The pros and cons of levodopa
The cardinal symptoms of Parkinson´s disease are all secondary to the loss of dopamine – replenishing dopamine levels by peroral administration of a dopamine precursor, levodopa, thus effectively restores normal motor function. To avoid side-effects caused by dopamine formation outside the brain, and to increase the amount of levodopa reaching the brain, levodopa is usually co-administered with carbidopa, a compound blocking peripheral conversion of levodopa to dopamine.
Due to the short half-life of levodopa, the serum levels of the molecule display marked fluctuations when it is administered as tablets. At the early stages of the disorder, this poses no major problem, since there are sufficient dopaminergic neurons still available that are capable of transforming levodopa to dopamine, store the transmitter and release it when appropriate. At later stages of the disease, the remaining dopaminergic neurons are, however, too few to fulfil this task – instead levodopa is taken up by non-dopaminergic neurons and released in a non-physiological manner, with marked fluctuations from hypokinesia to dyskinesias – the on-off complication – as result.
The benefit of levodopa infusions
It has since long been known that avoiding serum fluctuations of levodopa by administering the compound as a continuous intravenous infusion restores normal motor function in patients with on-off symptoms. In line with these early studies, continuous administration of levodopa plus carbidopa into the intestines by means of a pump and an implanted tube – Duodopa®/Duopa®– is now an approved and well-established treatment for late-stage Parkinson´s disease with on-off complications.
While it would be much more convenient to instead administer levodopa subcutaneously, in the same manner as insulin is administered to patients with diabetes, the poor solubility and stability of levodopa, impeding the formulation of highly concentrated levodopa solutions, until now has made this strategy inaccessible.
A levodopa-containing solution aimed for outpatient treatment of Parkinson´s disease should meet several criteria to be optimal for this purpose. It should be sufficiently concentrated to be administered by means of a portable pump. To prevent peripheral side effects and to enhance the amount of levodopa reaching the brain, it should contain not only levodopa but also carbidopa. It should be stable in refrigerator and preferably also in room temperature. And it should display a pH that does not cause adverse skin reactions and promotes rapid uptake from the subcutaneous tissue, i.e., 5-6.
The creation of such a solution is the discovery forming the basis of Dizlin Pharmaceuticals. Infudopa SubC™ thus is a levodopa- and carbidopa-containing solution with a pH of approximately 5 when administered to the patient, hence producing a rapid uptake of levodopa from the subcutaneous tissue with a bioavailability close to 100%.
The shelf life for this product is 36 months in refrigerator and a minimum of 3 months at room temperature. This excellent stability represents a considerable logistical advantage for patients, e.g., when travelling. Infudopa™ may serve as monotherapy also in patients requiring high levodopa levels. The rapid uptake enables individualized and flexible dosing.
Infudopa IntraV™ is a similar but different product aimed for intravenous administration to inpatients in situations where levodopa cannot be administrated orally or intestinally, e.g., prior to and after surgery.
At present, there is no levodopa solution aimed for subcutaneous or intravenous administration on the market.