Objective: To determine the pharmacokinetic (PK) profile of L-3,4-dihydroxyphenylalanine (L-DOPA) in the common marmoset (Callithrix jacchus).

Background: The common marmoset has been used to model Parkinson’s disease (PD) for nearly 4 decades and has played an invaluable role in refining our understanding of the pharmacological mechanisms underlying parkinsonism, dyskinesia and psychosis. Upon repeated administration of L-DOPA, the gold-standard anti-parkinsonian agent in the clinic, marmosets develop dyskinesia and psychosis-like behaviours (PLBs). Whereas doses in the range of 7.5 – 15 mg/kg are often administered to animals, the ensuing plasma exposure has not been thoroughly assessed and how comparable it is to the exposure achieved in the clinic remains incompletely characterised.

Method: Six marmosets were administered L-DOPA/benserazide 7.5/1.875 and 15/3.75 mg/kg orally (p.o.), as well as 15/3.75 mg intra-venously (i.v.). Serial blood samples were collected, plasma was harvested and analysed by high-performance liquid chromatography coupled with a hybrid Quadrupole-Orbitrap mass spectrometer operating in full-scan high resolution and accurate mass (HRAM) using a parallel reaction monitoring (PRM). L-DOPA PK parameters were determined by non-compartmental analysis.

Results: After p.o. intake, maximal plasma concentration (C_max) of L-DOPA was 1,486.9 ng/mL and 2,356.8 ng/mL after administration of the 7.5/1.875 and 15/3.75 mg/kg doses. Time to C_max (T_max) approximated 60 min for both doses, while half-life (T_1/2) was 89 and 60 min after L-DOPA/benserazide 7.5/1.875 and 15/3.75 mg/kg. Bioavailability (%F) was 39.9% and 32.7%, after administration of L-DOPA/benserazide 7.5/1.875 and 15/3.75 mg/kg. After i.v. administration, initial plasma concentration (C₀) reached 33,010.5 ng/mL, total clearance (Cl) was 1.04 L/h/kg, volume of distribution (V_z) was 1.14 L/kg and T_1/2 was 45 min.

Conclusion: In the clinic, C_max between 2,000 – 3,000 ng/mL are associated with an anti-parkinsonian benefit, while L-DOPA T_1/2 also approximates 1h. As such, our results indicate that doses commonly used in the marmoset to elicit dyskinesias, PLBs and alleviate parkinsonism lead to a plasma exposure comparable to that achieved in human.

« Back to 2023 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/characterisation-of-the-pharmacokinetic-profile-of-l-dopa-in-the-common-marmoset/