Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Opportunities and challenges of reformulation using levothyroxine as an example

Anne Jeschke (Abschlußjahr: 2022)

Summary
Language: English
Thyroid diseases are among all endocrinology diseases one of the most common diseases worldwide. The external administration of levothyroxine is the standard therapy for the treatment of hypothyroidism. For therapy, levothyroxine must be dosed carefully due to its narrow therapeutic window. Slight treatment deviations can cause side effects in the patient. For this, a constant active ingredient in the medicinal product must be guaranteed over the duration of the shelf life. Therefore, one effort of pharmaceutical companies is to change existing formulations in order to develop an even more stable and thus safer product for the patient. Due to its narrow therapeutic window and safety profile, levothyroxine is also referred to as a critical dose drug. The critical dose drug classification of levothyroxine was investigated and evaluated using the existing scientific literature. A step wise approach for the selection of scientific articles was chosen. The research in PubMed exposed 204 publication and nine article found by ad hoc research. After critical reading regarding inclusion criteria 16 articles remain. The reformulation of levothyroxine in line with the appropriate risk communication was taken on board by highlighting the challenges in the manufacturing process. In addition to comparing Germany with two also involved countries, a comparative analysis of the pharmaceutical companies involved was conducted.
The definitions for the classification of levothyroxine as a Narrow Therapeutic Index (NTI) drug or critical dose drug vary widely worldwide. Levothyroxine does not always meet the requirements for falling under the definition of a NTI. If the therapeutic range is exceeded, the term toxicity is used. Likewise, despite the narrow therapeutic window, it is not appropriate to speak of acute toxicity, since in bioequivalence studies patients are administered doses of 600 micrograms, which is about six times the dosage, but without endangering the health of the patient. There are significant advantages to levothyroxine when compared to other NTI drugs in terms of safety and tolerability. As a result, levothyroxine should be considered a critical dose drug, rather than an NTI.
Several special requirements arise when a drug is classified as a critical dose drug. Consequently, the treating prescriber must carefully titrate the dosage and monitor it closely. There should be a close follow-up of the patient when changing the composition of levothyroxine-containing products. The risk communication is unified within the European Union. Minor variations in the distribution list or implementation of Direct Healthcare Professional Communications (DHPC) and Patient Information Sheet (PIS) are possible in the member states. The result of the comparison of the risk communication in Germany with Hungary and the Czech Republic demonstrates that Hungary has published two DHPCs, one for prescribers and one for pharmacists, whereas the Czech Republic has included the PIS information in the leaflet.
The reformulation has a long-term benefit for the patient and the corresponding treatment and therefore an improvement in stability for this sensitive product. Moreover, there is potential for the further development of risk communication to an electronic version in order to more quickly access the relevant functions with this important information.
Pages: 36
Annexes: 1, Pages: 3