus an oral Levothyroxine solution in healthy volunteers

Abstract

Probably for genetic reasons a substantial part of the Greek population requires Levothyroxine treatment. Since commercially available Levothyroxine was first marketed, the manufacture and storage of the drug in tablet form has been complicated and difficult; and as cases of therapeutic failure have frequently been reported following treatment with this medicinal agent, quality control is an essential factor. Due to the unreliability of Levothyroxine-based commercial products, in the present study we decided to follow the Food and Drug Administration (FDA) guidelines*, and use a Levothyroxine solution as reference product. The bioavailability of the Levothyroxine sodium tablet formulation THYROHORMONE/Ni-The Ltd (0.2 mg/tab) and that of a reference oral solution (0.3 mg/100 ml) under fasting conditions were compared in an open, randomized, single-dose two-way crossover study. Twenty four healthy Caucasian volunteers (M/F=15/9, mean age=32.9+/-7.4yr) participated in the study. Bioavailability was assessed by pharmacokinetic parameters such as the area under plasma concentration-time curve from time zero up to the measurable last time point (AUC(last)) and the maximum plasma concentration (Cmax). Heparinized venous blood samples were collected pre-dose and up to a 48-hour period post-dose. Levothyroxine sodium in plasma samples was assayed by a validated electrochemiluninescent immunoassay technique. Statistical analysis showed that the post-dose thyrotropin-stimulating hormone (TSH) levels decreased significantly (p<0.05). Regarding Levothyroxine (T4), the point estimate of the test formulation to the reference formulation ratios (T/R) for AUC(last) and Cmax was 0.92 with 90% confidence limits (0.90, 0.94) and 0.93 with 90% confidence limits (0.91, 0.94), respectively. Regarding triiodo-L-thyronine (T3), the point estimate for the T/R ratios of AUC(last) and Cmax was 0.92 with 90% confidence limits (0.90, 0.95) and 0.94 with 90% confidence limits (0.92, 0.95), respectively. The 90% confidence limits for the pharmacokinetic parameters AUC(last) and Cmax lie within the acceptance limits for bioequivalence (0.80, 1.25), for both T3 and T4.

Oral L‐thyroxine liquid versus tablet in patients submitted to total thyroidectomy for thyroid cancer (without malabsorption): A prospective study

“…Previous analysis established that liquid L‐T4 does not require acid dissolution in the stomach but it can directly pass through gut mucosa showing quicker absorption time (area under the curve from 0 to 2 h wider than 50%; time to maximum concentration faster by a mean of 30 min), and overall better pharmacokinetics profile …”

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.…”

Biopharmaceutical characterization of levothyroxine sodium immediate-release tablets

“…Za levotiroksin je specifično da je to lek kod koga se u studijama bioekvivalencije različitih formulacija koristi doza znatno veća od kliničkih doza, da bi se redukovao uticaj endogenog nivoa levotiroksina na procenu bioekvivalencije. Dalje, u literaturi se može naći nekoliko studija u kojima je dokazana bioekvivalencija između tableta levotiroksina i oralnog rastvora levotiroksina, što ukazuje da biološka raspoloživost levotiroksina iz tableta ne zavisi od faktora formulacije [175][176][177][178][179]. Walter-Sack i saradnici su potvrdili bioekvivalentnost tableta levotiroksina različitih jačina sa rastvorom levotiroksina kao referentnim preparatom kroz osam različitih studija bioekvivalencije, pri čemu je primenjena metoda i bez i sa korekcijom koncentracije levotiroksina u odnosu na endogeni nivo [179].…”

“…Resorpcija će, pre svega, biti ograničena biofarmaceutskim i fiziološkim faktorima, a ne faktorima formulacije, pod uslovom da ekscipijensi prisutni u ispitivanim formulacijama ne utiču na gastrointestinalnu permeabilnost, i, posledično, na resorpciju leka. Ovakvi rezultati in silico simulacija su u saglasnosti sa publikovanim studijama u kojima je dokazana biološka ekvivalentnost preparata koji su pokazali in vitro različite brzine rastvaranja levotiroksina, kao i sa studijama u kojima je potvrđena biološka ekvivalentnost između tableta i oralnog rastvora levotiroksina [27,[175][176][177][178][179]. Ovakva saznanja omogućavaju postavljanje znatno šire specifikacije testa brzine rastvaranja levotiroksina.…”