ARTICLEBORGEN ET ALINFLUENCE OF GENDER AND FOOD ON SODIUM OXYBATEPHARMACOKINETICS AND PHARMACODYNAMICS
`
`
`
`
`
`The Influence of Gender and Food on the
`Pharmacokinetics of Sodium Oxybate
`Oral Solution in Healthy Subjects
`
`Lowell A. Borgen, PhD, Richard Okerholm, PhD,
`Dennis Morrison, DO, and Allen Lai, PhD
`
`Sodium oxybate (Xyrem®; gamma-hydroxybutyrate) oral so-
`lution was recently approved in the United States for the
`treatment of cataplexy in patients with narcolepsy. Two sin-
`gle-center, randomized, open-label studies in healthy volun-
`teers receiving single oral 4.5-g doses of sodium oxybate eval-
`uated effects of (1) gender on oxybate pharmacokinetics and
`(2) food on its oral bioavailability. In the latter study, one dose
`was administered after an overnight fast, another after a high-
`fat meal; 1 week separated treatments. Sodium oxybate
`pharmacokinetics was not significantly different between
`sexes. However, food significantly altered the bioavailability
`
`of oxybate by decreasing mean peak plasma concentration,
`increasing median time-to-peak concentration, and decreas-
`ing the area under the plasma concentration-time curve.
`Food did not affect elimination and urinary excretion of un-
`changed drug. No dose adjustment of sodium oxybate based
`on sex is indicated. Although significant food effects were ob-
`served, these are minimized in patients by the nocturnal dos-
`ing of sodium oxybate hours after the evening meal at a con-
`sistent time interval following food ingestion.
`Journal of Clinical Pharmacology, 2003;43:59-65
`©2003 the American College of Clinical Pharmacology
`
`Sodium oxybate (gamma-hydroxybutyrate) oral so-
`
`lution represents a novel approach to the
`pharmacotherapy of narcolepsy, a debilitating sleep
`disorder characterized by excessive daytime sleepi-
`ness, cataplexy, sleep paralysis, hypnagogic hallucina-
`tions, and the disruption of normal sleep patterns.1 So-
`dium oxybate differs from other symptomatic
`treatments presently used for narcolepsy such as anti-
`depressants and stimulants in that it appears to act
`more directly on the disrupted sleep architecture char-
`acteristic of this disorder.2,3 Thus, although sodium
`oxybate does not fully normalize nocturnal sleep in
`narcoleptic patients, it has shown significant beneficial
`effects on both daytime and nighttime symptoms of
`
`Inc., Minnetonka, Minnesota (Dr. Borgen);
`From Orphan Medical,
`Okerholm & Associates, Palm City, Florida (Dr. Okerholm); Bio-Kinetic
`Clinical Applications, Springfield, Missouri (Dr. Morrison); and CPKD So-
`lutions, Research Triangle Park, North Carolina (Dr. Lai). Dr. Borgen is a fel-
`low of the American College of Clinical Pharmacology. Financial support
`for this study was provided by Orphan Medical, Inc., Minnetonka, Minne-
`sota. Submitted for publication July 25, 2002; revised version accepted
`October 27, 2002. Address for reprints: Lowell A. Borgen, PhD, Orphan
`Medical, Inc., 13911 Ridgedale Drive, Suite 250, Minnetonka, MN
`55305.
`DOI: 10.1177/0091270002239707
`
`J Clin Pharmacol 2003;43:59-65
`
`narcolepsy, particularly the symptom of cataplexy.3-11
`In July 2002, the U.S. Food and Drug Administration
`approved sodium oxybate (as Xyrem® oral solution
`marketed by Orphan Medical, Inc.) for the treatment of
`cataplexy in narcoleptic patients. Used as an approved
`medication, gamma-hydroxybutyrate is a Schedule III
`drug; however, when used for illicit, nonmedical use
`(as GHB or its chemical analogs), it is classified as a
`Schedule I controlled substance.
`The oral pharmacokinetics of sodium oxybate has
`been assessed previously in healthy volunteers12 and in
`patients with narcolepsy13 as well as alcohol-dependent
`patients14 and patients with moderate or severe liver
`dysfunction.15 Overall, these studies have shown that
`the pharmacokinetics of oxybate in patients with
`narcolepsy is comparable to those in healthy subjects
`and in alcohol-dependent patients.12,13,16 While cirrho-
`sis modified the disposition kinetics of oxybate, it did
`not alter tolerability to the drug.14 These studies also in-
`dicated that oxybate is rapidly absorbed and has a half-
`life of approximately 1 hour.
`This short half-life of oxybate supports the proposal
`that the effects of sodium oxybate on daytime symp-
`toms are the result of the consolidation of nocturnal
`sleep.11 It also provides a pharmacokinetic basis for the
`
`59
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`AMN1033
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`

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`BORGEN ET AL
`
`clinical finding that a divided dosing schedule, with to-
`tal doses of 3 to 9 g sodium oxybate given in two por-
`tions at bedtime and 2.5 to 4 hours later, is most effec-
`tive in the treatment of narcolepsy.6,8,10,11 The
`development of the sodium oxybate oral solution for-
`mulation recognized the need for individualized dos-
`ing titration provided by a convenient liquid dosage
`form for the drug. The present studies were undertaken
`to describe the plasma pharmacokinetics of sodium
`oxybate oral solution in healthy males and females and
`to determine the effects of food on its oral
`bioavailability.
`
`METHODS
`
`Two randomized, open-label studies were conducted
`in healthy volunteers. One study evaluated the
`pharmacokinetics of a single dose of sodium oxybate
`oral solution in males and females; the other evaluated
`the oral bioavailability of sodium oxybate oral solution
`after an overnight fast and after a high-fat meal in a two-
`period, two-sequence, crossover design. The dose of
`sodium oxybate used in both studies was 4.5 g, which
`was chosen because it represents the maximum dose
`that is given in a single administration to patients with
`narcolepsy. Both studies were conducted at Bio-Kinetic
`Clinical Applications (Springfield, MO) after approval
`of the protocols and informed consent forms by the af-
`filiated institutional review board.
`
`Subjects
`
`For both studies, eligible subjects were nonsmoking
`male or female volunteers ages 18 to 55 years who were
`within 15% of their ideal body weight (according to
`1983 Metropolitan Life Insurance tables). They were
`deemed healthy based on physical examination, medi-
`cal history, 12-lead electrocardiogram, and clinical lab-
`oratory evaluations (hematology, serum chemistry, uri-
`nalysis, serum pregnancy test for females, and urine
`drug screen) performed at screening. Subjects were ex-
`cluded if they had known or suspected illicit drug use,
`hypersensitivity to sodium oxybate or related com-
`pounds, or any disease or condition that could affect
`absorption, distribution, metabolism, or elimination of
`sodium oxybate. Pregnant or nursing females were not
`admitted to either study, and women of childbearing
`potential were required to use adequate contraception.
`Subjects were required to have not used tobacco prod-
`ucts for 1 year, given blood or used investigational
`drugs within 30 days, given plasma within 14 days, or
`used any prescription or over-the-counter medication
`(excluding oral contraceptives) or alcohol within 48
`
`60 • J Clin Pharmacol 2003;43:59-65
`
`hours of dosing. All subjects gave written informed
`consent prior to participation in the studies.
`
`Study Designs and Procedures
`
`Gender study. Eighteen males and 18 females were
`chosen for the study; weight was matched as closely as
`possible (within ± 3 kg) between sexes. Subjects were
`required to enter the clinical research facility in the
`evening, approximately 3 hours before dosing with 4.5 g
`sodium oxybate oral solution (500 mg/mL; Orphan
`Medical, Inc.). Blood samples (5 mL) were collected be-
`fore dosing (0 hour); at 10, 20, 30, 45, and 60 minutes af-
`ter dosing; and at 30-minute intervals thereafter until 8
`hours after dosing. A 25-mL urine aliquot was collected
`during the hour before dosing, and all urine was col-
`lected in the 8-hour period after dosing. Subjects re-
`ceived a light meal approximately 2 hours prior to dos-
`ing; thereafter, they did not receive any food until the 8-
`hour blood collection was completed or water or other
`fluids until 2 hours after dosing. Subjects remained in
`the study facility until 3 hours after the final 8-hour
`blood sample was obtained.
`Food Study. Eligible subjects were randomized to
`one of two treatment sequences. In one sequence, sub-
`jects received a 4.5-g sodium oxybate oral dosage after
`an overnight fast; after a 7-day washout, they received
`the same study medication 30 minutes after a standard-
`ized high-fat meal. The standard meal consisted of 2
`fried eggs, 2 pieces of bacon, 4 ounces of hash brown
`potatoes, 2 slices of buttered toast, 8 ounces of whole
`milk, and 8 ounces of orange juice. This meal repre-
`sents approximately 150 protein calories, 250 carbohy-
`drate calories, and 500 fat calories. In the other se-
`quence, subjects received the 4.5-g dose of sodium
`oxybate in the opposite order, first after the high-fat
`meal and then after an overnight fast.
`Each dose of sodium oxybate was administered at
`approximately 7 a.m. In each treatment period, 18 sub-
`jects received the study medication after an overnight
`fast and 18 after a high-fat meal. Blood (5 mL) was col-
`lected before dosing (0 hour); at 10, 20, 30, 45, and 60
`minutes after dosing; at 30-minute intervals thereafter
`until 8 hours after dosing; and at 9 and 10 hours after
`dosing. A 25-mL urine aliquot was collected during the
`hour before dosing, and all urine was collected in 2-
`hour segments during the 10-hour period after dosing.
`In each treatment phase, subjects were required to en-
`ter the research facility on the evening before dosing
`and remain there until after the final blood and urine
`collection (10 h after dosing). Subjects received a light
`meal in the evening; thereafter, they did not receive any
`food (apart from the high-fat breakfast if appropriate)
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`AMN1033
`IPR of Patent No. 8,772,306
`
`

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`INFLUENCE OF GENDER AND FOOD ON SODIUM OXYBATE
`
`until after the 4-hour blood sample was collected or
`water or other fluids in the 2-hour periods before and
`after dosing.
`Safety was assessed in both studies by monitoring
`vital signs and occurrence of adverse events through-
`out the study.
`
`Analysis of Plasma and Urine Samples
`
`Whole blood was centrifuged at 4°C for 10 minutes at
`3000 rpm within 15 minutes of collection into
`heparinized Vaccutainers. Plasma was pipetted into
`polypropylene tubes and frozen at –20°C. Urine was
`stored refrigerated or on wet ice until the collection in-
`terval was complete; then it was mixed, the volume
`was recorded, and a 25-mL aliquot was stored frozen at
`–20°C. Plasma and urine samples were shipped on dry
`ice to Covance Laboratories, Inc. (Madison, WI), where
`concentrations of oxybate were determined. For the as-
`say, 2.0 mL water was added to plasma or urine sam-
`ples (0.1-mL aliquots), and sodium oxybate and the in-
`ternal standard (2-hydroxyvalerate; Aldrich) were
`extracted with methanol. Oxybate was determined by a
`validated liquid chromatography atmospheric pres-
`sure ionization tandem mass spectrometry (LC/MS/
`MS) assay with a limit of quantification (LOQ) of 5 μg/
`mL. The calibration curve was linear (r = 0.9952) over
`the relevant concentration range of 5 to 200 μg/mL.
`
`Pharmacokinetic Parameters
`
`Noncompartmental methods (WinNonlin, version 1.1)
`were used in the determination of pharmacokinetic pa-
`rameters, which were assessed from each subject’s
`plasma oxybate concentration versus time data for each
`dose. Pharmacokinetic endpoints were peak plasma con-
`centration of oxybate (Cmax), time from dosing to when
`Cmax was reached (tmax), area under the concentration-
`time curve extrapolated to infinity (AUC0-∞), elimina-
`tion rate constant (λz), apparent elimination half-life
`(t1/2), plasma clearance (CL/F), renal clearance (CLR),
`and apparent volume of distribution (Vz/F).
`The Cmax and tmax were observed values, λz was calcu-
`lated by log-linear regression analysis of the terminal
`phase of the plasma oxybate concentration versus time
`decay curve, and t1/2 was calculated as 0.693/λz. AUC0-∞
`was obtained through summation of AUClast (area un-
`der the curve from time 0 to last measurable concentra-
`tion, calculated by the linear trapezoidal rule) and
`AUCext (estimated by taking the ratio of the last measur-
`able concentration and λz). CL/F was determined from
`the ratio of dose and AUC0-∞, CLR was computed from
`the ratio of the total amount excreted unchanged to
`
`Table I Demographic Characteristics
`of Study Populations
`
`Parameter
`
`Gender Study
`(n = 36)
`
`Food Study
`(n = 36)
`
`18/0
`Sex (male/female)
`Race (C/B/H/O)a
`16/0/1/1
`27
`Mean age (years)
`75
`Mean weight (kg)
`a. C, Caucasian; B, Black; H, Hispanic; O, Other.
`
`0/18
`16/0/1/1
`34
`73
`
`0/36
`34/0/2/0
`30
`66
`
`AUC0-∞, and Vz/F was calculated from dose divided by
`AUC0-∞ • λz.
`
`Statistical Analysis
`
`Pharmacokinetic data are presented as mean (median
`for tmax) and standard deviation (SD). The effect of gen-
`der on sodium oxybate pharmacokinetics was deter-
`mined by an unpaired t-test of the log-transformed
`AUC0-∞, log-transformed Cmax, CL/F, t1/2, the percentages
`of the dose recovered unchanged in urine, and CLR. The
`Wilcoxon rank-sum test (a nonparametric analysis)
`was performed on tmax.
`The effect of food on sodium oxybate pharmacoki-
`netics was determined by an analysis of variance
`(ANOVA), including effects for sequence, subject
`within sequence, treatment, and period, of the AUC0-∞
`and Cmax after logarithmic transformation and compu-
`tation of the 90% confidence interval (CI). The CIs were
`compared to the reference intervals of 0.80 to 1.25 for
`AUC0-∞ and 0.70 to 1.43 for Cmax for description of the ef-
`fect of administration with food on the bioavailability
`of sodium oxybate. In addition, tmax, λz, and t1/2 were an-
`alyzed for significant effects of food. After the treat-
`ments, tmax was also compared by a nonparametric
`analysis.
`
`RESULTS
`
`Study Populations
`
`Demographic information regarding subjects in each of
`the studies is summarized in Table I. Data from all 36
`subjects (18 males, 18 females; 18 to 55 years old and
`weighing 57 to 96 kg) who entered the gender study
`were included in the safety analysis and in the
`pharmacokinetic statistics. Two of the 36 subjects (both
`29-year-old females) who entered the food study did
`not complete the study, and data from these subjects
`were not included in the pharmacokinetic analysis.
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`PHARMACOKINETICS AND PHARMACODYNAMICS
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`AMN1033
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`

`
`BORGEN ET AL
`
`Table II Pharmacokinetics of Sodium Oxybate
`in Healthy Males and Females
`
`Male
`(n = 18)
`
`Parameter
`AUC0-∞ (μg•h/mL)
`241 (81.7)
`Cmax (μg/mL)
`88.3 (21.4)
`a (h)
`1.00
`tmax
`0.65 (0.23)
`t1/2 (h)
`3.8 (1.3)
`CL/F (mL/min/kg)
`202 (61.4)
`Vz/F (mL/kg)
`3.1 (1.3)
`Urinary recovery (%)
`484 (185)
`CLR (mL/h)
`Data presented as mean ± standard deviation.
`a. Median.
`
`Female
`(n = 18)
`
`233 (81.5)
`83.0 (18.7)
`1.00
`0.61 (0.12)
`4.2 (1.6)
`218 (86.6)
`3.1 (1.8)
`510 (276)
`
`One subject did not return for the second treatment pe-
`riod because of adverse events experienced during the
`first treatment period; the other did not return because
`of reasons unrelated to the study. Data from all 36 sub-
`jects in the food study were included in the safety
`analysis.
`
`Pharmacokinetics of Sodium Oxybate
`in Healthy Males and Females
`
`Plasma concentration versus times curves for oxybate
`in males and females are shown in Figure 1, and
`pharmacokinetic parameters are summarized in Table
`II. There was no difference in the systemic exposure to
`oxybate between male and female subjects, and there
`was no significant difference (p > 0.05) between male
`and female volunteers for any of the pharmacokinetic
`parameters assessed.
`Oxybate was rapidly absorbed and quickly elimi-
`nated. Concentrations above 5 μg/mL (the assay LOQ)
`were observed at the first sampling time (10 min), and
`concentrations were below 5 μg/mL by 4 hours after
`dosing in most subjects. Mean plasma oxybate concen-
`trations in males and females were superimposable be-
`tween 1 and 8 hours after dosing (Figure 1), and the
`mean pharmacokinetic parameters related to the rate of
`absorption (Cmax, tmax) were similar between the sexes
`(Table II). Plasma concentrations of oxybate climbed
`rapidly, peaking at an average of 1.25 hours and 1.14
`hours in males and females, respectively, and then de-
`clined in a multiphasic manner (Figure 1). The convex
`nature of the log-concentration versus time data ob-
`served when the dose was administered after an over-
`night fast indicated the presence of a saturable process
`in the elimination of oxybate. The mean elimination
`half-life (estimated from the last three concentrations
`
`62 • J Clin Pharmacol 2003;43:59-65
`
`Figure 1. Mean ( SEM) plasma oxybate (GHB) concentration-time
`profiles in healthy adult males (n = 18) and females (n = 18) following
`a single oral dose of 4.5 g sodium oxybate oral solution.
`
`above the assay LOQ and observed over an interval of
`1 h) was 0.65 hours in males and 0.61 hours in females.
`AUC0-∞, estimates of plasma oral clearance, and mean
`apparent volumes of distribution (Table II) were not
`different between males and females.
`Urinary excretion of unchanged oxybate was a mi-
`nor elimination pathway in both sexes. For both men
`and women, the average urinary recovery of un-
`changed drug was about 3% in the 8-hour period fol-
`lowing dosing. Urinary excretion ranged from 1% to
`7% among the 36 subjects.
`
`Effect of Food on the Bioavailability
`of Sodium Oxybate
`
`Plasma concentration versus times curves for oxybate
`after an overnight fast and after a high-fat meal are
`shown in Figure 2, and pharmacokinetic parameters
`are summarized in Table III. Food significantly affected
`systemic exposure to oxybate. By 1 hour after dosing
`with sodium oxybate, plasma concentrations of
`oxybate were twice as high in subjects who received
`the drug after an overnight fast than in those who re-
`ceived it after a high-fat meal (Figure 2). Absorption
`was slower and peak plasma concentrations were ob-
`served later when sodium oxybate was dosed after a
`high-fat meal.
`Peak plasma concentrations of oxybate were lower
`in all 34 evaluable subjects in the fed state. The mean
`Cmax values were significantly decreased more than
`twofold in the fed condition as compared to the fasted
`state (p < 0.05). Mean AUC0-∞ values were likewise sig-
`nificantly higher in the fasted versus fed state (p <
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`AMN1033
`IPR of Patent No. 8,772,306
`
`

`
`INFLUENCE OF GENDER AND FOOD ON SODIUM OXYBATE
`
`Table III Effect of Food on the
`Pharmacokinetics of Sodium Oxybate
`
`Fasted State
`(n = 34)
`
`Parameter
`AUC0-∞ (μg•h/mL)
`289 (109)
`142 (34.2)
`Cmax (ng/mL)
`a (h)
`0.75
`tmax
`0.57 (0.30)
`t1/2 (h)
`3.7 (1.4)
`CL/F (mL/min/kg)
`192 (193)
`Vz/F (mL/kg)
`3.8 (2.0)
`Urinary recovery (%)
`490 (251)
`CLR (mL/h)
`Data presented as mean ± standard deviation.
`a. Median.
`*p < 0.05. **p = 0.001.
`
`Fed State
`(n = 34)
`
`188* (80.0)
`60.1* (20.1)
`2.00**
`0.68 (0.22)
`6.2 (3.2)
`384 (324)
`3.5 (1.8)
`826 (462)
`
`0.05). The median tmax of 2.00 hours in the fed state was
`significantly later than the median tmax of 0.75 hours in
`the fasted state (p = 0.0001).
`Based on the logarithmic transformations of Cmax and
`AUC0-∞, the mean (90% CI) ratio of fed/fasted for Cmax
`was 0.41 (0.37-0.46) and for AUC0-∞ was 0.63 (0.57-
`0.69). The 90% CIs for both parameters were outside
`the reference ranges that indicate equivalence (0.70-
`1.43 for Cmax and 0.80-1.25 for AUC0-∞).
`In both the fed and fasted conditions, decline in
`plasma concentrations of oxybate proceeded in a
`multiphasic manner (Figure 2). The mean elimination
`half-life was 0.68 hours when the dose was adminis-
`tered after a high-fat meal and 0.57 hours when the
`dose was administered after an overnight fast, a
`nonsignificant difference. Estimates of plasma oral
`clearance, mean apparent volumes of distribution, and
`renal clearance were not significantly different be-
`tween the fed and fasted states.
`Urinary excretion of unchanged oxybate was a mi-
`nor elimination pathway in both conditions. Urinary
`recovery of unchanged oxybate over the 10-hour
`postdose period averaged 3.5% (range = 1.2%-8.8%)
`for fasted subjects and 3.8% (range = 0.6%-11.0%) for
`fed subjects. Most of the urinary excretion occurred in
`the first 6 hours after dosing. Although the fraction ex-
`creted unchanged was unaffected by the treatments, re-
`nal clearance tended to be slightly higher when the
`dose was administered after a high-fat meal (Table III).
`
`Safety
`
`A total of 10 adverse events, including nausea, head-
`aches, hot flash, and itching, were reported by 8 of the
`36 volunteers during the gender study; most (70%)
`
`Figure 2. Mean (± SEM) plasma oxybate (GHB) concentration-time
`profiles in healthy adult females (n = 34) following a single oral dose
`of 4.5 g sodium oxybate oral solution under fasted and fed
`conditions.
`
`were experienced by females. A total of 86 adverse
`events, most commonly vomiting, nausea, and various
`CNS symptoms, were reported by 31 of the 36 female
`volunteers in the food effect study; most (79%) were re-
`ported when sodium oxybate was administered after
`an overnight fast. None of the adverse experiences in
`either study was classified as serious. One subject dis-
`continued the food effect study prematurely because of
`multiple nonserious adverse events experienced dur-
`ing the first treatment period in which she had received
`the drug after an overnight fast.
`Vital signs including measurements of blood pres-
`sure, heart rate, and respiratory rate were recorded
`within 1 hour before dosing and at 2, 6, and 10 hours af-
`ter the dose in each treatment period. No clinically sig-
`nificant changes in vital signs from baseline values
`were observed during either study.
`
`DISCUSSION
`
`Sodium oxybate oral solution is the first drug approved
`in the United States for the treatment of cataplexy in
`patients with narcolepsy. The maximum recom-
`mended daily dose is 9 g, in divided portions of 4.5 g
`given at bedtime and 2.5 to 4 hours later. This unusual
`dose regimen is based empirically on several early
`narcolepsy clinical trials conducted in Canada, the
`Netherlands, and the United States.4,6,8,9 From a
`pharmacokinetic perspective, dividing the nightly so-
`dium oxybate dose is rational because the elimination
`half-life of oxybate in narcoleptic patients is less than 1
`hour.13 The studies presented herein confirm the rapid
`elimination of oxybate after ingestion of the maximum
`recommended 4.5-g dose portion of sodium oxybate
`oral solution. Also, these studies extend findings from
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`BORGEN ET AL
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`clinical studies that sodium oxybate oral solution at
`recommended dosages is safe and well tolerated given
`that only 1 of the 72 healthy subjects in the two trials
`failed to complete the studies due to the occurrence of
`adverse effects.
`Oxybate is rapidly absorbed following ingestion of
`sodium oxybate oral solution. The mean time to
`achieve peak plasma oxybate concentration ranged
`from 45 minutes to 2 hours across different groups in
`the studies presented herein and was largest in the
`group receiving a high-fat meal. While the absorption
`characteristics of sodium oxybate were similar in
`males and females, they were significantly influenced
`by food, which delayed the absorption of oxybate on
`average by more than an hour compared to the fasted
`state. The significantly reduced bioavailability of
`oxybate when sodium oxybate oral solution was in-
`gested after a high-fat meal suggests that ingestion on
`an empty stomach will produce maximal systemic ex-
`posure. The effect of a high-protein or high-fiber meal
`has not been reported. Similarly, the effects of other
`agents that alter gastric motility or pH on oxybate
`bioavailability have not been reported. In patients with
`narcolepsy, the recommended nocturnal dosing gener-
`ally begins several hours after the evening meal, which
`should ameliorate any major food effects on the
`bioavailability of the drug.
`Others have reported that the absorption character-
`istics of sodium oxybate can also be influenced by
`dose, with tmax increasing as the dose increases, indicat-
`ing a capacity-limited absorption.12 Similar findings
`have been observed in our studies16 of sodium oxybate
`oral solution, in which the tmax value following a 2.25-g
`dose was approximately 0.9 hours and, after a 4.5-g
`dose, approximately 1.2 hours,16 consistent with the
`tmax observed in the gender study reported herein (1.25
`and 1.14 h in males and females, respectively). In this
`respect, peak plasma concentrations of oxybate were
`also reached somewhat earlier in patients with
`narcolepsy who received 3 g sodium oxybate (0.67 h).13
`The average apparent volume of distribution of
`oxybate divided by absolute bioavailability (Vz/F)
`ranged between 190 and 384 mL/kg across the studies
`reported herein and was not significantly affected by
`gender or food, although it was highest in the subjects
`fed a high-fat meal. These values were similar to those
`reported for healthy volunteers (335 mL/kg) and
`cirrhotic patients without and with ascites (198 and
`285 mL/kg, respectively).15
`Nonlinear elimination pharmacokinetics and
`capacity-limited disposition kinetics have also been
`described previously.17 Plasma clearance of oxybate
`has been shown to decrease as the oral dose of sodium
`
`64 • J Clin Pharmacol 2003;43:59-65
`
`oxybate increases.12,14 Similar findings have been ob-
`served in our studies of sodium oxybate oral solution,
`in which the mean oral plasma clearance for oxybate
`was 6.6 mL/min/kg at the lower end of the therapeutic
`dose range (4.5 g in 2 × 2.25-g portions given 4 h apart)
`and almost 50% less (3.6 mL/min/kg) at the maximum
`recommended dose (9 g in 2 × 4.5-g portions given 4 h
`apart).16 Plasma clearance of oxybate in the present
`studies ranged between 3.7 and 6.2 mL/min/kg and
`was not significantly affected by gender or food.
`Oxybate undergoes rapid elimination, with the half-
`life values in the present studies being approximately
`35 to 40 minutes, with no significant effects of gender
`or food. These are consistent with values reported else-
`where, and although a 40% increase in the mean appar-
`ent elimination half-life has been observed following
`the high versus low therapeutic dose range of sodium
`oxybate oral solution,16 this is not clinically relevant.
`As shown in the present studies, plasma levels of
`oxybate are negligible by 6 hours after the ingestion of
`4.5 g sodium oxybate oral solution in both males and fe-
`males and after an overnight fast or high-fat meal. Over-
`all, no accumulation of oxybate is expected with its
`nocturnal divided dosing schedule in patients. Consis-
`tent with biotransformation of oxybate to carbon diox-
`ide being the major mechanism of its clearance, recov-
`ery of unchanged drug was negligible in the present
`studies (< 4%). Renal clearance was unaffected by gen-
`der or food.
`The adverse events observed in this study are con-
`sistent with those observed in Phase 3 clinical trials.18
`The incidence of adverse events tended to be higher in
`females than males. Since males were somewhat
`heavier than females, this may be related to a higher
`mg/kg dose in the females. Likewise, all subjects in the
`food study were females, and most of the adverse
`events occurred after ingestion of the drug following an
`overnight fast. Since the bioavailability was lower
`when oxybate was ingested immediately after a meal,
`there were fewer adverse events compared to the inges-
`tion of oxybate in a fasted state.
`In summary, no dose adjustment based on gender is
`warranted. Although food significantly reduces sys-
`temic exposure to oxybate, this effect is likely to be
`minimal in patients if they follow the recommended
`dose schedule of taking the first dose of sodium
`oxybate oral solution at bedtime, which is usually sev-
`eral hours after their evening meal.
`
`We wish to acknowledge the analytical assistance of Glenn
`Hanson and his staff at Covance Laboratories, Dale Bourg and the
`clinical staff of Bio-Kinetic Clinical Applications, and the help of Dr.
`Joyce Willetts in preparation of the manuscript. The studies were
`funded by Orphan Medical, Inc.
`
`AMN1033
`IPR of Patent No. 8,772,306
`
`

`
`INFLUENCE OF GENDER AND FOOD ON SODIUM OXYBATE
`
`REFERENCES
`
`1. Scrima L: An etiology of narcolepsy-cataplexy and a proposed
`cataplexy neuromechanism. Int J Neurosci 1981;15:69-86.
`2. Mitler MM, Aldrich MS, Koob GF, Zarcone VP: Narcolepsy and its
`treatment with stimulants. Sleep 1994;17:352-371.
`3. Broughton R, Mamalek M: Effects of nocturnal gamma-
`hydroxybutyrate on sleep/waking patterns in narcolepsy-cataplexy. J
`Canadien Des Sciences Neurologique 1980;7:23-30.
`4. Broughton R, Mamelak M: The treatment of narcolepsy-cataplexy
`with nocturnal gamma-hydroxybutyrate. J Canadien Des Sciences
`Neurologique 1979;6:1-6.
`5. Bedard M-A, Montplaisir J, Godbout R, Lapierre O: Nocturnal
`gamma-hydroxybutyrate effect on periodic leg movements and sleep
`organization of narcoleptic patients. Clin Neuropharm 1989;12:29-
`36.
`6. Lammers GJ, Arends J, Declerck AC, Ferrari MD, Schouwink G,
`Troost J: Gammahydroxybutyrate and narcolepsy: a double-blind
`placebo-controlled study. Sleep 1993;16:216-220.
`7. Mamelak M, Webster P: Treatment of narcolepsy and sleep apnea
`with gamma-hydroxybutyrate: a clinical and polysomnographic case
`study. Sleep 1981;4:105-111.
`8. Mamelak M, Scharf MB, Woods M: Treatment of narcolepsy with
`γ-hydroxybutyrate: a review of clinical and sleep laboratory findings.
`Sleep 1986;9:285-289.
`9. Scharf M, Brown D, Woods M, Brown L, Hirschowitz J: The effects
`and effectiveness of γ-hydroxybutyrate in patients with narcolepsy. J
`Clin Psychiatry 1985;46:222-225.
`10. Scrima L, Hartman PG, Johnson FH, Hiller FC: Efficacy of gamma-
`hydroxybutrate versus placebo in treating narcolepsy-cataplexy:
`double-blind subjective measured. Biol Psychiatry 1989;26:331-343.
`
`11. Scrima L, Hartman PG, Johnson FH, Thomas EE, Hiller FC: The
`effects of γ-hydroxybutyrate on the sleep of narcolepsy patients: a
`double blind study. Sleep 1990;13:479-490.
`12. Palatini P, Tedeschi L, Frison G, Padrini R, Zordan R, Gallimberti
`L, et al: Dose-dependent absorption and elimination of gamma-
`hydroxybutyric acid in healthy volunteers. Eur J Clin Pharmacol
`1993;45:353-356.
`13. Scharf MB, Lai AA, Branigan B, Stover R, Berkowitz DB:
`Pharmacokinetics of gammahydroxybutyrate (GHB) in narcoleptic
`patients. Sleep 1998;21:507-514.
`14. Ferrara SD, Zotti S, Tedeschi L, Frison G, Castagna F, Gallimberti
`L, et al: Pharmacokinetics of γ-hydroxybutyric acid in alcohol de-
`pendent patients after single and repeated oral doses. Brit J Clin
`Pharmacol 1992;34:231-235.
`15. Ferrara SD, Tedeschi L, Frison G, Orlando R, Mazzo M, Zordan R,
`et al: Effect of moderate or severe liver dysfunction on the
`pharmacokinetics of γ-hydroxybutyric acid. Eur J Clin Pharmacol
`1996;50:305-310.
`16. Borgen L, Lane E, Lai A: Xyrem® (sodium oxybate): a study of
`dose proportionality in healthy human subjects [abstract]. J Clin
`Pharmacol 2000;40:1053.
`17. Palatini P, Ferrara SD: Pharmacokinetics of γ-hydroxybutyric
`acid. Alcologia 1996;8:185-191.
`18. The U.S. Xyrem Multicenter Study Group: A randomized, double
`blind, placebo-controlled multicenter trial comparing the effects of
`three doses of orally administered sodium oxybate with placebo for
`the treatment of narcolepsy. Sleep 2002;25:42-49.
`
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`AMN1033
`IPR of Patent No. 8,772,306