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PHARMACOKINETICS AND PHARMACODYNAMICS |
From TAP Pharmaceutical Products Inc, Lake Forest, Illinois. All authors are employees of TAP Pharmaceutical Products Inc.
Address for reprints: Reza Khosravan, PhD, Department of Drug Metabolism and Pharmacokinetics, TAP Pharmaceutical Products Inc, 675 North Field Drive, Lake Forest, IL 60045.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Febuxostat • pharmacokinetics • pharmacodynamics • xanthine oxidase • hepatic impairment
Management of hyperuricemia in gout utilizes inhibitors of xanthine oxidase (XO), uricosuric agents, or uricase. These agents lower uric acid concentrations in serum by inhibiting the production of uric acid (ie, inhibitors of XO) or by increasing the clearance of uric acid from the body (ie, uricosurics or uricase). In the United States, inhibitors of XO are the most widely prescribed category of drugs for the management of hyperuricemia in patients with gout. Currently, allopurinol is the only inhibitor of XO commercially available for the management of hyperuricemia associated with gout.
Febuxostat (2-[3-cyano-4-(2-methylpropoxy)-phenyl]-4-methylthiazole-5-carboxylic acid) (Figure 1A), a potent novel nonpurine selective inhibitor of XO, was shown to have great efficacy in lowering serum uric acid concentrations in animals.6-10 Studies in healthy subjects and subjects with hyperuricemia associated with gout have confirmed the ability of febuxostat to reduce serum uric acid concentrations in a dose-dependent manner.11-14
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99%) and appears to have a low to medium apparent volume of distribution at steady state of approximately 0.7 L/kg.13,15 The pharmacokinetics of febuxostat after a single dose appears to be linear in the 10-mg to 120-mg once-daily dose range.13 Febuxostat is mainly metabolized to its acyl-glucuronide metabolite and to its active oxidative metabolites 67M-1, 67M-2, and 67M-4 (Figure 1).13,16 Therefore, hepatic metabolism plays an important role in elimination of febuxostat from the body. Hepatic impairment is one of the medical conditions occasionally associated with gout that can affect the metabolism as well as the biliary excretion of different drugs. Because febuxostat is mainly metabolized by the hepatic system, it was important to investigate the effect of hepatic impairment on the pharmacokinetics, pharmacodynamics, and safety of febuxostat.17,18
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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All subjects received an 80-mg daily dose of febuxostat for 7 consecutive days. Blood and urine samples were collected for determination of pharmacokinetic and pharmacodynamic parameters.
Subjects
Study enrollment began after institutional review board (IRB) approval (Southern Institutional Review Board, Miami, Fla, and Human Subjects Research Committee, Minneapolis, Minn). Eligible male and female subjects between 30 and 70 years of age, inclusive, were allowed to enroll in the study after signed informed consent was obtained. With the exception of existing hepatic impairment (confirmed by a previous liver biopsy specimen or liver spleen scan) for subjects in groups II and III, subjects had no unstable concurrent disease and were generally in good health with a body mass index ranging from 17.2 to 36.1 kg/m2. Female subjects were either postmenopausal, surgically sterile, or using a medically accepted means of contraception. Subjects were excluded if they had a history (within the past 12 months) of alcohol and/or drug abuse, had a positive drug or alcohol screening result at the screening visit or on day –1, had hepatic cancer, or were diagnosed with gout. In addition, subjects were excluded if they had changes in prescription drug regimen(s) within 4 weeks before the initial dose of the study drug, were taking a urate-lowering medication within 2 weeks before the initial dose of the study drug, or had received any investigational drug within 4 weeks before the initial dose of the study drug. Female subjects were excluded from the study if they were pregnant or nursing a child. On the day before the study initiation, eligible subjects were to have a normal estimated creatinine clearance using Cockcroft-Gault formula.21
Drug Administration
An 80-mg oral dose of febuxostat, administered as four 20-mg tablets (manufactured by Teijin Ltd, Tokyo, Japan), was given to the 3 groups of subjects once daily at approximately 8:00 AM for 7 consecutive days after an overnight fast.
Sample Collection
Blood
Venous blood samples (5 mL) for the determination of plasma concentrations of febuxostat and its metabolites 67M-1, 67M-2, and 67M-4 were obtained before dosing on days 1 to 7 and after administration of the last dose of febuxostat (day 7) at specified times (0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours). Blood samples were stored on ice and centrifuged for plasma collection. The plasma samples were promptly frozen and stored at –20°C until shipped on dry ice to the bioanalytical laboratory where they were stored at –20°C until analyzed. Additional blood samples (5 mL) for the determination of uric acid, xanthine, and hypoxanthine in serum were obtained 24, 18, and 12 hours before the day 1 dose; before dosing on days 1 to 7; and 6, 12, and 24 hours after dosing on day 7. The samples remained at room temperature for 30 minutes to allow them to clot. The blood specimens were then centrifuged for serum collection. The resulting serum samples were immediately frozen and stored at –70°C until shipped on dry ice to the bioanalytical laboratory where they were stored at –70°C until analyzed. Blood samples were also obtained for clinical laboratory testing (eg, hematology/serum chemistry) at screening, days –1, 4, 6, 7, and on completion of the study on day 8.
Urine
Urine was collected during the following intervals: 24 to 18, 18 to 12, and 12 to 0 hours before dosing on day 1, and 0 to 6, 6 to 12, and 12 to 24 hours after dosing on day 7. During each collection interval, urine was refrigerated or stored on ice. After thoroughly mixing all the urine collected for each subject during each interval, the total volume and pH of the urine sample were recorded. From each composite urine sample for each collection interval, a 20-mL aliquot was removed for the determination of febuxostat and its metabolites 67M-1, 67M-2, and 67M-4 in urine. The urine aliquot was then promptly frozen and stored at –20°C until shipped on dry ice to the bioanalytical laboratory where it was stored at –20°C until analyzed. Subsequently, sodium hydroxide (10 N, 1% of the urine sample volume) was added to the remaining urine sample to raise the pH to above 10. A 20-mL aliquot of the pH-adjusted urine sample was removed for the determination of urinary uric acid, xanthine, and hypoxanthine concentrations. These aliquots were immediately frozen and stored at –70°C until shipped on dry ice to the bioanalytical laboratory where they were stored at –70°C until analyzed.
Plasma Protein Binding
The in vitro protein binding of [14C]febuxostat was determined in predose plasma samples that were analyzed in triplicate using an equilibrium dialysis technique. Plasma samples (1 mL), fortified with [14C]febuxostat at a nominal concentration of 1 µg/mL, were added to Teflon dialysis cells separated by dialysis membranes (Spectrum/Por Type 2, 12 000-14 000 molecular weight cutoff, 47 mm) and dialyzed against dialysis buffer (1 mL, pH 7.4, 80 mM phosphate buffer). Equilibrium dialysis was performed at approximately 37°C with the cells rotating at approximately 20 revolutions per minute for 2 hours. The dialyzed samples were withdrawn from the cells, and aliquots of the samples were mixed with a scintillation cocktail and analyzed by counting for 5 minutes using a scintillation counter.
Analytical Methods
Plasma Febuxostat
Plasma concentrations of febuxostat were measured using a validated high-performance liquid chromatography (HPLC) with fluorescence detection method. After addition of internal standard (2-naphthoic acid), plasma samples (0.5 mL) were deproteinized by the addition of 0.5 mL acetonitrile, mixed, centrifuged, and the resulting supernatant was acidified with 50 µl of glacial acetic acid. Febuxostat and the internal standard were resolved from the matrix components using a Phenomenex (Torrance, Calif) Capcell Pak C18 column with a mobile phase composed of 0.032% glacial acetic acid in water:acetonitrile (55:45, volume:volume [v:v]) delivered at a flow rate of 1 mL/min. Febuxostat was measured using fluorescence detection at excitation and emission wavelengths of 320 and 380 nm, respectively. The standard curve range for febuxostat was linear from 0.01 to 20 µg/mL. The interday coefficients of variation (CVs) for quality control (QC) samples (at 0.03, 1, and 15 µg/mL) were 
16.3%. There was one anomalous value for a febuxostat 0.03 µg/mL QC sample that caused the CV to be greater than 15% for that QC level. However, the curve that contained the anomalous value met the standard and QC acceptance criteria and the data were therefore included in the data set.
Plasma Metabolites 67M-1, 67M-2, and 67M-4
A validated HPLC-tandem mass spectrometry method was used to measure plasma concentrations of febuxostat metabolites 67M-1, 67M-2, and 67M-4. After addition of internal standards (deuterated 67M-1, 67M-2 and 67M-4), 0.2 mL plasma samples were deproteinized by the addition of 0.2 mL ammonium acetate and 1.0 mL of acetonitrile, mixed, incubated for 60 minutes at 2°C to 8°C, and then centrifuged at 10°C. The resulting supernatant was evaporated, reconstituted with 0.1 mL acetonitrile/0.1% formic acid (25:75, v:v), and recentrifuged, and the supernatant was injected. The metabolites and the internal standards were resolved from the matrix components using a Keystone (Bellefonte, Pa) BDSHypersil C8 50 x 2-mm column with a mobile phase composed of 25% acetonitrile and 75% water (0.1% formic acid) delivered at a flow rate of 0.40 mL/min. The standard curves for each metabolite were linear from 0.5 to 100 ng/mL. The interday CVs of QC samples (at 1.5, 15, and 75 ng/mL) were 6.7%, 5.4%, and 9.2% for 67M-1, 67M-2, and 67M-4, respectively.
Serum Uric Acid, Xanthine, and Hypoxanthine
Serum concentrations of uric acid, xanthine, and hypoxanthine were measured using a validated HPLC with ultraviolet (UV) detection method. After the addition of the internal standard (uridine), samples (0.1 mL) were diluted with potassium phosphate and filtered through Amicon (Bedford, Ma) Centrifree filters before injection. Uric acid, xanthine, hypoxanthine and the internal standard were separated using a Shiseido (Tokyo, Japan) Capcell Pak C18, UG120, 5 µm, 4.6 x 250-mm analytical column maintained at 35°C. The mobile phase was composed of 47 mM potassium phosphate monobasic delivered at a flow rate of 1.0 mL/min and measured by a UV detector at a wavelength of 250 nm. The standard curve for serum uric acid was linear from 10 to 1000 µmol/L and the standard curves for serum xanthine and hypoxanthine were linear from 0.2 to 20 µmol/L. The interday CVs of the QC samples were 4.7% for uric acid (at 30, 150, and 750 µmol/L), 14.5% for xanthine (at 0.6, 3, and 15 µmol/L), and 7.5% for hypoxanthine (at 0.6, 0.73, 3, and 15 µmol/L).
Urine Unchanged and Total Febuxostat
A validated HPLC method with fluorescence detection was used to measure urinary unchanged and total (unchanged plus conjugated) febuxostat concentrations. For unchanged febuxostat, after the addition of the internal standard (2-naphthoic acid), urine samples (0.5 mL) were deproteinized by adding 1.0 mL acetonitrile, mixed, and centrifuged, and the resulting supernatant was acidified with acetic acid before injection. For total febuxostat, urine samples (0.2 mL) were incubated with 2 N sodium hydroxide (NaOH) for 30 minutes (base hydrolysis); then 2 N hydrochloric acid (HCl) was added to neutralize sample pH. The hydrolyzed samples were then extracted with acetonitrile as above. Febuxostat and the internal standard were resolved from the matrix components on a Phenomenex Capcell Pak C18 column with a mobile phase composed of 0.032% glacial acetic acid in water:acetonitrile (45:55, v:v) delivered at a flow rate of 1 mL/min. Febuxostat was measured using fluorescence detection at excitation and emission wavelengths of 320 and 380 nm, respectively. The standard curve range for unchanged febuxostat was linear from 0.02 to 20 µg/mL, whereas that for total febuxostat was linear from 0.05 to 100 µg/mL. The interday CVs of the QC samples were 8.6% for unchanged febuxostat (at 0.06, 1, and 15 µg/mL) and 4.1% for total febuxostat (at 0.15, 10, and 75 µg/mL).
Urine Unchanged and Total 67M-1, 67M-2, and 67M-4
A validated HPLC-tandem mass spectrometry method was used to measure concentrations of unchanged and total febuxostat metabolites 67M-1, 67M-2, and 67M-4 in urine. After the addition of internal standards (deuterated 67M-1, 67M-2, and 67M-4), 0.2 mL urine samples for the determination of unchanged 67M-1, 67M-2, and 67M-4 were deproteinized by the addition of ammonium acetate and 0.2 mL of acetonitrile, mixed, incubated for 60 minutes at 2°C to 8°C, and then centrifuged at 10°C. The resulting supernatant was evaporated, reconstituted with 0.2 mL acetonitrile/0.25 mL 0.1% aqueous formic acid, and recentrifuged, and the supernatants were injected. For total 67M-1, 67M-2, and 67M-4, after addition of the internal standards, urine samples (0.2 mL) were incubated with 2 N NaOH for 60 minutes at 37°C (base hydrolysis); then 2 N HCl was added to neutralize the sample pH. The hydrolyzed samples were then extracted with acetonitrile as above. The metabolites and the internal standards were resolved from the matrix components on a Keystone BDSHypersil-C8 50 x 2-mm column with a mobile phase composed of 25% acetonitrile and 75% water (0.1% formic acid) delivered at a flow rate of 0.40 mL/min. The standard curve range for the unchanged metabolites was linear from 0.5 to 100 ng/mL, whereas that for the total metabolites was linear from 5 to 500 ng/mL. The interday CVs of the QC samples (at 1.5, 15, and 75 ng/mL) were 11.4% for unchanged 67M-1, 11.8% for unchanged 67M-2, and 6.5% for unchanged 67M-4. In addition, the interday CVs of the QC samples (at 15, 45, and 375 ng/mL) were 5.8% for total 67M-1, 5.8% for total 67M-2, and 7.0% for total 67M-4.
Urine Uric Acid, Xanthine, and Hypoxanthine
A validated HPLC-tandem mass spectrometry method was used to measure urinary concentrations of uric acid, xanthine, and hypoxanthine. After the addition of the internal standards (15N2-xanthine, 15N2-hypoxanthine, and 15N2-uric acid), samples (0.1 mL) were diluted with potassium phosphate, acidified with the addition of HCl, and centrifuged, and the supernatant was injected. Uric acid, xanthine, hypoxanthine, and the internal standards were resolved from the matrix components using an Agilent (Palo Alto, Calif) Zorbax Bonus-RP, 150 x 4.6-mm, 5 µm column with a mobile phase composed of 50 mM ammonium acetate, pH 4.5, delivered at a flow rate of 0.50 mL/min. The standard curve for uric acid was linear from 100 to 4500 µmol/L, and the standard curves for xanthine and hypoxanthine were linear from 10 to 1000 µmol/L. The interday CVs of the QC samples were 8.9% for uric acid (at 300, 1250, 3375, and 3395 µmol/L), 6.8% for xanthine (at 30, 67, 200, and 750 µmol/L), and 18.2% for hypoxanthine (at 30, 70, 200, and 750 µmol/L). There was one anomalous value for a hypoxanthine 200 µmol/L QC sample that caused the CV to be greater than 15% for that QC level. However, the curve that contained the anomalous value met the standard and QC acceptance criteria, and the data was therefore included in the data set.
Pharmacokinetic Analyses
For febuxostat and its metabolites 67M-1, 67M-2, and 67M-4, pharmacokinetic parameters were estimated by standard noncompartmental methods using WinNonlin Professional V.3.1 (Pharsight Corp, Mountain View, Calif). The observed peak plasma concentration (Cmax) and the time to reach the peak concentration (tmax) were taken directly from the plasma-concentration time data. The observed Cmax for unbound febuxostat (Cmax,u) was estimated as the product of the Cmax and the fraction of unbound febuxostat in plasma (fu). The apparent terminal elimination rate constant (
z) was estimated using least-squares regression analysis of the terminal log-linear portion of the plasma-concentration time profile, with the terminal portion identified by visual inspection. The apparent terminal-phase elimination half-life (t
z) was calculated as ln(2)/z. The area under the plasma concentration versus time curve for the dosing interval (AUC24) was calculated by the linear trapezoidal method. The area under the plasma concentration time curve for unbound febuxostat (AUC24,u) was estimated as the product of the AUC and the fraction of fu. Apparent steady-state clearance (CL/F) was calculated as Dose/AUC24. Apparent CL/F for unbound febuxostat was calculated as Dose/AUC24,u. The amount of drug excreted in the urine during the 24-hour collection interval (Ae24), the fraction of the dose excreted in urine over 24 hours expressed as a percentage (fe), and the renal clearance (CLR) were also determined for febuxostat and its metabolites 67M-1, 67M-2, and 67M-4.
Pharmacodynamic Analyses
The area under the serum concentration versus time curve for serum uric acid, xanthine, and hypoxanthine was estimated using standard noncompartmental methods using WinNonlin Professional V.3.1. The 24-hour mean serum concentration (Cmean,24) was calculated by dividing the area under the serum concentration versus time curve from time zero to 24 hours by 24. The urinary pharmacodynamic parameters that were estimated included Cmean,24,Ae24, and CLR for uric acid, xanthine, and hypoxanthine.
Safety Assessments
Safety and tolerability were assessed by the evaluation of subjects' vital sign measurements, 12-lead electrocardiogram (ECG), physical examination, clinical laboratory parameters, and adverse event monitoring.
Statistical Analyses
SAS System version 8.2 for Windows with the Windows NT operating system was used to perform the statistical analyses. All statistical tests were 2-sided at significance level of .05. The relationship between hepatic function and pharmacokinetic or pharmacodynamic parameters was assessed by analysis of variance (ANOVA) that included hepatic function group as the factor. The plasma pharmacokinetic parameters assessed were tmax, z, and natural logarithms of Cmax, Cmax,u (for febuxostat only), AUC24, and AUC24,u(for febuxostat only) for febuxostat and its metabolites. The urine pharmacokinetic parameters were Ae24 for unchanged and total febuxostat and metabolites and CLR for unchanged febuxostat and metabolites. The pharmacodynamic parameter assessed was percentage change from baseline in serum uric acid Cmean,24. The mean change or percentage change (for serum and urine uric acid) from baseline was tested versus 0 with a paired t test within each hepatic function group. Comparisons of pharmacokinetic and pharmacodynamic parameters of the mild and moderate hepatic impairment groups to the normal hepatic function group were performed within the framework of the ANOVA model.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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Safety
Febuxostat 80 mg once daily was well tolerated in each hepatic function group. The overall incidence of adverse events during dosing was higher for subjects in the moderate hepatic impairment (75%, 6 of 8) and mild hepatic impairment (63%, 5 of 8) groups as compared to subjects in the normal hepatic function group (25%, 3 of 12). The most common adverse events during the study were abdominal pain, diarrhea, headache, and urinary frequency. All adverse events were of mild intensity, and most were considered either possibly, probably, or definitely related to the study drug. The most frequent treatment-related adverse events observed during the study are summarized in Table II. There were no serious adverse events or clinically significant changes from baseline in laboratory values, physical examination, vital signs, or ECG readings during the study period.
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Plasma Protein Binding
[14C]Febuxostat was highly bound to plasma proteins from subjects in each hepatic function group. The mean percentage of unbound drug for subjects with mild and moderate hepatic impairment (0.7% and 0.6%, respectively) was similar to that for subjects with normal hepatic function (0.7%), as shown in Table III.
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Pharmacokinetics
Febuxostat
The mean concentration-time profiles for unbound febuxostat and for the metabolites in each hepatic function group on day 7, after the administration of a daily 80-mg oral dose of febuxostat for 7 days, are shown in Figure 2. Mean plasma pharmacokinetic parameters for febuxostat and its metabolites for each hepatic function group are summarized in Table III. The median time to reach the maximum observed concentration of febuxostat was 1.00 hour for subjects with normal hepatic function, and 1.00 and 0.75 hours for subjects with mild or moderate hepatic impairment, respectively. Mean unbound Cmax values were approximately 24% higher for subjects with mild and moderate hepatic impairment compared to subjects with normal hepatic function. Likewise, the extent of total plasma exposure to unbound febuxostat was approximately 28% and 24% higher for subjects with mild and moderate hepatic impairment, respectively. Elimination half-lives were similar for each hepatic function group, with t harmonic means ranging from 4.9 to 5.5 hours. Mean CL/F values, however, were 28% and 13% lower in subjects with mild and moderate hepatic impairment, respectively, compared to those with normal hepatic function. Although differences were observed for tmax, Cmax,u, AUC24,u, and tz between subjects with mild or moderate hepatic impairment and subjects with normal hepatic function after the administration of daily 80-mg oral doses of febuxostat for 7 days, none of the differences was statistically significant (P > .05).
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z values were similar between the hepatic function groups and ranged from 4.7 to 5.7 hours for 67M-1, from 5.0 to 7.7 hours for 67M-2, and from 5.0 to 6.7 hours for 67M-4. Although differences were observed for tmax, Cmax, AUC24, and z between subjects with mild or moderate hepatic impairment and subjects with normal hepatic function after the administration of daily 80-mg oral doses of febuxostat for 7 days, none of the differences was statistically significant (P > .05). The mean fe as 67M-1, 67M-2, and 67M-4 decreased from 3.7% to 2.7%, from 3.2% to 2.4%, and from 2.1% to 1.5%, respectively, comparing subjects with moderate hepatic impairment to subjects with normal hepatic function (Figure 3A). Renal clearance ranged from 13.2 to 18.7 L/h for 67M-1, from 11.5 to 14.9 L/h for 67M-2, and from 9.2 to 10.5 L/h for 67M-4 among the hepatic function groups (Figure 4A). None of these differences was statistically significant (P > .05). Similar to that for unchanged 67M-1, 67M-2, and 67M-4, the urinary excretion of total (unchanged plus conjugated) 67M-1, 67M-2, and 67M-4 tended to decrease with increasing hepatic impairment (Figure 3B). The mean fe as total 67M-1 decreased from 5.6% to 4.5%, total 67M-2 decreased from 4.2% to 3.4%, and total 67M-4 decreased from 2.5% to 1.8% for subjects with normal hepatic function compared to those with moderate hepatic impairment with none of the differences being statistically significant (P > .05).
Pharmacodynamics
Uric Acid
Mean serum pharmacodynamic parameters for uric acid, xanthine, and hypoxanthine are summarized in Table IV, and respective mean urinary pharmacodynamic parameters are summarized in Table V. Both baseline (day –1) and day 7 mean serum uric acid Cmean,24 values in subjects with normal hepatic function were lower than those in subjects with mild or moderate hepatic impairment. Based on the predose serum uric acid concentration data, steady-state serum uric acid concentrations appeared to have been reached by day 7 (Figure 5). After once-daily multiple dosing with febuxostat 80 mg, serum uric acid Cmean,24 values decreased by a mean of 62.5% (from 4.77 to 1.83 mg/dL) in subjects with normal hepatic function, and 48.9% (from 4.95 to 2.66 mg/dL) and 47.8% (from 5.45 to 2.85 mg/dL) in subjects with mild and moderate hepatic impairment, respectively. The percentage changes from the baseline were statistically significant (P .05) for each hepatic function group. Pairwise comparisons indicated the mean percentage change in serum uric acid Cmean,24 values for subjects with mild or moderate hepatic impairment were statistically significantly lower than the mean percentage change in serum uric acid Cmean,24 for subjects with normal hepatic function (P .005 for both comparisons). In conjunction with the decrease in serum uric acid concentrations, the day 7 mean percentage decrease in urinary uric acid Cmean,24 concentrations was 64.0%, 62.7%, and 42.5% for subjects with normal, mildly impaired, and moderately impaired hepatic function, respectively. These percentage changes from baseline were statistically significant (P .05) for each hepatic function group. Day 7 total daily uric acid excretion and the CLR of uric acid also decreased compared to baseline, and the decrease from the baseline in each parameter was lower in subjects with hepatic impairment compared to the decrease in those with normal hepatic function (Table V). All changes from baseline for day 7 urinary uric acid Ae24 were statistically significant (P .05) for each hepatic function group. Changes from baseline for day 7 urinary uric acid CLR were statistically significant (P .05) for subjects with normal hepatic function or mild hepatic impairment but not for subjects with moderate hepatic impairment.
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Xanthine
Serum xanthine baseline (day –1) Cmean,24 concentrations were slightly lower in subjects with normal hepatic function compared to those in subjects with hepatic impairment. After the administration of daily 80-mg oral doses of febuxostat for 7 days, serum xanthine Cmean,24 concentrations increased substantially, and the day 7 serum xanthine Cmean,24 changes from baseline were statistically significant (P .01) for each hepatic function group. There was also a substantial increase in urinary xanthine Cmean,24 concentrations on day 7 compared to baseline for each hepatic function group. In conjunction with the increase in xanthine serum concentrations, there was also an increase in total daily xanthine excretion and the CLR of xanthine. All changes from baseline for day 7 urinary xanthine Cmean,24, Ae24, and CLR, were statistically significant (P .05) for each hepatic function group, and the increase from the baseline in each parameter was lower in subjects with hepatic impairment compared to the increase in those with normal hepatic function.
Hypoxanthine
Baseline serum hypoxanthine Cmean,24 concentrations were higher in subjects with normal hepatic function compared to subjects with mild or moderate hepatic impairment. After the administration of daily 80-mg oral doses of febuxostat for 7 days, serum hypoxanthine concentrations did not change substantially, and none of the changes from baseline was statistically significant (P > .05) for any of the hepatic function groups. Baseline urinary concentrations of hypoxanthine were generally lower in subjects with normal hepatic function compared to those with hepatic impairment. After the administration of daily 80-mg febuxostat doses for 7 days, urinary hypoxanthine Cmean,24 concentrations increased substantially for each hepatic function group. However, the magnitude of the increase was less than that observed for xanthine. Likewise, the mean total daily excretion and CLR of hypoxanthine increased from baseline after administration of febuxostat for 7 days. All changes from baseline for day 7 urinary hypoxanthine Cmean,24, Ae24, and CLR, were statistically significant (P .05) and similar for each hepatic function group.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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The febuxostat pharmacokinetic data showed slight increases in both Cmax,u, AUC24,u, and fe mean values with hepatic impairment. In addition, the metabolite-to-drug AUC ratio mean values were slightly lower in subjects with hepatic impairment despite lower 67M-1 and 67M-2 mean CLR values in hepatic impairment groups as compared to the normal hepatic function group. The unchanged and total 67M-1, 67M-2, and 67M-4 mean fe values also seemed to be slightly lower in hepatic impairment groups (Figures 3A and 3B). The slight increase in febuxostat fe mean values, associated with a slight decrease in metabolite to drug AUC ratios and the unchanged and total metabolites fe mean values, indicate a slight decrease in phase I metabolism of febuxostat in subjects with hepatic impairment.
Although phase II metabolism can also be compromised in subjects with hepatic impairment,22,23 this study showed that the total febuxostat Ae24 (and fe) mean values were statistically significantly higher in subjects with hepatic impairment as compared to subjects with normal hepatic function. The higher renal excretion of total febuxostat in hepatically impaired subjects could possibly be because of a lower phase I metabolic clearance of febuxostat and/or a lower biliary clearance of the conjugated febuxostat. A lower phase I metabolic clearance of febuxostat would most likely lead to a greater fraction of the dose undergoing phase II metabolism; hence, a higher renal excretion of the conjugated and consequently total febuxostat. Although a higher total febuxostat Ae24 or fe may reflect a slight decrease in phase I metabolism of febuxostat, the decrease in the phase I metabolism of febuxostat (ie, the decrease in the sum of total 67M-1, 67M-2, and 67M-4 Ae24 values) does not sufficiently account for the increase in total febuxostat Ae24. Therefore, it is likely that the increase in the total febuxostat Ae24 was also the result of a decrease in the biliary excretion of conjugated febuxostat. A lower biliary clearance of the conjugated febuxostat would ultimately lead to a higher renal excretion of total febuxostat.
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Because febuxostat is expected to undergo enterohepatic recycling, a lower biliary excretion of conjugated febuxostat will result in a lower plasma exposure to febuxostat. Despite a potentially lower biliary excretion of conjugated febuxostat in subjects with hepatic impairment as compared to those with normal hepatic function that could have had a decreasing effect on the total plasma exposure to febuxostat, the AUC24 and AUC24,u mean values were slightly higher in subjects with hepatic impairment as compared to subjects with normal hepatic function. Because any decrease in the biliary excretion of conjugated febuxostat will have a normalizing effect on any increase in the AUC of febuxostat, the percentage increase in febuxostat Cmax and AUC24,u may underestimate the extent of decrease in phase I and phase II metabolism of febuxostat in subjects with hepatic impairment as compared to subjects with normal hepatic function.
This study did not include subjects with severe hepatic impairment because these subjects were more likely to have comorbid conditions that might have confounded the analyses. The findings from this study, however, provided some insights as to how severe hepatic impairment may alter the pharmacokinetics of febuxostat. In severe hepatic impairment, one would expect a greater decrease in the metabolism of febuxostat to cause a greater increase in the plasma exposure to febuxostat. However, the effect of a decrease in metabolism of febuxostat on total exposure to febuxostat could be counteracted by the effects of a decrease in the biliary excretion of conjugated febuxostat.
Pharmacodynamics
After multiple dosing with febuxostat, there was a statistically significant decrease from baseline in the serum and urine uric acid Cmean,24 mean values in each hepatic function group. The decrease in serum uric acid concentrations occurred despite slight decreases from the baseline in uric acid CLR mean values in each hepatic function group. The relative decrease in the CLR of uric acid may be the result of the competitive inhibition of the active renal secretion of uric acid by xanthine.26
In conjunction with the decrease in serum and urinary uric acid concentrations, there was a substantial increase from baseline in serum and urinary xanthine Cmean,24 mean values in each hepatic function group. The increase in serum xanthine concentrations was despite substantial increases in xanthine CLR from the baseline. In the purine metabolic pathway, xanthine is produced from hypoxanthine by XO and also from guanine by guanase. Subsequently, xanthine is metabolized to uric acid by XO,27 with only a small fraction being excreted unchanged renally. Because a portion of xanthine is produced from guanine, it is not surprising to see a substantial increase in serum xanthine concentration with XO inhibition.
There appeared to be no notable change from baseline in serum concentrations of hypoxanthine in each hepatic function group attributable to the increase in the CLR of hypoxanthine as well as a possible decrease in the net production of hypoxanthine. A decrease in the net production of hypoxanthine could be the result of a decrease in amidophosphoribosyltransferase activity, the rate-limiting step in the generation of hypoxanthine from the de novo pathway.27
Based on the pharmacodynamic results from this study, there was a statistically significantly lower mean percentage decrease in serum uric acid Cmean,24 values in subjects with hepatic impairment as compared to subjects with normal hepatic function. This lower percentage decrease in serum uric acid was despite slightly higher maximum and total exposure to unbound febuxostat in hepatic impairment groups as compared to the normal hepatic group. After multiple dosing with febuxostat, the percentage decrease in serum uric acid concentration will be affected by the percentage inhibition of XO as well as the relative increase in serum xanthine concentrations and the relative decrease in uric acid clearance. The percentage inhibition of XO would be dependent on the concentration of unbound febuxostat. Higher concentrations of unbound febuxostat would more than likely cause a higher percentage inhibition of XO and ultimately a greater percentage decrease in serum uric acid concentrations. As a result, it is very unlikely that the lower percentage decrease in serum uric acid in subjects with mild and moderate hepatic impairment was related to any differences in the inhibition of the XO. After multiple dosing with febuxostat, it is expected that the greater the relative increase in serum xanthine concentrations, the smaller the percentage decrease in serum uric acid will be for the same level of inhibition of the enzyme. In this study, however, the relative increase in serum xanthine Cmean,24 mean values appeared to be slightly lower in the hepatic impairment groups as compared to the normal hepatic group. Therefore, it is also unlikely that the lower percentage decrease in serum uric acid Cmean,24 in subjects with hepatic impairment was because of a difference in the relative increase in serum xanthine concentrations. Finally, a relative decrease in uric acid total body clearance (ie, renal plus nonrenal clearance) could have affected the percentage decrease in serum uric acid after multiple doses of febuxostat. The greater the relative decrease in total body clearance of uric acid, the lower the percentage decrease in serum uric acid will be. Even though the extent of the relative decrease in the CLR of febuxostat appeared to be smaller, it is possible that there was a greater relative decrease in nonrenal clearance of uric acid in the hepatic impairment groups as compared to the normal group after multiple dosing with febuxostat. It has been shown that a substantial amount of uric acid is transported into the bile in the liver.28 There is also the possibility that xanthine or even febuxostat or some of its metabolites may be using the same biliary transport system, which may be more easily saturable in subjects with hepatic impairment, and hence, more likely to cause a decrease in the biliary clearance of uric acid. Therefore, the decrease in total body clearance of uric acid may have been more pronounced in subjects with hepatic impairment, leading to a lower percentage decrease in serum uric acid concentrations.
At the end, despite statistically significant differences between the mean percentage decrease in serum uric acid Cmean,24 in subjects with hepatic impairment as compared to that in subjects with normal hepatic function, these differences were relatively small (13% to 14%) and were not considered clinically significant. In fact, the results from other phase I studies in which normal healthy subjects received the same dosing regimen showed percentage decreases in serum uric acid of 58.2% ± 11.1%, 54.9% ± 7.5%, and 51.2% ± 14.3%.26,29,30 These mean values were slightly lower than those observed in the normal hepatic group (ie, 62.5 ± 7.5%) and closer to those observed in the mild and moderate hepatic function groups (ie, 48.9 ± 13.5% and 47.8 ± 6.8%, respectively). Therefore, from a clinical standpoint, the lower percentage decreases in serum uric acid in subjects with hepatic impairment does not require any dose adjustments.
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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Parts of the results were presented at the 68th annual scientific meeting of the American College of Rheumatology in 2004 and will be presented at the 34th annual meeting of the American College of Pharmacology in 2005.
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REFERENCES |
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