To assess the safety, pharmacokinetics, and pharmacodynamics of febuxostat in subjects with normal renal function or renal impairment, febuxostat (80 mg/d) was orally administered for 7 days to subjects with normal renal function (n = 11, CLcr >80 mL/min/1.73 m) or to subjects with mild (n = 6, CLcr 50-80 mL/min/1.73 m), moderate (n = 7, CLcr 30-49 mL/min/1.73 m), or severe renal impairment (n = 7, CLcr 10-29 mL/min/1.73 m). The pharmacokinetics of febuxostat and its active quantifiable metabolites 67M-1, 67M-2, and 67M-4 as well as the pharmacodynamics of uric acid, xanthine, and hypoxanthine were determined in plasma (or serum) and urine. Febuxostat was safe and well tolerated. Regression analyses indicated that febuxostat tmax and Cmax,u values were not affected by CLcr. However, for AUC24,u, CLu/F, and t1/2z, regression analyses indicated a statistically significant relationship with CLcr. With the exception of 67M-1 Cmax, regression analyses for 67M-2 and 67M-4 Cmax, and for AUC24 for all 3 metabolites indicated a statistically significant linear relationship with CLcr. Irrespective of renal function group, the mean serum uric acid concentrations decreased by 55% to 64% by day 7. Although plasma exposure to febuxostat and its metabolites was generally higher in subjects with increasing degrees of renal impairment, the percentages of decrease in serum uric acid were comparable regardless of the renal function group. A once-daily 80-mg dose of febuxostat appears to be safe and well tolerated in different renal function groups and does not appear to require any dose adjustment based on differences in renal function.
Febuxostat was well tolerated at once-daily doses of 10-240 mg. There appeared to be a linear pharmacokinetic and dose-response (percentage decrease in serum uric acid) relationship for febuxostat dosages within the 10-120 mg range. Febuxostat was extensively metabolised and renal function did not seem to play an important role in its elimination from the body.
Two key bottlenecks in pharmaceutical bioanalysis are sample cleanup and chromatographic separations. Although multiple approaches have been developed in the past decade to either shorten or multiplex these steps, they remain the rate limiting steps as ADME (Absorption, Distribution, Metabolism, and Excretion) property screening is being routinely incorporated into the drug discovery process. In this work, a novel system incorporating an automated Direct Analysis in Real Time (DART) ionization source coupled with a triple-quadrupole mass spectrometer has been developed and evaluated for quantitative bioanalysis. This system has the capability of directly analyzing samples from their biological matrixes and therefore potentially eliminating the need for sample cleanup and chromatographic separations. A LEAP Technologies autosampler was customized to perform the automated sample introduction into the DART beam with high precision, which significantly improved the reproducibility of the method. Additional pumping was applied to the atmospheric pressure inlet on the mass spectrometer to compensate for the increased vacuum load because of the use of high-flow helium by the DART. This resulted in an improvement of detection sensitivity by a factor of 10 to 100 times. Matrix effects for a diversified class of compounds were evaluated directly from untreated raw plasma and were found to range from approximately 0.05 to 0.7. Precision and accuracy were also tested for multiple test compounds over a dynamic range of four orders of magnitude. The system has been used to analyze biological samples from both in vivo pharmacokinetic studies and in vitro microsomal/S9 stability studies, and the results generated were similar to those obtained with conventional LC/MS/MS methods. Overall, this new automated DART-triple quadrupole mass spectrometer system has demonstrated significant potential for high-throughput bioanalysis.
Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite rigorous exclusion or control of known disease, polymorphisms (CYP2C19, CYP3A5, ABCB1, PON1), noncompliance, co-medications, diet, smoking, alcohol, demographics, and pre-treatment platelet hyperreactivity. Thus, as yet unidentified factors contribute to high on-treatment platelet reactivity with its known increased risk of major adverse cardiovascular events. (A Study of the Effects of Multiple Doses of Dexiansoprazole, Lansoprazole, Omeprazole or Esomeprazole on the Pharmacokinetics and Pharmacodynamics of Clopidogrel in Healthy Participants: NCT00942175).
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