Abstract
Tozadenant is one of the selective adenosine A2a receptor antagonists with a potential to be a new Parkinson’s disease (PD) therapeutic drug. In this study, a liquid chromatography-mass spectrometry based bioanalytical method was qualified and applied for the quantitative analysis of tozadenant in rat plasma. A good calibration curve was observed in the range from 1.01 to 2200 ng/mL for tozadenant using a quadratic regression. In vitro and preclinical in vivo pharmacokinetic (PK) properties of tozadenant were studied through the developed bioanalytical methods, and human PK profiles were predicted using physiologically based pharmacokinetic (PBPK) modeling based on these values. The PBPK model was initially optimized using in vitro and in vivo PK data obtained by intravenous administration at a dose of 1 mg/kg in rats. Other in vivo PK data in rats were used to validate the PBPK model. The human PK of tozadenant after oral administration at a dose of 240 mg was simulated by using an optimized and validated PBPK model. The predicted human PK parameters and profiles were similar to the observed clinical data. As a result, optimized PBPK model could reasonably predict the PK in human.
Highlights
Parkinson’s disease (PD) is a well-known progressive neurodegenerative disease that has motor symptoms such as postural instability, tremor, bradykinesia, and rigidity
We describe the development and qualification of an LC-MS/MS method for tozadenant in rat plasma
The results show that the increase in area under the curve (AUC) and maximum plasma concentration (Cmax ) of tozadenant was dose-dependent at a single intravenous or oral administration at a dose range of 1 to
Summary
Parkinson’s disease (PD) is a well-known progressive neurodegenerative disease that has motor symptoms such as postural instability, tremor, bradykinesia, and rigidity. The motor symptoms of PD are caused by reduced dopamine levels in the basal ganglia [1,2]. Several drugs that can influence the amount of dopamine in basal ganglia have been used to improve the motor symptoms of PD. The precursor of dopamine, L-DOPA (L-dihydroxy-phenyl-alanine), has been used as a gold standard for over 40 years [3]. While L-DOPA therapies are effective for the first several years, long-term treatment with. L-DOPA therapies result in several adverse effects, including motor fluctuation and dyskinesia [1,3,4,5,6]. Alternative therapies are needed for the treatment of PD patients taking long-term
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