A rapid, simple and highly sensitive UPLC-MS/MS method for quantitation of pimavanserin in plasma and tissues: Application to pharmacokinetics and brain uptake studies in mice

Pimavanserin is a new drug approved by the FDA for Parkinson's disease psychosis and other neurological disorders such as Alzheimer's disease. In this study, we developed a UPLC-MS/MS method to quantify pimavanserin disposition in the brain and its pharmacokinetics in mice. Vilazodone was used as the internal standard. Pimavanserin and IS were extracted by liquid-liquid extraction using tert-butyl methyl ether and separated using an Acquity UPLC BEH™ C₁₈ column. The mobile phase consisted of solvent A (0.1% formic acid in acetonitrile) and B (0.1% formic acid in 20 mM ammonium acetate buffer) (A: B, 70:30 v/v) at a flow rate of 0.25 ml/min. The multiple reaction monitoring transitions were performed at m/z 428.23 → 98.15 for pimavanserin and m/z 441.70 > 155.03 for the IS. The developed method was found to be sensitive, fast, and reproducible. The linearity of the method was ˃0.99 over the range of 0.1–300 ng/mL in plasma and 0.25–300 ng/g in the brain homogenate. Precision and accuracy were within the acceptance range. The method was applied to pharmacokinetics and brain uptake studies, which showed that pimavanserin penetrates the blood-brain barrier and reaches a Cₘₐₓ of 21.9 ± 6.66 ng/g in 2.0 h. We also found that pimavanserin brain to plasma ratio (Kbᵣₐᵢₙ/ₚₗₐₛₘₐ) is 0.16 ± 0.05 and it is rapidly eliminated.