DRUG INTERACTIONS
`
`Pharmacokinetic Interactions of Concomitant
`Administration of Febuxostat and NSAIDs
`
`Reza Khosravan, PhD, Jing-Tao Wu, PhD, Nancy Joseph-Ridge, MD, and
`Laurent Vernillet, PharmD, PhD
`
`To evaluate the effect of febuxostat on the pharmacokinet-
`ics of indomethacin and naproxen and vice versa, 2 multi-
`ple-dose, 3-period crossover studies were performed in
`healthy subjects. In study 1, subjects received febuxostat 80
`mg once daily, indomethacin 50 mg twice daily, or both. In
`study 2, subjects received febuxostat 80 mg, naproxen 500 mg
`twice daily, or both. Twenty-four-hour blood samples were
`collected on day 5 in study 1 and day 7 in study 2. In study
`1, 90% confidence intervals of geometric mean ratios for
`maximum plasma concentration (Cmax) and area under the
`curve (AUC) were within the 0.80 to 1.25 no-effect range for
`febuxostat and indomethacin. In study 2, 90% confidence
`intervals for febuxostat Cmax and AUC extended above that
`range, with increases of 28% and 40% in Cmax and AUC24,
`respectively. However, 90% confidence intervals for naproxen
`
`Cmax and AUC were within the 0.80 to 1.25 range.
`Febuxostat had no effect on the plasma pharmacokinetics
`of indomethacin and naproxen. Similarly, indomethacin
`had no effect on the plasma pharmacokinetics of febuxo-
`stat. Although naproxen caused an increase in plasma
`exposure to febuxostat, this increase is not expected to be
`clinically significant. Therefore, based on the plasma phar-
`macokinetic data in healthy subjects, febuxostat may be
`administered with indomethacin or naproxen with no dose
`adjustments for febuxostat, indomethacin, or naproxen.
`
`Keywords: Febuxostat; drug-drug interaction; NSAID;
`indomethacin; naproxen; pharmacokinetics
`Journal of Clinical Pharmacology, 2006;46:855-866
`©2006 the American College of Clinical Pharmacology
`
`Gout is the most common form of inflammatory
`
`arthritis in men older than 40 years and is char-
`acterized by recurrent attacks of acute inflammation in
`1 or more joints because of deposition of monosodium
`urate crystals in the joint cavity.1,2 Elevated serum
`concentrations of uric acid (hyperuricemia) are seen
`in more than 90% of patients with gout, and hyper-
`uricemia is considered the precursor of gout.1 The
`condition generally occurs after years of sustained
`hyperuricemia, and a clear relationship between
`serum uric acid and the risk of developing gout has
`been demonstrated.1,3 According to the most recent
`National Health and Nutrition Examination Survey
`(NHANES III), gout is estimated to affect approxi-
`mately 5.1 million people in the United States, and
`its prevalence is increasing rapidly because of an
`
`From TAP Pharmaceutical Products, Inc, Lake Forest, Illinois. Funded by
`TAP Pharmaceutical Products, Inc. Presented in part at the 69th annual
`scientific meeting of the American College of Rheumatology (November
`2005). Submitted for publication December 16, 2005; revised version
`accepted April 11, 2006.
`DOI: 10.1177/0091270006289848
`
`increase in 2 important risk factors of hyperuricemia:
`aging and obesity.4,5
`The 2 important cornerstones of gout management
`are (1) management or control of hyperuricemia and
`(2) treatment or prevention of acute attacks of gout.6
`Management or control of hyperuricemia in gout
`involves inhibitors of xanthine oxidase, uricosuric
`agents, or uricase. These agents lower uric acid con-
`centrations in serum by inhibiting production of
`uric acid (ie, inhibitors of xanthine oxidase) or by
`increasing clearance of uric acid from the body (ie, uri-
`cosurics or uricase). In the United States, inhibitors
`of xanthine oxidase are the most widely prescribed
`category of drugs for hyperuricemia management in
`patients with gout. For treatment or prevention of
`acute gout attacks (including those caused by the
`initiation of antihyperuricemic therapy), 3 categories
`of drugs commonly have been used: antimitotics (eg,
`colchicine), nonsteroidal anti-inflammatory drugs
`(NSAIDs), and systemic steroids (eg, prednisone).6
`Because of the adverse events associated with
`colchicine therapy, NSAIDs (eg, indomethacin and
`naproxen), where they are not contraindicated, are
`the drugs of choice in treating or preventing acute
`
`J Clin Pharmacol 2006;46:855-866
`
`855
`
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`

`

`KHOSRAVAN ET AL
`
`attacks of gout. Systemic steroids are recommended
`only when patients do not respond to colchicine
`or NSAIDs or when colchicine or NSAIDs are
`contraindicated.
`Febuxostat (2-[3-cyano-4-(2-methylpropoxy)-phenyl] -
`4-methylthiazole-5-carboxylic acid)
`is a potent
`novel nonpurine selective inhibitor of xanthine
`oxidase (NP-SIXO) and was shown to have great
`efficacy in lowering serum uric acid concentra-
`tions in animals.7-11 Results of phase I, II, and III
`studies in healthy subjects and subjects with hyper-
`uricemia associated with gout have confirmed the
`ability of febuxostat to reduce serum uric acid
`concentrations in humans in a dose-dependent man-
`ner.12-15 In healthy human subjects, orally adminis-
`tered febuxostat is rapidly absorbed with the time to
`reach the observed maximum plasma concentration
`(tmax) of approximately 1 hour. The drug is highly
`bound to albumin in blood (~99%) and appears to
`have a low to medium apparent volume of distribu-
`tion at steady state of approximately 0.7 L/kg.
`Febuxostat is metabolized mainly to its acyl-
`glucuronide metabolite (via uridine diphosphoglu-
`curonosyltransferases [UGT] 1A1, 1A3, 1A7, 1A8,
`1A9, 1A10, and 2B7; unpublished data) and, to a
`lesser extent, its active oxidative metabolites (via
`cytochrome P-450 1A1, 1A2, 2C8, and 2C9; unpub-
`lished data).16-18 Approximately 33% and 11% of the
`orally administered dose is recovered in urine as the
`acyl-glucuronide of febuxostat and as the oxidative
`metabolites and their glucuronide conjugates, respec-
`tively.18 Only a small fraction (< 2%) of the orally
`administered dose was excreted
`renally as
`unchanged febuxostat, indicating that renal elimina-
`tion plays a minor role in the elimination of febuxo-
`stat from the body.18
`During initiation of antihyperuricemic therapy,
`a rapid decrease in serum uric acid concentrations
`may precipitate an acute attack of gout. Therefore,
`febuxostat may need to be administered with NSAIDs
`such as indomethacin or naproxen. Similar to febux-
`ostat, indomethacin and naproxen also undergo
`glucuronidation and are highly protein bound.19-24
`According to the literature, probenecid, a urico-
`suric agent, inhibits the glucuronidation of both
`indomethacin and naproxen.25,26 In addition, results
`of in vitro and in vivo studies have shown that
`naproxen and/or indomethacin themselves may
`cause inhibition of the glucuronidation of other
`drugs.27-29 Therefore, we decided to investigate the
`effect of febuxostat on the pharmacokinetics of
`indomethacin and naproxen and vice versa.
`
`856 • J Clin Pharmacol 2006;46:855-866
`
`METHODS
`
`Subjects
`
`Two studies were conducted to investigate the effect
`of febuxostat on the pharmacokinetics of indomethacin
`and naproxen and vice versa. Enrollment for both
`studies started after investigational review board
`(Quorum Review Inc; Seattle, Wash) approval. Eligible
`healthy male and female subjects between 18 and 55
`years of age, inclusive, were allowed to enroll in each
`study after signed informed consent was obtained.
`Subjects were required to have a body mass index
`less than 30 kg/m2, a normal serum creatinine level,
`no history of drug sensitivity or allergic reaction to
`any drug, no hypersensitivity to aspirin and NSAIDs,
`and no comorbid, uncontrolled metabolic or psychi-
`atric conditions. Exclusion criteria included a diag-
`nosis of gout, a history of xanthinuria or recurrent
`gastrointestinal lesions, evidence of occult blood in
`stool, clinically significant abnormal laboratory test
`or electrocardiographic results, a concurrent disease
`state that required long-term daily medication, a
`history of cancer with less than 5 years of remission,
`and positive test results for hepatitis B, hepatitis C,
`or human immunodeficiency virus antibody. In
`addition, subjects were excluded from the study if
`they had taken any over-the-counter or prescrip-
`tion medication within 1 and 4 weeks, respectively,
`of the initial dose of study drug; used tobacco or
`other nicotine-containing products within 3 months
`before the initial dose of study drug; or had a history
`of alcohol or drug abuse. Female subjects were
`excluded from the study if they were pregnant or
`breastfeeding. Both studies were conducted at
`Seaview Research, Inc (Miami, Fla).
`
`Experimental Design
`
`Both studies were phase I, single-center, open-label,
`multiple-dose, randomized, 3-period crossover stud-
`ies. In each study, an attempt was made to enroll
`equal numbers of subjects of each sex. Subjects were
`assigned randomly to 1 of 3 regimen sequences, as
`shown in Figure 1.
`During confinement to the testing facility, subjects
`abstained from all food and beverage except for sched-
`uled meals provided by the testing facility. Caffeine,
`alcohol, high-purine foods, and grapefruit and grape-
`fruit juice were not to be consumed. Subjects were
`instructed to abstain from eating high-purine foods
`a week before confinement. During confinement, all
`
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`

`INTERACTIONS OF CONCOMITANT ADMINISTRATION OF FEBUXOSTAT AND NSAIDS
`
`Regimen A
`Study 1: FBX Alone
`Study 2: FBX Alone
`
`Regimen B
`Study 1: FBX+INM
`Study 2: FBX+NPX
`
`Regimen C
`Study 1: INM Alone
`Study 2: NPX Alone
`
`Period 1
`
`Period 2
`
`Period 3
`
`Dosing
`Interval
`
`Washout
`Interval
`
`Dosing
`Interval
`
`Washout
`Interval
`
`Dosing
`Interval
`
`Final
`Evaluation
`
`Sequence I
`
`Sequence II
`
`Sequence III
`
`Figure 1. Diagram of regimen orders for sequences I, II, and III
`in studies 1 and 2. FBX, febuxostat 80 mg once daily; INM,
`indomethacin 50 mg twice daily; NPX, naproxen 500 mg twice
`daily. Dosing interval: 5 days in study 1 and 7 days in study 2.
`Washout interval: 2 days in study 1 and 7 days in study 2. Final
`evaluation: the day after the dosing interval in period 3 in studies
`1 and 2 for subjects who completed the study.
`
`subjects were served meals relative to the time of
`dosing with approximate times of breakfast at 0730
`hours, lunch at 1300 hours, dinner at 1800 hours, and
`an evening snack at 1930 hours. Breakfast and snack
`were to be finished within 30 minutes. No food was
`allowed from 2000 hours until 0730 hours the next
`morning. Water was allowed as desired except 1 hour
`before and 1 hour after drug administration.
`In study 1, subjects were confined to the testing
`facility and supervised for approximately 21 consec-
`utive days. Confinement began at approximately
`1100 hours on day –1 of period 1 to obtain all the
`necessary laboratory test results and ended when all
`study procedures were completed on day 6 of period
`3. On dosing days, days 1 to 5 of each period (ie, dos-
`ing interval; Figure 1), the doses were administered
`according to the regimen assigned for the period. For
`regimen A, four 20-mg tablets of febuxostat were
`administered at 0800 hours with 240 mL of water.
`For regimen B, four 20-mg tablets of febuxostat and
`a single 50-mg capsule of indomethacin were admin-
`istered at 0800 hours with 240 mL of water. A single
`50-mg capsule of indomethacin was administered at
`2000 hours with 240 mL of water. For regimen C, a
`single 50-mg capsule of indomethacin was adminis-
`tered at 0800 hours and at 2000 hours with 240 mL
`of water. There were 2 days between the last dose in
`
`a period and the first dose of the subsequent period
`when no doses were administered (ie, washout
`interval; Figure 1). However, subjects remained
`confined on these days. On days 1 through 5 of each
`period, venous blood samples were collected within
`5 minutes before the morning administration of
`study drugs for the determination of febuxostat
`and/or indomethacin concentrations in plasma. On
`day 5 of regimens A and B, venous blood samples
`were collected at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12,
`16, and 24 hours after the morning administration of
`febuxostat for the determination of febuxostat in
`plasma. Venous blood samples were collected at
`0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 12.25, 12.5, 13,
`13.5, 14, 15, 16, 18, and 24 hours after the day 5
`morning administration of indomethacin in regimens
`B and C for the determination of indomethacin con-
`centrations in plasma. On day 6 of period 3, final
`study procedures were conducted after the 24-hour
`sample was obtained. Blood samples also were
`obtained for clinical laboratory testing (eg, hematol-
`ogy/serum chemistry) at screening and days –1 and
`6 of each period for subjects who completed the
`study.
`In study 2, subjects were confined to the testing
`facility and supervised for approximately 9 days
`in each period. Confinement began for each period at
`approximately 1100 hours on day –1 and ended at
`approximately 1000 hours on day 8. On dosing days,
`days 1 to 7 of each period (ie, dosing interval; Figure 1),
`the doses were administered according to the regi-
`men assigned for the period. For regimen A, four 20-
`mg tablets of febuxostat were administered at 0800
`hours with 240 mL of water. For regimen B, four 20-
`mg tablets of febuxostat and a single 500-mg capsule
`of naproxen were administered at 0800 hours with
`240 mL of water. In addition, a single 500-mg capsule
`of naproxen was administered at 2000 hours with
`240 mL of water. For regimen C, a single 500-mg cap-
`sule of naproxen was administered at 0800 hours
`and at 2000 hours with 240 mL of water. There were
`7 days between the last dose in a period and the
`first dose in the subsequent period when no doses
`were administered (ie, washout interval; Figure 1).
`Subjects were not confined on these days. On days
`1, 3, 6, and 7 of each period, venous blood samples
`were collected within 5 minutes before the morning
`administration of study drugs for the determination
`of febuxostat and/or naproxen concentrations in
`plasma. On day 7 of the periods in which febuxostat
`was administered, venous blood samples were col-
`lected at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, and
`
`DRUG INTERACTIONS
`
`857
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`

`

`KHOSRAVAN ET AL
`
`24 hours after the morning administration of study
`drugs for the determination of febuxostat in plasma.
`On day 7 of the periods in which naproxen was
`administered, venous blood samples were collected
`at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 12.25, 12.5, 13,
`13.5, 14, 15, 16, 18, and 24 hours after the morning
`administration of study drugs for the determination
`of naproxen concentrations in plasma. On day 8 of
`period 3, final study procedures were conducted after
`the 24-hour sample was obtained. Blood samples also
`were obtained for clinical laboratory testing (eg,
`hematology/serum chemistry) at screening and days
`–1, 4, and 8 of each period for subjects who com-
`pleted the study.
`In both studies, the blood specimen was placed
`on ice immediately after collection. The sealed spec-
`imen was kept on ice until centrifuged at approxi-
`mately 5°C within 2 hours of collection. The plasma
`was then separated and transferred to a polypropy-
`lene vial. All samples were frozen at approximately
`–20°C until shipped on dry ice to the bioanalytical
`lab, where they were stored at approximately –20°C
`until analyzed.
`
`Analytical Methods
`
`Plasma concentrations of febuxostat were measured
`using a validated method of high-performance liquid
`chromatography (HPLC) with fluorescence detection
`at excitation and emission wavelengths of 320 and 380
`nm, respectively. In brief, after addition of internal
`standard (2-naphthoic acid), plasma samples (0.5 mL)
`were deproteinized by addition of 0.5 mL of acetoni-
`trile, mixed, and centrifuged, and the resulting super-
`natant 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, v:v). The calibration curve
`range for febuxostat was linear from 0.01 to 20 µg/mL
`(R2 > 0.996). Quality control (QC) samples (at 0.03, 1,
`and 15 µg/mL) were analyzed with the plasma
`samples from each study. The lower limit of quantita-
`tion with a 0.5-mL plasma sample was 0.01 µg/mL for
`febuxostat. In study 1, QC samples showed absolute
`deviations from the theoretical concentrations of
`22.0% or less and coefficients of variation of 106.6%
`or less for febuxostat. There was 1 anomalous value for
`the 0.03-µg/mL QC on 1 of the calibration curves,
`which caused the coefficient of variation to be 106.6%
`for that QC level. However, the calibration curve met
`
`858 • J Clin Pharmacol 2006;46:855-866
`
`the standard and QC acceptance criteria and was
`included in the data set. In study 2, QC samples
`showed absolute deviations from the theoretical con-
`centrations of 7.0% or less and coefficients of variation
`of 10.3% or less for febuxostat.
`Plasma concentrations of indomethacin were deter-
`mined using a validated HPLC method with UV detec-
`tion at a wavelength of 260 nm. Briefly, after addition
`of the internal standard (diclofenac), plasma samples
`were mixed with the extraction solvent (pentane/
`methylene chloride; 2:1, v:v), centrifuged, and flash
`frozen, and the resulting organic phase was evaporated
`to dryness and reconstituted with the mobile phase
`(sodium acetate buffer/methanol/acetonitrile;67:13:20,
`v:v:v). Indomethacin and the internal standard were
`resolved on a CSC (Montreal, Canada) analytical col-
`umn (CSC-S ODS-1, 5 µm, 15 cm × 0.46 mm). The cal-
`ibration curve range for indomethacin was linear from
`24.9 to 19920.0 ng/mL (R2 > 0.997). The lower limit of
`quantitation with a 0.5-mL plasma sample was 24.9
`ng/mL for indomethacin. The QC samples (at 75, 7960,
`and 15 920 ng/mL) analyzed with the plasma samples
`from this study showed absolute deviations from the
`theoretical concentrations of 9.4% or less and coeffi-
`cients of variation of 5.4% or less for indomethacin.
`Plasma concentrations of naproxen were deter-
`mined using a validated HPLC method with fluores-
`cence detection with excitation and emission
`wavelengths of 230 and 370 nm, respectively. In brief,
`after addition of the internal standard (2-napthy-
`lacetic acid), plasma samples were mixed with the
`extraction solvent (methylene chloride), centrifuged,
`and flash frozen, and the resulting organic phase was
`evaporated and reconstituted with the mobile phase
`(acetonitrile and phosphoric acid). A Waters (Milford,
`Mass) symmetry C18 column was used to separate the
`peaks. The calibration curve for naproxen was linear
`from 0.1 to 100 µg/mL (R2 > 0.993). The lower limit of
`quantitation with a 0.1-mL plasma sample was 0.1
`µg/mL for naproxen. The QC samples (at 0.25, 3, and
`70 µg/mL) analyzed with the plasma samples from
`this study showed absolute deviations from the theo-
`retical concentrations of 3.3% or less and coefficients
`of variation of 12.1% or less for naproxen.
`
`Data Analysis
`
`Pharmacokinetic parameters for febuxostat, naproxen,
`or indomethacin in plasma were determined with
`standard noncompartmental methods using WinNonlin
`Professional V.3.1 software (Pharsight Corp, Mountain
`View, Calif). The pharmacokinetic parameters estimated
`
`MYLAN PHARMS. INC. EXHIBIT 1017 PAGE 4
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`

`

`INTERACTIONS OF CONCOMITANT ADMINISTRATION OF FEBUXOSTAT AND NSAIDS
`
`Table I Demographic Data for Subjects Completing Studies 1 and 2
`
`Study
`1 (n = 26)
`2 (n = 24)
`
`Sex,a
`M/F
`
`13/13
`11/13
`
`Age,b
`Y
`36.3 ± 8.7 (21-52)
`38.0 ± 9.4 (21-53)
`
`Race,c
`H/W
`
`22/4
`21/3
`
`Height,b
`cm
`166 ± 10 (150-185)
`166 ± 9 (150-183)
`
`Weight,b
`km
`72.7 ± 8.8 (58-95)
`71.1 ± 10.4 (49-90)
`
`Body Mass
`Index,b
`kg/m2
`26.4 ± 2.2 (22.5-29.7)
`25.7 ± 2.9 (19.5-28.9)
`
`a. Number of male/female subjects completing studies 1 and 2.
`b. Data presented are mean ± SD (range).
`c. Number of Hispanic/white subjects.
`
`included the observed maximum plasma concentration
`(Cmax); tmax; the apparent terminal elimination half-life
`(t1/2); the area under the plasma concentration-time
`curve (AUC) from time 0 to 12 hours after dose (AUC12)
`for indomethacin or naproxen and from time 0 to 24
`hours after dose (AUC24) for febuxostat, indomethacin,
`or naproxen; the oral clearance (CL/F); and the steady-
`state apparent volume of distribution (Vss/F).
`To assess the effect of indomethacin (study 1)
`and naproxen (study 2) on the pharmacokinetics of
`febuxostat, data from the 2 regimens with febuxostat
`(ie, regimens A and B) were used. Analyses of vari-
`ance were performed on tmax and the natural loga-
`rithms of Cmax and AUC24 of febuxostat, with factors
`for sequence, subjects nested within sequence, period,
`and regimen. The factor of subjects within sequence
`was considered random, and all other factors were
`fixed. The effect of indomethacin and naproxen on
`the pharmacokinetics of febuxostat was assessed via
`point estimates and 90% confidence intervals for the
`ratio of central values of regimen B to regimen A for
`febuxostat Cmax and AUC24. In addition, to assess the
`effect of febuxostat on the pharmacokinetics of
`indomethacin and naproxen, data from the 2 regimens
`with indomethacin and naproxen were used (ie, reg-
`imens B and C). Analyses of variance were per-
`formed on AM tmax and the natural logarithms of AM
`Cmax, AM AUC12, and AUC24 of indomethacin and
`naproxen, with factors for sequence, subjects nested
`within sequence, period, and regimen. The factor of
`subjects within sequence was considered random,
`and all other factors were fixed. The effect of febux-
`ostat on the pharmacokinetics of indomethacin and
`naproxen was assessed via point estimates and 90%
`confidence intervals for the ratio of central values of
`regimen B to regimen C for AM Cmax, AM AUC12, and
`AUC24 of indomethacin and naproxen. A conclusion
`of no effect was made if the 90% confidence inter-
`vals for the ratios of central values were within the
`0.80 to 1.25 range.
`
`RESULTS
`
`Study Subjects
`
`In study 1, 26 (13 male, 13 female) of the 27 subjects
`enrolled completed the study; 1 subject prematurely
`discontinued from the study because of an adverse
`event (contact dermatitis). In study 2, 24 (11 male,
`13 female) of the 27 subjects enrolled completed the
`study; 3 subjects prematurely discontinued from the
`study because of adverse events (angioedema, abnor-
`mal liver function test results, or increased cough).
`In study 2, 25 of the 27 subjects enrolled completed
`regimens A and B, whereas 24 of the 27 subjects
`enrolled completed regimens B and C. A summary of
`the demographic data for subjects who completed
`studies 1 and 2 is presented in Table I.
`
`Pharmacokinetics
`
`Effect of Indomethacin on Pharmacokinetics of
`Febuxostat
`In study 1, pharmacokinetic parameters for febuxo-
`stat when administered alone (reference) or with
`indomethacin (test) are presented in Table II. The
`plasma concentration profile of febuxostat when
`administered alone and when administered with
`indomethacin is depicted in Figure 2. The plasma
`profiles for both regimens overlapped each other,
`and the mean pharmacokinetic parameters of the
`2 regimens were similar. After administration of
`febuxostat with indomethacin, the median febuxostat
`tmax value remained unchanged, and the mean esti-
`mates for other pharmacokinetic parameters, includ-
`ing febuxostat Cmax, AUC24, t1/2, CL/F, and Vss/F, were
`within 11% of the respective parameters in the febux-
`ostat-alone regimen (Table II). The effects of period
`and sequence were not statistically significant (P > .05)
`for any of the febuxostat pharmacokinetic parameters
`
`DRUG INTERACTIONS
`
`859
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`

`KHOSRAVAN ET AL
`
`Table II Febuxostat Mean ± SD Pharmacokinetic Parameter Estimates and Geometric Mean Ratios After
`Multiple Oral Doses of Febuxostat Alone or With Indomethacin or Naproxen
`
`Regimen
`Study 1 (n = 26)
`FBX
`FBX + INM
`GMR (90% CI)c
`Study 2 (n = 25)
`FBX
`FBX + NPX
`GMR (90% CI)d
`
`tmax,a
`h
`
`Cmax,
`µg/mL
`
`AUC24,
`µg·h/mL
`
`t1/2,b
`h
`
`CL/F,
`L/h
`
`Vss/F,
`L
`
`1.5 (0.5-3.0)
`1.5 (0.5-3.0)
`NA
`
`1.5 (0.5-4.0)
`1.5 (0.5-4.0)
`NA
`
`2.00 ± 0.94
`1.78 ± 0.49
`0.93 (0.82-1.06)
`
`7.13 ± 1.97
`7.20 ± 1.81
`1.02 (0.97-1.06)
`
`6.0 ± 2.5 [5.2]
`6.0 ± 2.1 [5.2]
`NA
`
`1.75 ± 0.38
`2.25 ± 0.56
`1.28 (1.18-1.39)
`
`6.88 ± 1.56
`9.69 ± 2.63
`1.40 (1.33-1.46)
`
`6.2 ± 1.8 [5.6]
`7.8 ± 4.1 [6.7]
`NA
`
`12.1 ± 3.5
`11.8 ± 2.8
`NA
`
`12.3 ± 3.4
`8.9 ± 2.7
`NA
`
`60.2 ± 16.1
`60.0 ± 15.7
`NA
`
`58.6 ± 15.0
`49.3 ± 14.1
`NA
`
`AUC24, area under the plasma concentration-time curve from time 0 to 24 hours after dose; CI, confidence interval; CL/F, oral clearance; Cmax, observed
`maximum plasma concentration; FBX, febuxostat; GMR, geometric mean ratio; INM, indomethacin; NA, not applicable; NPX, naproxen; t1/2, apparent
`terminal elimination half-life; tmax, time to reach the observed maximum plasma concentration; Vss/F, steady-state apparent volume of distribution.
`a. Median (range).
`b. Harmonic mean in brackets.
`c. FBX + INM over FBX geometric mean ratio (the 90% CI of the ratio).
`d. FBX + NPX over FBX geometric mean ratio (the 90% CI of the ratio).
`
`Effect of Febuxostat on Pharmacokinetics of
`Indomethacin
`In study 1, pharmacokinetic parameters for indo-
`methacin when administered alone (reference) or
`with febuxostat (test) are presented in Table III. The
`plasma concentration profiles of indomethacin when
`administered alone and when administered with
`febuxostat are shown in Figure 3. The plasma pro-
`files for both regimens overlapped each other, and
`the mean pharmacokinetic parameters of the 2 regi-
`mens were similar. After administration of indo-
`methacin with febuxostat, the median indomethacin
`tmax remained relatively unchanged, and the mean
`estimates for other pharmacokinetic parameters,
`including indomethacin Cmax, AUC12, AUC24, t1/2 (ie,
`harmonic), and CL/F, were within 17% of the respec-
`tive parameters in the indomethacin-alone regimen
`for both AM and PM doses; the apparent changes in
`the mean Vss/F estimates did not follow a consistent
`trend after AM and PM dosing (ie, 24% lower after AM
`dosing vs 45% higher after PM dosing). These appar-
`ent changes were not considered clinically signifi-
`cant because of the high variability associated with
`some of the mean estimates. The changes in median
`Vss/F values after administration of indomethacin
`with febuxostat were within 12% of the median val-
`ues after administration of indomethacin alone. The
`effects of period and sequence were not statistically
`significant (P > .05) for any of the pharmacokinetic
`parameters analyzed, with the exception of the effects
`of period and sequence on AM AUC12, which were
`statistically significant (P ≤ .05), most likely because
`
`0
`
`6
`
`12
`Time (h)
`
`18
`
`24
`
`Febuxostat Alone
`
`Febuxostat + Indomethacin
`
`3
`
`2
`
`1
`
`0
`
`Plasma Febuxostat Concentration (µg/mL)
`
`Figure 2. Mean plasma concentration-time profiles of febuxostat
`after multiple oral doses of febuxostat (80 mg once daily for 5
`days) alone or febuxostat and indomethacin (50 mg twice daily
`for 5 days) in healthy subjects (study 1). Error bars indicate SD.
`
`analyzed. In addition, the 90% confidence intervals
`for febuxostat Cmax and AUC24 geometric mean ratios
`for the 2 regimens were within 0.80 to 1.25 (Table II),
`indicating that indomethacin had no effect on the
`pharmacokinetics of febuxostat. No statistically signif-
`icant (P > .05) differences were observed between the
`means of the 2 regimens for febuxostat tmax and the
`natural logarithm of Cmax and AUC24.
`
`860 • J Clin Pharmacol 2006;46:855-866
`
`MYLAN PHARMS. INC. EXHIBIT 1017 PAGE 6
`
`

`

`INTERACTIONS OF CONCOMITANT ADMINISTRATION OF FEBUXOSTAT AND NSAIDS
`
`Table III
`
`Indomethacin Mean ± SD Pharmacokinetic Parameter Estimates and Geometric Mean Ratios
`After Multiple Oral Doses of Indomethacin Alone or With Febuxostat in Study 1
`
`Regimen
`(n == 26)
`
`tmax,a
`h
`
`Cmax,
`µg/mL
`
`AUC12,
`µg⋅⋅h/mL
`
`AUC24,
`µg·h/mL
`
`t1/2,b
`h
`
`CL/F,
`L/h
`
`Vss/F,
`L
`
`AM dose
`INM
`FBX + INM
`GMR (90% CI)c
`
`PM dose
`INM
`FBX + INM
`
`1.3 (0.5-3.0)
`1.5 (1.0-4.0)
`NA
`
`17.80 ± 3.80
`8.71 ± 2.06
`2.76 ± 0.54
`17.69 ± 3.36
`9.26 ± 1.80
`2.74 ± 0.68
`0.98 (0.91-1.06) 1.07 (1.04-1.10) 1.00 (0.96-1.03)
`
`7.2 ± 4.1 [5.2] 3.02 ± 0.67 22.5 ± 9.0
`5.7 ± 1.7 [5.2] 2.79 ± 0.51 17.2 ± 4.7
`NA
`NA
`NA
`
`2.0 (1.0-6.0)
`2.0 (0.5-6.0)
`
`1.92 ± 0.65
`1.77 ± 0.63
`
`9.09 ± 1.96
`8.43 ± 1.91
`
`17.80 ± 3.80
`17.69 ± 3.36
`
`4.9 ± 2.4 [4.2] 2.87 ± 0.60 22.1 ± 7.0
`5.7 ± 3.4 [4.4] 3.37 ± 2.21 32.1 ± 40.2
`
`AUC12, area under the plasma concentration-time curve from time 0 to 12 hours after dose; AUC24, area under the plasma concentration-time curve from
`time 0 to 24 hours after dose; CI, confidence interval; CL/F, oral clearance; Cmax, observed maximum plasma concentration; FBX, febuxostat; GMR, geo-
`metric mean ratio; INM, indomethacin; NA, not applicable; t1/2, apparent terminal elimination half-life; tmax, time to reach the observed maximum plasma
`concentration; Vss/F, steady-state apparent volume of distribution.
`a. Median (range).
`b. Harmonic mean in brackets.
`c. FBX + INM over INM geometric mean ratio (the 90% CI of the ratio).
`
`Effect of Naproxen on Pharmacokinetics of
`Febuxostat
`In study 2, pharmacokinetic parameters for febuxo-
`stat when administered alone (reference) or with
`naproxen (test) are presented in Table II. The plasma
`concentration profile of febuxostat when adminis-
`tered alone and when administered with naproxen
`is illustrated in Figure 4. In addition, the mean
`and individual plots of febuxostat Cmax and AUC24
`for febuxostat alone and febuxostat-with-naproxen
`regimens are presented in Figure 5. The plasma
`febuxostat concentration profile for febuxostat when
`administered with naproxen appeared to be higher
`as compared to when administered alone. After
`administration of febuxostat with naproxen, febuxo-
`stat mean tmax remained relatively unchanged, but
`febuxostat mean Cmax, AUC24, and t1/2 increased by
`approximately 28%, 41%, and 26%, respectively, as
`compared to the mean values after administration of
`febuxostat alone. In addition, the febuxostat mean
`CL/F and Vss/F values decreased by 28% and 16%,
`respectively, after administration of febuxostat with
`naproxen. The effects of period and sequence were
`not statistically significant (P > .05) for any of the
`febuxostat pharmacokinetic parameters analyzed.
`The 90% confidence intervals of febuxostat Cmax and
`AUC24 geometric mean ratios for the 2 regimens
`extended above the upper bound of the 0.80 to 1.25
`no-effect range (Table II). Febuxostat Cmax and AUC24
`geometric means were higher by approximately 28%
`and 40%, respectively, for the febuxostat-with-
`naproxen regimen as compared to the febuxostat-
`alone regimen. In addition, the differences between
`
`AM Dose
`
`PM Dose
`
`0
`
`6
`
`12
`Time (h)
`
`18
`
`24
`
`Indomethacin Alone
`
`Febuxostat + Indomethacin
`
`4
`
`3
`
`2
`
`1
`
`0
`
`Plasma Indomethacin Concentration (µg/mL)
`
`Figure 3. Mean plasma concentration-time profiles of indo-
`methacin after multiple oral doses of indomethacin (50 mg twice
`daily for 5 days) alone or febuxostat (80 mg once daily for 5 days) and
`indomethacin in healthy subjects (study 1). Error bars indicate SD.
`
`of random assignment of subjects to sequence groups.
`In addition, the 90% confidence intervals for AM Cmax,
`AM AUC12, and AUC24 geometric mean ratios of the 2
`regimens were within 0.80 to 1.25 (Table III), indicat-
`ing that febuxostat had no effect on the pharmacoki-
`netics of indomethacin. No statistically significant
`(P > .05) differences between the means of the 2 regi-
`mens were observed for AM indomethacin tmax and the
`natural logarithm of Cmax, AUC12, and AUC24.
`
`DRUG INTERACTIONS
`
`861
`
`MYLAN PHARMS. INC. EXHIBIT 1017 PAGE 7
`
`

`

`KHOSRAVAN ET AL
`
`(test) are presented in Table IV. The plasma concen-
`tration profiles of naproxen when administered alone
`and when administered with febuxostat are presented
`in Figure 6. The mean plasma profiles for both regi-
`mens overlapped each other, and the mean pharma-
`cokinetic parameters between the 2 regimens were
`similar. After administration of naproxen with febux-
`ostat,
`the median
`tmax of naproxen remained
`unchanged for the AM dose and was delayed by 0.5
`hours for the PM dose as compared to the naproxen-
`alone regimen. The naproxen mean Cmax, AUC12,
`AUC24, t1/2 (ie, harmonic), CL/F, and Vss/F values for
`the naproxen-with-febuxostat regimen were within
`12% of the respective parameters in the naproxen-
`alone regimen for both the AM and PM doses. The
`effects of period and sequence were not statistically
`significant (P > .05) for any of the naproxen pharma-
`cokinetic parameters analyzed. In addition, the 90%
`confidence intervals for Cmax and AUC geometric
`mean ratios of the 2 regimens were within 0.80 to
`1.25, indicating that febuxostat had no effect on the
`pharmacokinetics of naproxen. No statistically signif-
`icant (P > .05) differences between the means of the
`2 regimens were observed for AM naproxen tmax and
`the natural logar