Pharmacokinetics of single-dose and multiple-dose memantine in healthy chinese volunteers using an analytic method of liquid chromatography-tandem mass spectrometry

• Published in: Clinical therapeutics 2008-04, Vol.30 (4), p.641-653
• Main Authors: Liu, Ming-Yan, MD, Meng, Sheng-Nan, PhD, Wu, Hui-Zhe, MD, Wang, Shuang, MD, Wei, Min-Jie, MD, PhD
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adult; Alzheimer Disease - blood; Alzheimer Disease - drug therapy; Biological and medical sciences; China; Chromatography, Liquid - methods; Dopamine Agents - administration & dosage; Dopamine Agents - pharmacokinetics; Dose-Response Relationship, Drug; Female; healthy volunteer; Humans; Internal Medicine; LC/MS; Male; Medical Education; Medical sciences; memantine; Memantine - administration & dosage; Memantine - pharmacokinetics; pharmacokinetics; Pharmacology. Drug treatments; Reference Values; Reproducibility of Results; Tandem Mass Spectrometry - methods
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2008.04.005

Abstract Objective: This study consisted of 2 phases: development of a liquid chromatography-tandem mass spectrometry (LC/MS) method for determination of memantine in human plasma and characterization of single-dose and multiple-dose pharmacokinetic profiles of memantine in healthy Chinese volunteers using the LC/MS method. Methods: An analytic method of LC/MS for determination of memantine in human plasma was developed and validated and was applied to this singlecenter, open-label, single-dose and multiple-dose pharmacokinetic study conducted in healthy native Chinese volunteers. Subjects were randomized to receive a single dose of 5, 10, or 20 mg of memantine to study the linear characteristics of pharmacokinetics, or a multiple dose of 5 mg once daily for 14 days to study the drug accumulation. The pharmacokinetic parameters calculated included Cmax , Tmax , AUC, t1/2 ,mean residence time (MRT), maximum steady-state plasma concentration (Cssmax ), minimum steady-state plasma concentration (ssmin ), average steady-state plasma concentration (Cssav ), and fluctuation percentage (DF). All values were expressed as mean (SD). Sequential blood samples were collected from 0 to 360 hours for single-dose pharmacokinetic determinations after the dose on day 1; in the multiple-dose pharmacokinetic arm, the sequential blood samples were also obtained from 0 to 360 hours on day 14 after collecting the predose samples at 0 hour on days 11, 12, and 13. Memantine concentrations in plasma were determined by LC/MS method. A calibration curve was constructed by 7 memantine concentrations and processed by least-squares linear regression analysis (w = 1/x2 ). Safety assessments, including adverse events (AEs), were performed at all study visits. Results: The LC/MS method for determination of memantine in human plasma was developed and validated. The standard calibration curve for spiked human plasma containing memantine was linear in the concentration range of 0.2 to 200.0 ng/mL. The correlation coefficient was greater than 0.9960 (n = 6). The lower limit of quantification for memantine in human plasma was 0.2 ng/mL, and the intraday and interday coefficients of variation were all lower than 15%. The mean recoveries of the 0.4, 20.0, and 180.0 ng/mL levels were 78.87%, 81.55%, and 81.98%, respectively. The coefficients of variation were all lower than 15% after being treated at room temperature for 24 hours, for 45 days at -40°, and within 3 freeze-and-thaw cycles in plasma