Levodopa and dopamine decarboxylase inhibitors

Levo-DOPA (L-DOPA) is a precursor of dopamine. Dopamine itself does not cross the blood-brain barrier and so is not effective as a drug. L-DOPA does enter the brain and is converted to dopamine in the striatum.

L-DOPA is usually given in conjunction with an inhibitor of dopamine decarboxylase. The inhibitor does not cross the blood-brain barrier hence the side-effects of peripheral dopamine production, such as nausea, are reduced while the central actions of L-DOPA are augmented.

NICE states that it is not possible to identify a universal first-choice drug therapy for people with early Parkinson's disease (PD). A possible initial first-choice therapy is levodopa therapy (2)

• the dose of levodopa should be kept as low as possible to maintain good function in order to reduce the development of motor complications
• modified-release levodopa preparations may be used to reduce motor complications in people with later PD, but should not be drugs of first choice

Levodopa, with a peripheral inhibitor of the aromatic L-amino acid decarboxylase such as carbidopa, is the most effective symptomatic treatment for PD; however, as PD progresses, oral medication inadequately controls symptoms due to an increasingly narrowing therapeutic window (3).

Foslevodopa/foscarbidopa, is a formulation of LD/CD phosphate prodrugs (3)

• by generating prodrugs of levodopa and carbidopa the solubility is increased by > 100-fold which allows for a highly concentrated foslevodopa/foscarbidopa solution and enables its administration through a minimally invasive subcutaneous (SC) infusion
• upon delivery to the body, foslevodopa/foscarbidopa is quickly and almost completely metabolized to levodopa/carbidopa by alkaline phosphatases
• continuous subcutaneous infusion (CSCI) of foslevodopa/foscarbidopa alone can achieve high sustained and steady-state therapeutic levels of plasma

Reference:

1. Clarke CE (1999). Managing early Parkinson's disease. The Practitioner; 243: 39-47.
2. NICE (June 2006). Parkinson's disease
3. Rosebraugh M, Liu W, Neenan M, Facheris MF. Foslevodopa/Foscarbidopa Is Well Tolerated and Maintains Stable Levodopa and Carbidopa Exposure Following Subcutaneous Infusion. J Parkinsons Dis. 2021;11(4):1695-1702.