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PHARMACOKINETICS AND PHARMACODYNAMICS

The Effect of Age and Gender on Pharmacokinetics, Pharmacodynamics, and Safety of Febuxostat, a Novel Nonpurine Selective Inhibitor of Xanthine Oxidase

Reza Khosravan, PhD, Michael J. Kukulka, BS, Jing-Tao Wu, PhD, Nancy Joseph-Ridge, MD and Laurent Vernillet, PharmD, PhD

From TAP Pharmaceutical Products Inc, Lake Forest, Illinois. Dr Khosravan is currently at Pfizer Global Research & Development, La Jolla Laboratories, San Diego, California. Dr Vernillet is currently at Genentech, Inc, 1 DNA Way, South San Francisco, California.

Address for reprints: Reza Khosravan, PhD, 10646 Science Center Drive, San Diego, CA 92121.


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 ACKNOWLEDGEMENTS
 REFERENCES
 
Febuxostat is a novel nonpurine selective inhibitor of xanthine oxidase, which is currently being developed for the management of hyperuricemia in patients with gout. The effect of age and gender on the pharmacokinetics, pharmacodynamics, and safety of once-daily oral febuxostat 80 mg was assessed in healthy male and female subjects after 7 days. Following multiple dosing with febuxostat, there were no statistically significant differences in the plasma or urinary pharmacokinetic or pharmacodynamic parameters between subjects aged 18 to 40 years and ≥65 years. Although unbound peak concentration (Cmax,u) and area under the concentration-time curve (AUC24,u) for febuxostat were higher in women as compared with men (31.5 vs 23.6 ng/mL, P ≤ .01, and 62.8 vs 53.9 ngxh/mL, P ≤ .05, for Cmax,u and AUC24,u, respectively), the differences were not considered clinically significant and could be largely accounted for by weight differences between male and female subjects. For pharmacodynamic parameters, even though the percentage decrease in serum uric acid 24-hour mean concentration was slightly greater in women than in men (59% vs 52%, P ≤ .01), this difference was not considered clinically meaningful. Febuxostat was well tolerated in male and female subjects in both age groups. Age or gender had no clinically significant effect on the pharmacokinetics, pharmacodynamics, or safety of febuxostat. Therefore, febuxostat does not require any dose adjustments based on age or gender.

Key Words: Age • febuxostat • gender • pharmacodynamics • pharmacokinetics

Gout is a common form of inflammatory arthritis that is caused by the deposition of monosodium urate crystals in joints, bones, and even parenchymal organs. If left untreated, gout may result in progressive disease characterized by joint and bone destruction from tophaceous deposits and renal impairment due to gouty nephropathy. Hyperuricemia has long been considered as the most important risk factor for the onset of gout1,2 and is clearly associated with its common manifestations.3 Hyperuricemia is best defined as extracellular fluid urate supersaturation, which reflects an enlarged body pool of uric acid and subsequent increased risk of monosodium urate crystal precipitation.4

The prevalence of gout, estimated to affect more than 5.1 million people in the United States,5 has been increasing over the past decade possibly due to an overall increase in levels of obesity and the aging population, both of which are important risk factors for the development of hyperuricemia.6,7

The key goal of gout management is the reduction of serum uric acid concentrations and subsequently the total uric acid pool in the body. As xanthine oxidase (XO) catalyzes the last 2 steps of purine catabolism (oxidation of hypoxanthine to xanthine and xanthine to uric acid), XO inhibitors have been used to reduce serum uric acid concentrations via reduced uric acid production. This is in contrast to uricosuric agents, which work by enhancing the urinary excretion of uric acid.8


Figure 1
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  		Figure 1. Chemical structures of febuxostat and metabolites 67M-1, 67M-2, and 67M-4.

 
Febuxostat (2-[3-cyano-4-(2-methylpropoxy)-phenyl]-4-methylthiazole-5-carboxylic acid; Figure 1A), a novel and potent selective inhibitor of XO, is currently under development for the management of hyperuricemia in patients with gout.9,10 Animal studies have shown that febuxostat is effective in lowering serum uric acid concentrations,9,11-14 and 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.10,15-17

In healthy human subjects, orally administered febuxostat is rapidly absorbed with a time to reach peak concentration (tmax) of approximately 1 hour. In addition, febuxostat is highly bound to albumin in blood (~99%) and appears to have a low to medium apparent volume of distribution at steady state of approximately 0.7 L/kg.10,18 A once-daily dose of febuxostat 10 to 120 mg displays linear pharmacokinetics10 and appears to be mainly metabolized to an acyl-glucuronide metabolite (via uridine diphosphoglucuronyl transferases 1A1, 1A3, 1A7, 1A8, 1A8, 1A9, 1A10, and 2B7) and to its active oxidative metabolites 67M-1, 67M-2, and 67M-4 (via cytochrome P-450 1A1, 1A2, 2C8, and 2C9; Figure 1B, C, and D).10,19 Thus, less than 5% of a dose of febuxostat is detected in urine as the parent drug. In addition, a dose of febuxostat 80 mg once daily has previously been shown to require no adjustment when administered to individuals with renal insufficiency20 or mild-to-moderate hepatic impairment.21

Because the incidence of gout increases with age, febuxostat may be a potential therapeutic agent for use in patients with gout who are older than 65 years and who may also have accompanying age-related changes relevant to drug pharmacokinetics, pharmacodynamics, and safety. In addition, because both men and women can suffer from hyperuricemia associated with gout, there is interest in whether gender may also have any effect on these parameters. Therefore, this study was performed to investigate the effect of age and gender on the pharmacokinetics, pharmacodynamics, and safety of febuxostat 80 mg once daily.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 ACKNOWLEDGEMENTS
 REFERENCES
 
Study Design
A phase 1, parallel-group, multiple-dose, open-label study was undertaken to investigate the pharmacokinetics, pharmacodynamics, and safety of febuxostat. Forty-eight healthy subjects were equally divided into 4 study groups: men aged 18 to 40 years inclusive, women aged 18 to 40 years inclusive, men aged ≥65 years, and women aged ≥65 years.

Subjects were admitted to the testing facility (SeaView Research, Miami, Florida) and supervised from day –2 until all study procedures were completed on day 8. The institutional review board of the participating medical center approved the protocol, and all subjects voluntarily gave written informed consent before any study-related procedure was initiated.

During the study, all subjects received oral febuxostat 80 mg (4 x 20-mg tablets; manufactured by Teijin Ltd, Tokyo, Japan) once daily for 7 consecutive days following an overnight fast of at least 8 hours. Subjects received scheduled meals provided by the testing facility and were not allowed to consume caffeine, alcohol, high-purine foods, grapefruit, or grapefruit juice. Blood and urine samples were collected for determination of pharmacokinetic and pharmacodynamic parameters.

Subjects
Male and female subjects aged 18 to 40 years inclusive or ≥65 years were allowed to enroll in the study. Inclusion criteria included good general health, no unstable concurrent disease, and a satisfactory overall condition based on the results of medical history, physical examination, laboratory tests, and a 12-lead electrocardiogram (ECG). Subjects were also required to have a body mass index ≤35 kg/m2. Female subjects had to be postmenopausal, surgically sterile, or using medically accepted contraception. All subjects were required to have serum creatinine concentrations within the reference range of 0.5 to 1.4 mg/dL for male subjects and 0.5 to 1.2 mg/dL for female subjects. Subjects with serum creatinine results beyond the laboratory reference range required approval to enroll.

Exclusion criteria included a diagnosis of gout, a history (within the past 12 months) of alcohol and/or drug abuse, or a positive drug or alcohol screening result. Subjects were also excluded if they had used any investigational drugs or prescription medications within 4 weeks (with the exception of oral contraceptives, hormone replacement therapy, or injectable contraceptives) or had used any over-the-counter medications within 1 week prior to the initial dose of study drug (with the exception of low-dose aspirin therapy for cardiovascular prophylaxis). Female subjects were excluded from the study if they were pregnant or nursing a child.

Sample Collection
Plasma, serum, and urine samples were collected for the determination of febuxostat, active febuxostat metabolites (67M-1, 67M-2, 67M-4), uric acid, xanthine, and hypoxanthine concentrations. These samples were analyzed at MDS Pharma Services (Lincoln, Nebraska). Venous blood samples (5 mL) collected predose (days 1-7) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours postdose on day 7 were stored on ice and centrifuged for plasma collection. Additional blood samples (5 mL) collected predose (days 1-7) and at 24, 18, and 12 hours prior to day 1 dose and 6, 12, and 24 hours postdose on day 7 were kept at room temperature for 30 minutes to allow them to clot. The blood specimens were then centrifuged for serum collection. The plasma and serum samples were immediately frozen and stored at approximately –70°C until analyzed.

During each collection interval (ie, 0- to 6-, 6- to 12-, and 12- to 24-hour intervals on day –1 and 7), 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 day 7 urine sample, a 20-mL aliquot was removed to allow determination of febuxostat and its metabolites 67M-1, 67M-2, and 67M-4. The urine aliquot was promptly frozen and stored at approximately –20°C until analyzed. Subsequently, sodium hydroxide (10 N, 1% of the urine sample volume) was added to the remaining urine sample to achieve pH >10. A 20-mL aliquot of the pH-adjusted urine sample was then removed for the determination of urinary uric acid, xanthine, and hypoxanthine concentrations. These aliquots were promptly frozen and stored at approximately –70°C until analyzed.

Plasma Protein Binding
The in vitro protein binding of [14C]febuxostat at a nominal concentration of 1 µg/mL was determined in predose plasma samples, obtained from an additional 15-mL venous blood sample from each subject on day 1 prior to dosing. Protein binding was determined using an equilibrium dialysis technique (ABC Laboratories, Columbia, Missouri).

Analytical Methods
All analytical methods used in this study have been previously reported.20-22 Briefly, plasma concentrations of febuxostat and its metabolites (67M-1, 67M-2, and 67M-4) were determined using a validated high-performance liquid chromatography (HPLC) method with fluorescence detection and mass spectrometric detection, respectively.20,21 Lower limits of quantitation were 10 ng/mL for febuxostat with a 0.5-mL sample and 0.5 ng/mL for each metabolite with a 0.2-mL plasma sample.

Serum concentrations of uric acid, xanthine, and hypoxanthine were determined using a validated HPLC with ultraviolet detection method.22 The lower limit of quantitation with a 0.1-mL serum sample was 10.0 µM for uric acid and 0.2 µM for xanthine and hypoxanthine.

Urine concentrations of febuxostat were determined using a validated HPLC method with fluorescence detection.20,21 Urinary unchanged and total (unchanged plus conjugated) febuxostat concentrations were measured. The lower limit of quantitation with a 0.2-mL urine sample was 20 ng/mL for unchanged febuxostat and 50 ng/mL for total febuxostat.

A validated HPLC method with tandem mass spectrometric detection was used to measure concentrations of unchanged and total febuxostat metabolites 67M-1, 67M-2, and 67M-4 in urine.20,21 Unchanged and total 67M-1, 67M-2, and 67M-4 each had a lower limit of quantitation of 0.5 ng/mL with a 0.2-mL urine sample.

Urinary concentrations of uric acid, xanthine, and hypoxanthine were measured using a validated HPLC method with mass spectrometric detection.20,21 The lower limit of quantitation with a 0.1-mL urine sample was 100 µM for uric acid and 10.0 µM for xanthine and hypoxanthine.

Quality control samples included in each analyte/matrix run met the acceptance criteria established for this study.

Pharmacokinetic Analyses
For febuxostat and its metabolites 67M-1, 67M-2, and 67M-4, pharmacokinetic parameters were estimated by standard noncompartmental methods using Win-Nonlin Professional V.3.1 (Pharsight Corporation, Mountain View, California). The observed peak plasma concentration (Cmax) and the time to reach Cmax (tmax) were taken directly from the plasma concentrationtime data. The observed peak plasma concentration for unbound febuxostat (Cmax,u) was estimated as the product of Cmax and the fraction of unbound febuxostat in plasma (fu). The apparent terminal-phase elimination rate constant ({lambda}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 (t1/2z) was calculated as ln(2)/{lambda}z. The areas under the plasma concentration versus time curve from time 0 to the last measurable concentration (AUCt) and for the dosing interval (AUC24) were calculated by the linear trapezoidal method. In situations in which the last quantifiable concentration (Ct) occurred before 24 hours, the extrapolated AUC to 24 hours (AUCt-24) was estimated according to the linear trapezoidal rule (AUC24 was calculated by adding AUCt to the extrapolated AUCt-24). The AUC for unbound febuxostat (AUC24,u) was estimated as the product of AUC and fu. Apparent clearance (CL/F) for febuxostat at steady state was calculated as dose/AUC24. Apparent clearance for unbound febuxostat (CLu/F) at steady state 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.

Pharmacodynamic Analyses
The area under the serum concentration versus time curve for uric acid, xanthine, and hypoxanthine was estimated by 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 0 to 24 hours (AUC24) by 24. Urinary pharmacodynamic parameters that were estimated included 24-hour mean concentration (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 (upon rising on days –1 and 8; upon rising and 90 minutes postdose on days 1 through 7), 12-lead ECG (days 1 and 7 [1 hour postdose]), physical examination (days 1 and 8), clinical laboratory parameters (days –1, 4, 7 predose, and 8), and adverse event monitoring throughout the entire study. All subjects who received at least 1 dose of study drug were included in the safety analyses.

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 a significance level of .05.

A 2-way analysis of variance (ANOVA) was used to investigate the effects of gender and age on febuxostat pharmacokinetic parameters. This ANOVA model included factors for age category, gender, and the interaction of age category and gender. Age was treated as a categorical variable, with subjects either in the younger (18-40 years) or the older (≥65 years) age categories. The plasma parameters analyzed included tmax, {lambda}z, and the natural logarithms of Cmax, Cmax,u, AUC24, and AUC24,u. The urine parameters analyzed included Ae24 and CLR. When the main effect for gender was statistically significant for a parameter, analyses of covariance (ANCOVAs) were performed to explore the explanatory value of total body weight by including it as a continuous variable in the statistical model.

For pharmacodynamic parameters, a 2-way ANOVA was used to investigate the effects of gender and age on the percentage change in serum uric acid Cmean,24 from baseline to day 7. Again, age was treated as a categorical variable with subjects either in the younger (18-40 years) or the older (≥65 years) age categories. When the main effect for gender was statistically significant, separate ANCOVAs were performed to explore the explanatory value of total body weight and AUC24,u by including them as a continuous variable in the statistical model.

No inferential statistics were used in comparing any safety variables. All treatment-emergent adverse events were summarized using descriptive statistics by gender and age group. Incidence rates for adverse events were calculated using the number of patients having 1 or more occurrences of an adverse event and the number of patients in that demographic group. Changes in, and absolute values for, laboratory test results and vital signs were also summarized using descriptive statistics for each gender and age group.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 ACKNOWLEDGEMENTS
 REFERENCES
 
Demographics
Twenty-four adult male and 24 adult female subjects, with 12 of each gender in both age categories of 18 to 40 years and ≥65 years, entered and completed the present study. No subject discontinued treatment prematurely. Mean demographic parameters for those subjects completing the study are summarized in Table I. No significant differences in demographic parameters were noted between the study groups, although lower creatinine clearance values in subjects aged ≥65 years were reported. As expected, the mean body weight of the female subjects was lower than that of the male subjects (68.3 kg vs 80.6 kg).


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  		Table I Summary of Baseline Demographic Data by Subject Category

 
Plasma Protein Binding
Febuxostat was highly bound to plasma proteins in all subjects, with a mean ± SD plasma unbound fraction of 0.007 ± 0.001 for all subject categories apart from those aged ≥65 years (0.007 ± 0.002). These values corresponded to a mean protein binding value of 99.3% in each age or gender category.

Pharmacokinetics
The mean concentration-time profiles for unbound febuxostat 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 age and gender category are summarized in Tables II and III, respectively. There was no statistically significant age category by gender interaction for any of the febuxostat, 67M-1, 67M-2, or 67M-4 pharmacokinetic parameters tested.


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  		Table II Febuxostat Plasma and Urine Pharmacokinetic Parameters for Each Age and Gender Category on Day 7

 


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  		Table III Febuxostat Metabolites 67M-1, 67M-2, and 67M-4 Plasma and Urine Pharmacokinetic Parameters for Each Age and Gender Category on Day 7

 
Febuxostat. The mean tmax, Cmax,u, AUC24,u, and t1/2z values for febuxostat for subjects aged ≥65 years were similar to the mean values for subjects aged 18 to 40 years (P > .05; Table II).

The mean tmax values were similar between the 2 gender categories (P > .05). The mean Cmax,u values for febuxostat on day 7 for female subjects were approximately 33% higher than the mean Cmax,u values for male subjects (P ≤ .05), possibly due to the slightly lower volume of distribution and unbound total body clearance in female subjects compared with male subjects (Vss/F of 37.9 L in women vs 48.2 L in men, and CL/F of 9.35 L/h in women vs 10.83 L/h in men). In addition, AUC24,u values for febuxostat were significantly higher (by approximately 16.5%) in female subjects compared with male subjects (P ≤ .05). The t1/2z was similar for both genders (Table II).

Metabolites 67M-1, 67M-2, and 67M-4. Mean tmax values for 67M-1 and 67M-4 as well as Cmax, AUC24, and t1/2z values for 67M-1, 67M-2, and 67M-4 on day 7 for subjects aged ≥65 years were similar to those for subjects aged 18 to 40 years (P > .05). In addition, the AUC ratios with respect to the parent drugs were similar between the 2 age categories (Table III).

Mean tmax values for 67M-1, 67M-2, and 67M-4 on day 7 for women were similar to those for men, and mean Cmax values were 26%, 5%, and 31% higher, respectively (Table II). Gender differences in Cmax for 67M-1 and 67M-4 were statistically significant (P ≤ .05). Mean AUC24 values for 67M-1, 67M-2, and 67M-4 for women were 18% higher, 3% lower, and 26% higher, respectively, compared with mean AUC24 values for men, and none of the differences were statistically significant (P > .05) or deemed to be clinically significant. The t1/2z and AUC ratios for each of the metabolites appeared similar between gender categories (Table III).


Figure 2
Figure 2
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  		Figure 2. Mean plasma concentration-time profiles with respect to age (A) and gender (B) for unbound febuxostat on day 7 after once-daily multiple oral dosing with febuxostat 80 mg for 7 days.

 
Pharmacodynamics
Mean serum pharmacodynamic parameters for uric acid, xanthine, and hypoxanthine are summarized in Table IV.


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  		Table IV Serum Uric Acid, Xanthine, and Hypoxanthine Pharmacodynamic Parameters for Each Age and Gender Category at Baseline (Day –1) and Day 7

 
Uric acid. Based on the predose serum uric acid concentration data, steady-state serum uric acid concentrations appeared to have been reached by day 7 (Figure 3). There was no statistically significant age category by gender interaction for the percentage change in serum uric acid Cmean,24 values in the 2-way ANOVA model (Table IV). The mean percentage decrease from baseline in Cmean,24 values for serum uric acid were similar between subjects aged ≥65 years (56.2%) and subjects aged 18 to 40 years (54.9%), with both age groups achieving statistically significant mean percentage decreases (P ≤ .05) in serum uric acid from baseline. However, mean percentage changes in urinary uric acid Cmean,24 from baseline (day –1) to day 7 were greater in older subjects as compared with the younger subjects (63.5% vs 28.2%), although the decrease in the younger group was more than likely underestimated because of a single subject whose value (240% increase from baseline) appeared to be an outlier as compared with the median value for the category (–52%). The percentage decrease in uric acid mean Ae24 and CLR from baseline was slightly greater in the elderly group (69% and 32%, respectively) as compared with the younger group (61% and 14%, respectively).


Figure 3
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  		Figure 3. Mean predose serum uric acid concentrations on days –1 to 7 with administration of daily oral doses of febuxostat 80 mg on days 1 to 7.

 
The mean serum uric acid Cmean,24 at baseline was 28% lower in female subjects compared with male subjects (Table IV). The mean percentage decrease from baseline in Cmean,24 values for serum uric acid was slightly greater in women as compared with men (59.3% vs 51.8%, P ≤ .05), with both gender groups achieving statistically significant (P ≤ .05) mean percentage decreases in serum uric acid from baseline. Mean urinary uric acid Cmean,24 and Ae24 values at baseline were approximately 41% and 33%, respectively, lower in women than in men. The mean percentage change from baseline for urinary uric acid Cmean,24 was similar in male and female subjects, with mean values on day 7 decreasing by 45.8% and 46.7% in male and female subjects, respectively. However, the mean percentage decrease in urinary uric acid Cmean,24 may have been underestimated in women because of a single subject whose value (240%) appeared to be an outlier as compared with the median value for the category (–61%). The percentage decrease in uric acid mean Ae24 and CLR from baseline was similar in female (69% and 21%, respectively) and male subjects (63% and 25%, respectively).

Xanthine. Significant increases from baseline in serum xanthine concentrations were reported for both age categories after multiple dosing with febuxostat, with increases in serum xanthine Cmean,24 values being similar across both age categories (Table IV). In addition, even though the increase in urinary xanthine Cmean,24 mean values on day 7 were smaller, the extent of the increase from baseline in xanthine Ae24 and CLR values on day 7 appeared to be similar in subjects aged ≥65 years compared with subjects aged 18 to 40 years.

The increase from baseline in serum xanthine Cmean,24 value was marginally lower in female subjects compared with male subjects (Table IV). Although mean baseline urinary xanthine Cmean,24 and Ae24 values in female subjects were lower by 20% and 8%, respectively, than in male subjects, the increase from baseline for Cmean,24 and Ae24 values in female subjects were similar to those seen in male subjects. However, a higher increase from baseline in renal clearance of xanthine in female subjects was reported following multiple dosing with febuxostat, which may explain the smaller increase from baseline in serum xanthine concentrations seen in female subjects than in male subjects.

Hypoxanthine. Following multiple dosing with febuxostat, no substantial change in serum hypoxanthine concentrations was reported in either age category (Table IV). Baseline urinary Cmean,24 and Ae24 mean values for hypoxanthine in subjects aged ≥65 years appeared lower than those in the younger age category. However, overall changes from baseline for urinary Cmean,24 and Ae24 hypoxanthine mean values were similar in both age categories. In addition, baseline CLR and subsequent change from baseline for CLR appeared similar in both age categories. There appeared to be no substantial change in serum hypoxanthine pharmacodynamic parameters in male or female subjects following multiple dosing with febuxostat. At baseline, values of urinary Ae24 and CLR in women were approximately half those of men. Although a parallel increase in Ae24 and CLR was seen from baseline to day 7 in both male and female subjects, the fold increase from baseline was greater in female subjects for both parameters compared with male subjects.

Safety
Febuxostat 80 mg once daily was well tolerated in each of the 4 study groups. The overall incidence of treatment-emergent adverse events appeared higher for older subjects compared with younger subjects (58% [14/24] vs 29% [7/24]) and in female subjects compared with male subjects (63% [15/24] vs 25% [6/24]). Most adverse events were mild and transient and considered possibly related to study drug. Headache and constipation were the most frequently reported adverse events by age group or gender group. No deaths, serious adverse events, or premature discontinuations due to adverse events occurred during the study period.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 ACKNOWLEDGEMENTS
 REFERENCES
 
Pharmacokinetics and Pharmacodynamics
The current study was undertaken to investigate the effect of age and gender on the pharmacokinetics, pharmacodynamics, and safety of febuxostat 80 mg once daily. Febuxostat was well tolerated and was found to have a significant uric acid–lowering effect that was accompanied by increases in serum xanthine concentrations, decreases in urinary uric acid excretion, and increases in urinary xanthine and hypoxanthine excretion, all of which confirmed inhibition of XO activity by febuxostat as previously reported in healthy subjects and special populations.10,20,21 In addition, plasma protein binding of febuxostat in the present study was comparable with values previously reported.20,21 Although the overall incidence of adverse events appeared to differ according to both age and gender (no statistical analyses were performed), no patient experienced serious adverse events or discontinued treatment prematurely because of an adverse event. Findings of this study indicated no safety concerns with febuxostat in any patient subgroup.

Age Effect
Following multiple oral dosing with febuxostat, there was no statistically significant difference in the plasma exposure of febuxostat and its metabolites 67M-1, 67M-2, and 67M-4 between the age categories. Similarly, the AUC ratios and the fraction of the dose excreted as unchanged and total febuxostat and its metabolites generally appeared to be the same between the age categories, indicating a lack of substantial changes in phase 1 and phase 2 metabolism of febuxostat with age. For unchanged febuxostat and metabolites, the CLR was slightly lower in subjects aged ≥65 years compared with subjects aged 18 to 40 years, although this was as expected because of diminished renal function in subjects aged ≥65 years, as evidenced by their relatively lower creatinine clearance values.

The percentage decrease in serum uric acid and the increase in serum xanthine appeared to be the same between the age categories. In addition, there appeared to be no substantial change in serum hypoxanthine concentrations in both age groups. The difference between the percentage decrease in urinary uric acid Cmean,24 values between the 2 age categories was mainly due to an outlier observation in the young group. In fact, the percentage decreases in urinary uric acid Ae24 mean values were similar between the 2 age groups (ie, 69% in the elderly group vs 61% in the young group). In addition, the extent of increase from baseline in urinary xanthine and hypoxanthine Ae24 was similar between the age categories. Therefore, the pharmacokinetics and pharmacodynamics of febuxostat did not appear to be substantially affected by age.

Gender Effect
Following multiple dosing with febuxostat, Cmax,u and AUC24,u of febuxostat were higher in women as compared to men because of slightly lower total body clearance and/or volume of distribution of febuxostat in women. Following an ANCOVA, with inclusion of total body weight at baseline as a covariate, the P values for the gender effect for these parameters were no longer statistically significant (P > .05). Therefore, the differences could be largely accounted for by weight differences between male and female subjects and were therefore not due to gender differences alone. The difference in total plasma exposure to metabolites was not statistically significantly different between genders. In addition, the AUC ratios and the fraction of the dose excreted as unchanged and total febuxostat and its metabolites generally appeared to be the same between genders, indicating a lack of substantial differences in the phase 1 and phase 2 metabolism of febuxostat between genders.

The baseline serum uric acid Cmean,24 and urine uric acid Cmean,24 and Ae24 were lower in women as compared with men because of possibly lower purine production in women. The percentage decrease in serum uric acid Cmean,24 was slightly greater in women than in men (59% vs 52%). Following an ANCOVA, with inclusion of total body weight and febuxostat AUC24,u as covariates, this difference still remained statistically significant. Although the difference in the percentage decrease in serum uric acid Cmean,24 between the genders was statistically significant (P ≤ .05) and could not be accounted for by a linear covariate model (with body weight or febuxostat AUC24,u as a continuous variable), this difference was not considered clinically meaningful. In addition, similar decreases in urinary uric acid and increases in serum xanthine Cmean,24 and urinary xanthine and hypoxanthine Ae24 were noted between female subjects and male subjects. Therefore, the pharmacokinetics and pharmacodynamics of febuxostat were not substantially affected by gender.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
ACKNOWLEDGEMENTS
 REFERENCES
 
The results of this phase 1 study in healthy subjects demonstrate that the pharmacokinetics, pharmacodynamics, and safety of febuxostat do not appear to be substantially affected by age or gender following multiple dosing for 7 days. Therefore, no dose adjustment based on gender or age alone is necessary when administering febuxostat.


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 ACKNOWLEDGEMENTS
REFERENCES
 
The authors would like to thank Galen Witt, William Palo, and Patricia MacDonald for their critical review of the manuscript and assistance with management of the study and statistical analyses; MDS Pharma Services for performing analyses of pharmacokinetic samples; and Rx Communications for collaborating with the authors to develop a first draft of the manuscript and incorporate subsequent revisions.

DOI: 10.1177/0091270008322035

Financial disclosure: This study (TMX-01-016) was sponsored by TAP Pharmaceutical Products Inc.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 ACKNOWLEDGEMENTS
 REFERENCES
 

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Febuxostat: a new treatment for hyperuricaemia in gout
Rheumatology, May 1, 2009; 48(suppl_2): ii15 - ii19.
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