Pharmacokinetics, pharmacodynamics and safety of febuxostat, a non-purine selective inhibitor of xanthine oxidase, in a dose escalation study in healthy subjects.

BACKGROUND: Febuxostat is a novel non-purine selective inhibitor of xanthine oxidase currently being developed for the management of hyperuricemia in patients with gout. OBJECTIVE: To investigate the pharmacokinetics, pharmacodynamics and safety of febuxostat over a range of oral doses in healthy subjects. METHODS: In a phase I, dose-escalation study, febuxostat was studied in dose groups (10, 20, 30, 40, 50, 70, 90, 120, 160, 180 and 240 mg) of 12 subjects each (10 febuxostat plus 2 placebo). In all groups, subjects were confined for 17 days and were administered febuxostat once daily on day 1, and days 3-14. During the course of the study, blood and urine samples were collected to assess the pharmacokinetics of febuxostat and its metabolites, and its pharmacodynamic effects on uric acid, xanthine and hypoxanthine concentrations after both single and multiple dose administration. Safety measurements were also obtained during the study. RESULTS: Orally administered febuxostat was rapidly absorbed with a median time to reach maximum plasma concentration following drug administration of 0.5-1.3 hours. The pharmacokinetics of febuxostat were not time dependent (day 14 vs day 1) and remained linear within the 10-120 mg dose range, with a mean apparent total clearance of 10-12 L/h and an apparent volume of distribution at steady state of 33-64 L. The harmonic mean elimination half-life of febuxostat ranged from 1.3 to 15.8 hours. The increase in the area under the plasma concentration-time curve of febuxostat at doses >120 mg appeared to be greater than dose proportional, while the febuxostat maximum plasma drug concentration was dose proportional across all the doses studied. Based on the urinary data, febuxostat appeared to be metabolised via glucuronidation (22-44% of the dose) and oxidation (2-8%) with only 1-6% of the dose being excreted unchanged via the kidneys. Febuxostat resulted in significant decreases in serum and urinary uric acid concentrations and increases in serum and urinary xanthine concentrations. The percentage decrease in serum uric acid concentrations ranged from 27% to 76% (net change: 1.34-3.88 mg/dL) for all doses and was dose linear for the 10-120 mg/day dosage range. The majority of adverse events were mild-to-moderate in intensity. CONCLUSION: 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.

The effect of mild and moderate hepatic impairment on pharmacokinetics, pharmacodynamics, and safety of febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase.

To assess the effect of hepatic impairment on the pharmacokinetics, pharmacodynamics, and safety of febuxostat at steady state, multiple once-daily 80-mg oral doses of febuxostat were administered to subjects with normal hepatic function and to subjects with mild or moderate hepatic impairment. There were no statistically significant differences in the plasma pharmacokinetic parameters for unbound febuxostat and its active metabolites between subjects with mild or moderate hepatic impairment and those with normal hepatic function. The percentage decrease in serum uric acid appeared to be lower in hepatic impairment groups (49% [mild] and 48% [moderate]) as compared to the normal hepatic group (62%). This lower percentage decrease was minimal and not considered clinically significant. Febuxostat 80 mg once daily appears to be generally safe and well tolerated in mildly and moderately impaired hepatic function groups, and dose adjustment is not required in subjects with mild to moderate hepatic impairment.

The effect of hepatic insufficiency on the safety and pharmacokinetics of paricalcitol (Zemplar).

BACKGROUND/AIMS: Paricalcitol is highly protein bound, extensively metabolized and eliminated primarily by hepatobiliary excretion. This study was designed to determine if hepatic disease alters the pharmacokinetics or affects the safety of paricalcitol. METHODS: Subjects with mild (n = 5) or moderate (n = 5) hepatic impairment, and subjects with normal hepatic function (n = 10) enrolled in and completed the study. Each subject was administered a single 0.24 microg/kg intravenous dose of paricalcitol, injected within 1 min. RESULTS: For both total and unbound paricalcitol, there were no statistically significant differences in the pairwise comparisons between hepatic function groups in paricalcitol concentration at 5 min postdose (C5) or area under the plasma concentration-time curve from time zero to infinity (AUC(0-infinity), except C5 of total paricalcitol between mild and moderate impairment groups (p = 0.02). Paricalcitol binding to plasma proteins was extensive in all hepatic function groups (mean values >99.7%); unbound fraction was greater in subjects with moderate impairment than either healthy subjects or subjects with mild impairment (p < 0.01). Paricalcitol appeared to be well tolerated both by healthy subjects and subjects with mild to moderate hepatic insufficiency. CONCLUSION: No adjustment of paricalcitol dose is required for subjects with mild to moderate hepatic impairment. However, caution should be exercised in extrapolating the results from this study to subjects with severe hepatic impairment.

Metabolism and excretion of [14C] febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase, in healthy male subjects.

Absorption, metabolism, and excretion of one 80 mg oral dose of [(14)C] febuxostat ([thiazole-4-(14)C] 2-[3-cyano-4-isobutoxyphenyl]-4-methyl-5-thiazolecarboxylic acid) were studied in 6 healthy subjects. Mean cumulative recovery in excreta was 94% (49% urine and 45% feces) of the dose over 9 days; 87% of the dose was profiled. Seventeen radioactive peaks were observed in urine and fecal chromatograms. Unchanged febuxostat contributed to a combined total in excreta of 10% to 18% of the dose, indicating that it was extensively metabolized and well absorbed. Metabolites were 67M-1 (10%) and 67M-2 (11%) hydroxylated febuxostat, febuxostat acyl-glucuronide (30%), 67M-4 di-carboxylic acid (14%), 67M-1 sulfate conjugate (3%), and dehydrated 67M-1/67M-2 acyl-glucuronide (0.5%). Febuxostat and these metabolites accounted for 82% of profiled dose; unidentified peaks individually contributed <1.3% of the dose. Febuxostat and total radioactivity plasma C(max) values were observed at 0.5 hour postdose, suggesting that febuxostat was quickly absorbed. At 4 hours postdose, plasma chromatographic profiles contained 6 peaks: febuxostat (85%), 67M-1 (4%), 67M-2 (5%), febuxostat acyl-glucuronide (4%), 67M-4 (1%), and 67M-1 sulfate (0.5%). Compared to total radioactivity, febuxostat accounted for 94% at C(max) and 83% of the area under the concentration-time curve (AUC) values. Based on the whole blood to plasma total radioactivity, little radioactivity was associated with red blood cells.

Metabolism and disposition of the HIV-1 protease inhibitor lopinavir (ABT-378) given in combination with ritonavir in rats, dogs, and humans.

PURPOSE: The objective of this study was to examine the metabolism and disposition of the HIV protease inhibitor lopinavir in humans and animal models. METHODS: The plasma protein binding of [14C]lopinavir was examined in vitro via equilibrium dialysis technique. The tissue distribution of radioactivity was examined in rats dosed with [14C]lopinavir in combination with ritonavir. The metabolism and disposition of [14C]lopinavir was examined in rats, dogs, and humans given alone (in rats only) or in combination with ritonavir. RESULTS: The plasma protein binding of lopinavir was high in all species (97.4-99.7% in human plasma), with a concentration-dependent decrease in binding. Radioactivity was extensively distributed into tissues, except brain, in rats. On oral dosing to rats, ritonavir was found to increase the exposure of lopinavir-derived radioactivity 13-fold. Radioactivity was primarily cleared via the hepato-biliary route in all species (>82% of radioactive dose excreted via fecal route), with urinary route of elimination being significant only in humans (10.4% of radioactive dose). Oxidative metabolites were the predominant components of excreted radioactivity. The predominant site of metabolism was found to be the carbon-4 of the cyclic urea moiety, with subsequent secondary metabolism occurring on the diphenyl core moiety. In all the three species examined, the primary component of plasma radioactivity was unchanged lopinavir (>88%) with small amounts of oxidative metabolites. CONCLUSIONS: Lopinavir was subject to extensive metabolism in vivo. Co-administered ritonavir markedly enhanced the pharmacokinetics of lopinavir-derived radioactivity in rats, probably due to inhibition of presystemic and systemic metabolism, leading to an increased exposure to this potent HIV protease inhibitor.