Posting: # 18153
We plan to conduct the bioequivalence study of levodopa and benserazide. We approached several experts to write a protocol of the study. However, they informed us that there is a substantial lack of information on the pharmacokinetics of benserazide to finalize the protocol. We probably cannot ask our competent authority for advice because they may not have necessary information. Thus, we have several important questions in relation to benserazide.
Should we quantify in serum only Benserazide or its metabolite, or both?
What are criteria for bioequivalence (bioequivalence should be established only on the levodopa data or on the data of both components? bioequivalence acceptance criteria?)?
What is the best design for the study?
Any suggestions where and from whom we can obtain reliable advice on the above-mentioned issues will be appreciated.
Edit: Category changed; see also this post #1. [Helmut]
(edited by Mauricio Sampaio on 2018-01-10 16:35)
Posting: # 18162
First of all we need remember what is the Benserazide and its function in this fixed combination.
Benserazide is a DOPA decarboxylase inhibitor, which is unable to cross the blood–brain barrier. It is a peripherally-acting aromatic L-amino acid decarboxylase. So, Benserazide is a lyase enzyme and catalyzes several different decarboxylation reactions.
Benserazide inhibits the peripheral conversion of l-dopa into dopamine. This allows dopamine to build up solely in the brain and the adverse effects caused by peripheral dopamine, such as vasoconstriction, nausea, and arrhythmia, are minimized.
» We approached several experts to write a protocol of the study. However, they informed us that there is a substantial lack of information on the pharmacokinetics of benserazide to finalize the protocol.
Benserazide show a rapid increase and rapid decrease in its plasma concentration and the pharmacokinetics of systemic benserazide does not seem to contribute to the elimination of levodopa. (look the references below)
Therefore, Benserazide has non significant therapeutic effect on its own, and its effect occurs synergically in combination with levodopa (used in the management of Parkinson's disease). If Benserazide (isolated/alone) has not therapeutic effect, why I need to quantify in bioequivalence study? Forget quantification of Benzeraside!
In conclusion, your plan (the best design) to conduct the bioequivalence study of levodopa and benserazide must quantify only levodopa and its metabolite 3-O-methyldopa. Why ? Because, 3-O-methyldopa is one of the most important active metabolites of L-DOPA and its half-life (15 hours approximately) is longer than L-DOPA's half-life, which is about one hour. This means that the accumulate of 3-O-methyldopa in plasma and in the brain help chronic patients suffering from Parkinson's disease.
Pay attention : Both components (levodopa and its metabolite 3-O-methyldopa) need reach the target of bioequivalence acceptance criteria.