Innovative Form of Levothyroxine Ensures Accurate Dosing for Patients
In the treatment of hypothyroidism, precise dosing of replacement therapy is critical. An innovative formulation of levothyroxine has been developed to meet the updated, stricter standards of regulatory authorities, thereby ensuring the desired therapeutic effect.
Stricter Registration Conditions
Levothyroxine (L-T4) is one of the most prescribed medications in developed countries. However, practice and literature indicate that even small deviations in its dosage can be associated with significant differences in therapeutic response. A log-linear relationship between its dose and biological effect has been described, and the curve depicting this relationship is very steep. It is no surprise that L-T4 medications have been under increased scrutiny from drug regulatory authorities for over 20 years, which have categorized L-T4 among drugs with a narrow therapeutic index based on these pharmacodynamic characteristics.
L-T4 medications are subject to stricter quality requirements, especially regarding the accuracy of the active ingredient content in the tablet and its stability. In 2009, the U.S. Food and Drug Administration (FDA) began requiring more precise specifications of the active ingredient content in tablets throughout their shelf life (originally 90-110%, after the change 95-105%). Later, some national regulators from European countries also adopted these standards.
The bioequivalence criteria for these medications were also tightened. For any change in the formulation of an already approved medication or the development of a new generic, a bioequivalence study must be conducted, examining, above all, the biological availability of the drug from the new formulation. The area under the plasma concentration-time curve (AUC) and the maximum plasma concentration (Cmax) are monitored. For most drugs, the 90% confidence intervals for both parameters must be within 80-125% compared to the reference product. However, for L-T4 and other drugs with a narrow therapeutic index, a narrower range of 90.0-111.1% applies.
Innovative Dosage Form of Levothyroxine
The physico-chemical stability of the original formulation was improved by replacing lactose with mannitol and adding a small amount of citric acid. These excipient changes eliminated the undesirable reaction between lactose and L-T4, which led to the formation of the degradation product levothyroxine-2-ketolactose.
The innovative tablets meet all regulatory authorities' criteria for dosage accuracy throughout the drug's shelf life (3 years) in all climate zones (active ingredient content in the range of 95-105%) and for bioequivalence compared to the original dosage form (90.0-111.1%). The mean values of AUC and Cmax between the innovative and original formulation in the conducted bioequivalence study were almost identical.
Additionally, a clinical study was conducted to verify the dose proportionality of the new dosage form. In the study, healthy volunteers were given a dose of 600 μg L-T4 composed of tablets of 3 different strengths (12× 50 µg; 6× 100 µg; 3× 200 µg). Parameters AUC and Cmax were also evaluated. The study demonstrated comparable biological availability of L-T4 regardless of tablet strength.
Use of the Innovative Form in Clinical Practice
L-T4 absorption and therapeutic response in hypothyroid patients can be influenced by factors such as gastrointestinal diseases and other comorbidities, concomitant medications and supplements, diet, significant weight changes, or pregnancy. Some of these factors can be easily influenced (e.g., administering the medication on an empty stomach or adequately treating the comorbidity), others only with difficulty or not at all. The innovative L-T4 formulation, however, allows for better determination and adherence to the optimal dose for the specific patient in the context of these factors. It may be particularly beneficial for patients who have previously shown fluctuations in therapeutic response. Already treated patients can be switched to the new tablet form in a 1:1 dose ratio without the need for dose retitration or thyroid function testing beyond regular monitoring. This is only necessary in the event of any adverse incident. Another undeniable advantage of the innovative formulation is higher stability in various climatic conditions.
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Source: Lipp H.-P., Hostalek U. A new formulation of levothyroxine engineered to meet new specification standards. Curr Med Res Opin 2019; 35 (1): 147-150, doi: 10.1080/03007995.2018.1545635.
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