Pharmacokinetics And Pharmacodyna-Mics Of Febuxostat In Healthy Chinese Volunteers

Objective:Febuxostat, a non-purine, selective xanthine oxidase/xanthine dehydrogenase inhibitor, was bound in a long, narrow channel leading to the molybdenum-pterin active site of bovine milk xanthine dehydrogenase, as revealed by a crystal structure determination. Enzyme activity was inhibited by febuxostat blocking substrate binding. Febuxostat was primarily metabolized by the liver, rather than rely on renal excretion. On April21,2008, Febuxostat received marketing approval by the European Medicines Agency. And on February16,2009, it was approved by the U.S. Food and Drug Administration. It has not yet been listed in China. This dissertation is to acquire the clinical pharmacokinetic data by the determination of domestic febuxostat and to acquire the pharmacokinetic parameters and at last to provide evidences for the new drug application and clinical applications of febuxostat.Methods:1. Determination of febuxostat plasma concentrations. Twelve healthy volunteers were enrolled into this research including the two parts of contents.①In the single and multiple doses pharmacokinetic study, three different level dosage, three-period, crossover studies were performed in healthy male and female subjects. Subjects either received multiple40-mg, multiple80-mg or single120-mg doses of febuxostat in fasting conditions.②In the food effect studies, randomized, two-period, crossover study was performed in healthy male and female subjects. Subjects received single80-mg doses in fasting or nonfasting (i.e. high-fat breakfast) conditions. HPLC-MS/MS method was developed for determination of febuxostat plasma concentrations. Pharmacokinetic parameters of febuxostat were generated with DAS2.1.1software.2. HPLC-UV method was developed for determination of uric acid, xanthine and hypoxanthine serum concentrations.Results:The main febuxostat pharmacokinetic parameters of a single oral administration of40,80,120mg division were as follows:AUC0-t were (9266.28±3720.80) ng·ml/-1·h,(21925.22±11303.59) ng·mL-1·h and (33845.27±15744.68) ng·mL-1·h; AUC0-∞, were (9426.72±3715.53) ng·mL-1·h,(22118.06±1374.98) ng·mL-1·h and (34102.50±15895.04) ng·L-1·h; MRT0-t were (4.16±1.00) h,(4.52±0.66) h and (4.58±0.76) h; MRTo-∞were (4.70±1.29) h,(4.84±0.82) h and (4.88±0.98) h; t1/2z were (5.10±2.63) h,(5.48±2.02) h and (5.73±4.09) h; Tmax were (1.90±1.05) h,(2.13±0.83) h and (1.96±0.84) h; CLz/F were (4.88±1.86) L·h-1,(4.46±1.92) L·h-1and (4.16±1.56) L·h-1Vz/F were (34.12±19.69) L,(31.72±11.17) L and (31.99±16.83) L; Cmax were (2857.89±1072.38) ng·mL-1,(6750.10±3516.50) ng·mL-1and (9534.84±4369.62) ng·mL-1.The main febuxostat pharmacokinetic parameters of multiple oral administration of40,80mg division were as follows:AUCSS were (7877.01±3728.81) ng·mL-1-h and (16822.71±7244.85) ng·mL-1·h; AUC0-t were (8039.59±4054.88) ng·mL-1·h and (17053.28±7738.57) ng·mL-1·h; AUCo-∞were (8215.28±4142.48) ng·mL-1·h and (17255.52±7846.97) ng·mL-1·h; MRT0-t were (4.55±1.48) h and (4.50±0.88) h; MRT0-∞ were (5.18±1.83) h and (4.83±1.03) h; ti/2z were(5.74±4.52) h and (5.07±2.41) h; Tmax were (2.21±1.57) h and (1.79±0.89) h; CLz/F were (5.86±2.33) L·h-1and (5.43±2.07) L·h-1; Vz/F were (38.73±15.60) L and (34.85±9.01) L; Css_max were (2480.43∧1399.36) ng·mL-1and (4717.31±2054.50) ng·mL-1; Css_min were (24.27±29.18) ng·mL-1and (45.54±46.94) ng·mL-1; Cav were (328.21±155.37) ng·mL-1and (700.95±301.87) ng·mL-1; DF were (7.25±2.52) ng·mL-1and (6.95±2.23) ng·mL-1.On the feeding and fasting state, the main febuxostat pharmacokinetic parameters of oral administration of80mg division were as follows:AUC0-t were (17240.06±5067.33ng·mL-1·h and (19346.89±7644.93) ng·mL-1·h; AUC0-∞were (17365.82±5100.10) ng·mL-1·h and (19602.30±7635.54) ng·mL-1·h; MRT0-t were (5.95±1.47) h and (4.69±0.68) h; MRT0-∞were (6.17±1.52) h and (5.24±0.99) h; t1/2z were (4.59±1.48) h and (6.40±3.22) h; Tmax were(2.71±1.91) h and (.88±1.05) h; CLz/F were (5.01±1.56) L·h-1and (2.34±0.97) L·h-1; Vz/F were (2.76±16.65)L and (20.41±11.01) L; Cmax were (3469.43±1420.15) ng·L-1and (5280.54±2036.03) ng·mL-1.Good linearity of uric acid (y=0.9995) in human serum was obtained between1.667and166.667μg·mL-1with good accuracy and reproducibility. Good linearity of xanthine (γ=0.9994) in human serum was obtained between0.033and3.338μg·mL-with good accuracy and reproducibility. Good linearity of hypoxanthine (y=0.9996) in human serum was obtained between0.033and3.338μg·mL-1with good accuracy and reproducibility. Intra-and inter-day validation were both less than15%.Conclusion:In the single dose effect studies, pharmacokinetic parameters (Cmax, AUC0-t and AUC0-∞) had good linear relationships with doses; in the multiple dose effect studies, there appeared to be no consistent change in the volume of distribution with increasing doses and with administration of multiple doses. Therefore, increasing the dose and administration of multiple doses did not appear to affect the tissue distribution of febuxostat; after oral administration of80-mg febuxostat under fasting (reference) or fest (test) conditions, even though food caused a decrease in the rate and extent of absorption of febuxostat, this decrease was not associated with a clinically significant change in febuxostat pharmacodynamic effect. Therefore, febuxostat can be administered regardless of food intake; in the single and multiple doses effect studies, some pharmacokinetic parameters showed a significant difference between male and female. None adverse event was reported during the studies, showed febuxostat was well tolerated.A rapid, accurate and specific method was developed and validated for the determination of uric acid, xanthine and hypoxanthine in human serum. It was suitable for the pharmacodynamic studies of febuxostat.