6. Protocol OMC-SXB-ll: Effect of Food on the Pharmacokinetics of GHB.
`
`Title:'
`
`A Study to Examine the Effect of Food on the Bioavailability of Xyrem Oral
`Solution in Healthy Volunteers.
`
`Objective:
`The main purpose of this study was to describe the plasma pharrnacokinetics of
`gamma—hydroxybutyrate (using an ,M assay) following a 4.5 g dose of Xyrem
`oral solution administered after a standardized high fat meal and after an overnight fast.
`In addition, the safety and tolerability of the drug were evaluated.
`
`Study Design and Methods:
`two-
`two—period,
`This study utilized a single—center, single-dose, Open-label,
`treatment, crossover, randomized design. After qualifying for the study, each subject was
`randomized to one of two treatment sequences. All subjects spent the night before dosing
`at the study facility. During the morning of period 1, half the subjects ingested 4.5 g of
`the study drug following a standardized high fat breakfast served half an hour before
`dosing; the other subjects ingested an equivalent dose of the study drug in a fasting state.
`There was a 7-day washout between periods 1 and 2. During period 2,
`individual
`subjects crossed over to the other treatment. Serial plasma samples were collected pre—
`dose and up to 10 hours following Xyrem dosing for the determination of pertinent
`pharmacokinetic parameters and evaluation of the effect of administration with food. All
`urine voided was collected in two-hour increments up to 10 hours post—dose. Throughout
`the treatment phase, each volunteer was monitored for the occurrence of adverse events
`(ABS) and changes in vital signs.
`
`Subjects:
`Thirty-six healthy female volunteers (34 Caucasian and 2 Hispanic; 18 to 55 years
`of age; 52 to 84 kg in weight) enrolled in the study and 34 completed the study.
`If a
`female subject was of childbearing potential, a negative serum pregnancy test was
`required prior to study entry. One subject did not return for period 2 because of ABS in
`period 1
`consisting of dizziness, nausea, vomiting,
`apnea, hypoventilation and
`involuntary defecation. Another subject did not return for period 2 because of an illness
`(not related to study drug administration).
`
`Test Product, Dose and Mode of Administration:
`
`Xyrem was supplied as an oral solution containing 500 mg sodium oxybate per
`milliliter. It was supplied by Orphan Medical in bottles of 180 ml. (Lot No: EH75).
`
`Criteria for Evaluation:
`
`Pharmacokinetic evaluation included the determination of peak concentration
`(Cmax), corresponding peak times (tmax), area under the curve (AUCinf), oral plasma
`clearance (CL/F), elimination half—life (ll/2), percentage of dose excreted unchanged in
`urine and renal clearance (CL).
`Non—compartmental methods were used in the
`determination of various pertinent pharmacokinetic parameters. The effect of food was
`determined by ANOVA of logarithmically transformed AUCmf and Cmax and computation
`
`32
`
`

`

`of the 90% confidence interval about the ratio of the mean results observed after a high
`fat meal and after an overnight fast. A non-parametric comparison (Wilcoxon rank sum
`test) was used in the comparison of fed and fasting tmax values.
`
`Assay Validation:
`assay. For both plasma and
`The assay used to quantitate GHB was an .
`urine, the calibration curve was linear for the concentration range from
`
`
`
`
`with a lower limit of quantitation (LLOQ) of .
`
`The between day variability did
`
`not exceed 10% for the QC samples of 15, 75, 150, and 400 ug/ml. For the accuracy of
`the method, the deviations from the mean were —7.1% for the low QC sample, -5.7% for
`the intermediate QC sample, —3.2% for the high QC sample, and 0.9% for the over the
`curve QC sample. Comparatively for urine, the deviations from the mean were -1% for
`the low QC sample, —8.8% for the intermediate QC sample, and -3.4% for the high QC
`sample.
`
`Results:
`
`Figure 6. Effect of Food on the Plasma Concentrations of GHB Following a 4.5 g
`oral dose.
`
`150
`
`225
`
`2‘
`
`5‘
`
`er-a
`
`
`
`MumGHBConcentration019mm
`
`T
`
`4
`
`A
`
`‘
`
`ri'
`
`\
`
`0.0
`
`20
`
`2.0
`
`3.0
`
`4.0
`
`5.0
`
`6.0
`
`m
`
`3.0
`
`9.0
`
`10.0
`
`11.0
`
`Schadulad I‘m (hr)
`Mimcn'. m Pinning
`6—64 Far!
`
`33
`
`

`

`Figure 7. Cumulative Renal Excretion of GHB Following an oral dose of 4.5 g.
`
`
`
`
`
`CumulativaUrinaryauction(96]
`
`
`
`Table 16: GHB Pharmacokinetic Parameters
`
`[Arithmetic Mean (iSD)**3
`
`
`
`
`Cw (pg/mm
`60.1* (20.1)
`142 (34.2)
`
`-——i *0."
`
`0'68 (0.22,
`
`0.57 {0.30)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`W“
`
` I
`
`
`
`
`*Statistically significant at p < 0.05.
`**Median is reported for tmax.
`
`34
`
`

`

`Table 17: Gamma—Hydroxybutyrate Pharmacokinetic Parameters:
`
`Effect of Food (90% Confidence Intervals)
`
`.
`Parameter (units)
`
`
`
`
`
`
`
`AUCinfflig-hI/ml)
`
`Least Squares Geometric
`
`
`
`Ratio of
`
`
`90% Confidence
`
`Means
`
`Means
`
`Interval
`
`Fed (n=34)
`
`Fasting
`
`(n=34)
`
`168.7
`
`269.4
`
`0.57—0.69
`
`
`
`
`
`
`On average Cmx decreased by 59% and AUCinf decreased by 37%. The 90%
`confidence intervals were outside the reference ranges (0.80 — 1.25 for both Cmx and
`AUCjnf) that indicate bioequivalence. Absorption of sodium oxybate appeared to be
`slower following food consumption, resulting in a later tmax of 2 hr compared to 0.75 hr.
`The tmax values for fed and fasting states were significantly different (p=0.0001). The
`apparent halfilife of GHB was less than 1 h for both dosing conditions. Urinary excretion
`of unchanged drug was a minor elimination pathway and unaffected by the treatment
`conditions (means were 3.5% [fasting] and 3.8% [fed]). More adverse events were
`experienced when_Xyrem was administered after an overnight fast than when it was
`administered after a high fat meal, probably as a result of the higher plasma
`concentrations of drug observed when Xyrem was administered after a fast. According to
`the sponsor, all of the adverse events were well tolerated by healthy adult volunteers and
`resolved without sequelae.
`
`Conclusion:
`
`Food decreased the systemic exposure of gamma-hydroxybutyrate with decreases in
`Cmax and AUC of 59% and 37%, respectively.
`In addition,
`the data showed that
`considerable absorption occurred up to 4 h following administration of the drug. This
`pronounced effect of food on the bioavailability of GHB suggests that timing of food
`intake relative to administration is crucial in obtaining the maximum bioavailability of
`the drug. Therefore, Xyrem should be taken in the fasted state.
`
`7. Effect of Hepatic Impairment on the Pharmacokinetics of GHB.
`
`Title: Effect of moderate or severe liver dysfunction on the pharmacokinetics of y—
`hydroxybutyric acid.
`
`Objective:
`Since GHB is primarily metabolized by the liver, a hepatic impairment study
`would be warranted. The sponsor has submitted a previously published study (Ferrara et
`al, 1996) to support labeling recommendations in this special population. The main
`
`35
`
`

`

`purpose of this study was to assess the effect of moderate or severe liver dysfunction on
`the pharrnacokinetics of y—hydroxybutyric acid.
`
`Subjects:
`Sixteen male patients with biopsy—proven liver cirrhosis (8 with ascites and 8
`without ascites) were studied (mean age; 55 and 60 yrs.) All nonascitic patients were
`categorized as Child’s Pugh class A (score of 5), whereas ascitic patients were Child’s
`class C (score of 15). Exclusion criteria included a history of hypersensitivity to the
`administered drugs, recent history of GI bleeding, severe encephalopathy, a CLCR < 50
`ml/min, and presence of any other disease. None of the patients were heavy smokers
`All of the patients abstained from alcohol and other drugs two weeks prior to the study,
`apart from those used to treat cirrhosis: diuretics, H2—blockers, and vitamin supplements.
`
`Study Design and Methods.
`A liver metabolic function of each patient was evaluated by measuring antipyrine
`clearance and the formation rate of lidocaine metabolite, monoethylglycinexylidide
`(MEGX). GHB, lidocaine, and antipyrine were administered at 8 am. following an
`overnight fast. On day 1, each patient underwent a MEGX liver function test. Lidocaine
`was infused over 2 min. and serial blood samples were collected up to l h. On day 3,
`antipyrine was administered orally at a dose of 10 mg/kg. Subsequently, blood samples
`were collected over 48 h. On day 8, GHB, dissolved in black cherry syrup was
`administered orally at a dose of 25 mg/kg (1.75 g). Blood samples were collected at
`serial time points up to 6 h.
`In addition, urine was collected before and up to 24 h
`following administration of the drug.
`
`Analytical Methods.
`GHB was quantitated in plasma and urine using a previously described
`assay (Data to support assay validation was not included in the study). The limit of
`
`
`
`detection for the assay was W The calibration curve had a correlation coefficient
`
`of 0.997 over the relevant concentration range up to 50 pg/ml. The intra- and interassay
`
`. coefficients of variation were both below 3% at 5 pg/ml and 2% at 50 ug/ml.
`
`Pharmacokinetic Analysis.
`Noncompartmental approaches were used to estimate various pharrnacokinetic
`parameters, including the maximum observed plasma concentration (Cmax), observed time
`to Cmax (tmax), terminal half—life (ti/2), area under the plasma concentration-time curve
`(AUC), area under the first moment of the plasma concentration—time curve (AUMC),
`mean residence time (MRT), apparent oral clearance (CLpo), renal clearance (CL,), and
`apparent volume of distribution following oral administration (VI/f).
`
`36
`
`

`

`Results.
`
`Figure 8. Semilogarithmic plot of mean (SEM) plasma concentrations of GHB vs.
`time. Filled circles; cirrhotics without ascites, open circles; cirrhotics with
`ascites.
`
`3‘3
`
`
`
`
`
`
` 3Gmpmmacommitment(”on")
`
`8 s .
`
`
`
`
`
`
`
`Time 1M
`
`Table 18. Mean (SD) pharmacokinetic parameters of GHB after oral
`administration of 25 mg/kg.
`WM
`
`Healthy volontecrs‘
`
`Cirrbotics
`without 3565165
`
`cirrhotics
`With ascites.
`
`47 (1:);
`68 (19)? _
`46 {22)
`‘
`mi“
`‘45 (33-603:
`45 new?"
`30 (20—45%
`‘)
`53%;
`5543 {2566)"
`5:25 assay"
`2542 (2 :20)
`AUC (51g~nil"~min)
`4.1mm
`4.5 (3.5)"
`9.1950)
`CL. (1111‘ min-“'«kg—‘i
`255 (62)“
`193 (553*
`335 {l 14)
`Vzil'fini’kg’l)
`55 (29’...
`32 our
`22 (3)
`{as (min)
`no (45)
`_
`71 my
`53 (9)
`MM (min)
`0.43 (10)
`1.63 (0.64)“
`0.33 (9.50}
`Urinary recovery
`1. i
`-
`(“In close)
`.013 0.009;
`r
`'
`‘ “ -'
`
`0“W JOE‘S (0.030) { ._..—-«~'
`0.067 (0.043}
`)
`CLn (mt-mm -kg
`‘ Data from ref. [10] [\Vzlf, urinary weaver)! and C LR not presented Ehcrcin)
`hMedian vain: (range): ‘P < 0.05, "P < {ml or *"P < 0.06! vs healthy volunteers
`
`,
`
`*
`
`
`
`Following administration of GHB, various pharmacokinetic parameters differed
`significantly in patients with hepatic impairment compared with healthy volunteers.
`In
`cirrhotic patients without ascites, Cmax and AUC increased by 1.5- and 2—fold. The
`apparent oral clearance decreased 2—fold and the percent of administered dose recovered
`in urine was doubled.
`In patients with ascites,
`the total systemic exposure (AUC)
`doubled and CLp0 decreased 2-fold. T1 /2 and MRT increased by more than 2—fold.
`
`37
`
`

`

`Conclusion:
`
`The results of this study suggest that the GHB dose should be decreased by one-
`half in patients that are hepatically impaired.
`l(Note: According to the reference used,
`the healthy subjects ( 22 — 26 yrs.) were not age-matched with the patients in this
`study).
`IPalatini et al, 1993. Dose-dependent absorption and elimination of GHB in healthy
`volunteers. EurJ. Clin. Pharmacol., 45:353-6.
`
`8. Protocol OMC- SXB-12: Pharmacokinetic Interaction of GHB with Zolpidem
`Title: A Study To Determine The Interaction Potential Of Xyrem® (Sodium Oxybate,
`Sodium y—Hydroxybutyrate) With Ambien® (Zolpidem Tartrate) In Normal Healthy
`Volunteers.
`
`Objectives:
`The purpose of this study was to describe the plasma pharrnacokinetics of
`gamma-hydroxybutyrate ‘W
`
`1 assay) and zolpidem 7M
`..__.—— assay) in normal healthy human subjects. In addition, the safety and tolerability
`of sodium oxybate administered as an oral solution alone or in combination with 5 mg of
`zolpidem tartrate as a tablet (Ambien) were compared.
`
`Study Center:
`
`—-—-—~——-———--—--—-———-
`
`__________\_~
`
`Study Design and Methods:
`three-
`three—period,
`This Phase I study utilized a single—center, open—label,
`treatrnent, crossover, randomized design. After qualifying for study entry based on
`medical history and satisfying the inclusion/exclusion criteria, each subject was
`randomized to one of three treatment sequences. All subjects spent the night before
`dosing at the study facility. During the morning of period 1, one third of the subjects
`ingested 3 g of Xyrem following an overnight fast; one third of the subjects ingested a 5
`mg Ambien tablet after an overnight fast; and one third of the subjects ingested both 3 g
`Xyrem and a 5 mg Ambien tablet after an overnight fast. There was a 7—day washout
`between periods 1, 2 and 3. During periods 2 and 3, individual subjects crossed over to
`the other treatments according to the sequence to which they had been randomized.
`Serial plasma samples were collected pre-dose and up to 24 h following dosing for the
`determination of pertinent pharmacokinetic parameters and evaluation of the effect of co—
`administration. Throughout the treatment phase, each volunteer was monitored for the
`occurrence of adverse events (ABS) and changes in vital signs.
`
`38
`
`

`

`Subjects:
`Fifteen healthy volunteers (five female; 14 Caucasian and one Multiracial; 19 to
`51 years of age; 56 to 98 kg in weight) were selected on the basis of general good health
`as confirmed by physical examination, medical history, and clinical
`laboratory
`evaluations.
`
`Test product, Dose, and Mode of Administration:
`Xyrem was supplied as an oral solution containing 500 mg sodium oxybate
`(gamma—hydroxybutyrate) per milliliter. It was supplied by Orphan Medical in bottles of
`180 ml [Lot No: EH75]. Ambien was supplied as tablets containing 5 mg zolpidem
`tartrate (equivalent to 4.02 mg zolpidem base) [Lot No: 9L474]. The 3 treatments
`compared in this study were single oral doses of 3 grams sodium oxybate administered
`alone, 5 mg Ambien tablet administered alone and the combination of 5 mg Ambien
`tablet and 3 grams sodium oxybate. Each treatment was administered after an overnight
`fast. The dose was administered at approximately 0700 hours (7 am). Each Xyrem
`dose was diluted with 60 ml room—temperature water and the dosing cup was rinsed with
`another 180 ml water. Each Ambien dose was administered with 240 ml water. For the
`
`combination treatment the Ambien tablet was administered with the 60 ml Xyrem dose
`and followed by the 180 ml dosing cup rinsings.
`
`Criteria for Evaluation:
`
`Phannacokinetic evaluation included the determination of peak concentration
`(me), corresponding peak times (tmax), area under the curve (AUCmf), oral plasma
`clearance (CL/F), elimination half—life (tug) of gamma-hydroxybutyrate and of zolpidem
`when administered alone and in combination. Non-compartmental methods were used in
`the determination of various pertinent pharmacokinetic parameters. Descriptive statistics
`(mean, median, standard deviation, coefficient of variation, maximum, and minimum)
`were computed for pertinent pharmacokinetic parameters for both treatments. The effect
`of co—administration of zolpidem tartrate on gamma—hydroxybutyrate pharmacokinetics
`was determined by an ANOVA of logarithmically transformed AUCinf and Cmax and
`computation of the 90% confidence interval about the ratio of the mean results observed
`after administration in combination and alone. A non—parametric analysis (Wilcoxon
`signed rank test) was used in the comparison of tmax values.
`
`
`
`Assay Validation:
`assay. For plasma, the
`The assay used to quantitate GHB was an ,
`calibration curve was linear for the concentration range from ———-—-—-—'——7
`7 with a lower
`U
`limit of quantitation (LLOQ) of 7".-.“ The within-day variability ranged from 2.1 to
`6.7% for the QC samples of 15, 75, and 150ug/m1. For the accuracy of the method, the
`deviations from the mean were —8.5% for the low QC sample, -5.9% for the intermediate
`QC sample, and -4.7% for the high QC sample.
`assay. The
`For zolpidem, the assay used for quantitation was a
`within-day variability ranged from 0.91 to 7.8% for the QC samples of 3, 30, and 300
`ng/ml. For the accuracy of the method, the deviations from the mean for all the QC
`samples were all within 5.8% when the samples were processed manually. Using an
`automated sample—processing unit, the deviations from the mean for all the QC samples
`
`
`
`39
`
`

`

`were all within 10.8%. The calibration curve was linear for the concentrations ranging
`
`from M with a lower limit of quantitation (LLOQ) of
`
`Results:
`
`Figure 9: Plasma Concentration-Time Profile of GHB Following (Zn-administration
`of Ambien.
`
`(m‘le
`
`Manncan:Consultation
`
`0.0
`
`2.0
`
`4.0
`
`S .(I
`
`8.0
`
`10-0
`
`12.0
`
`MD
`
`11-08mm
`
`t-H mun alone
`
`.44 mm plus Amman
`
`5:};qu 'fima {ht}
`
`APPMES HHS WAY
`Gill fiRlGlfiAL
`
`APPEMS THlS WAY
`
`034 GRlGlllAl.
`
`40
`
`

`

`Table 19
`
`
`
`
`
`
`
`
`
`
`Gamé-fiydroxybutyrate Phamacokinetic Parameters:
`
`[Arithmetic Mean (iSD) **}
`
`,
`Parameter (unlts)
`
`Xyrem Alene
`(
`15)
`
`n:
`
`
`
`
`
`Xyrem With
`.
`(
`15)
`Ambler:
`
`n=
`
`
`
`
`
`
`** Median is reported for Tm.
`
`There were no significant effects of ere-administration of Ambien
`
`with Xyrem (p>0.05) .
`
`Table 20: Gamma-Hydroxybutyrate Pharmacokinetic Parameters:
`
`Effect of Ambien Co-Administration (90% Confidence Intervals)
`
`Least Squares Geometric
`
`.
`Parameter (umts)
`
`Means
`With Ambien
`
`
`
`Alone
`
`Ratio of
`Means
`
`90% Confidence
`Interval
`
`(n=15)
`(n=15)
`
`
`Cm“ (pg/ml)
`,85'5
`81.0
`1,06
`0.85 M 1.31
`
`
`Aucmfmg-hr/ml)
`133-4
`1300
`1-03
`0'93 ” ”4
`
`
`APPEARS THlS WAY
`0ft Gasman
`
`41
`
`

`

`Figure 10: Effect of GHB on the Plasma Pharmacokinetics of Zolpidem
`105
`
`1‘.
`
`9"?
`,
`
`‘2
`
`l/
`
`75
`
`
`
`
`
`MZolpddmConmmfinn(ham) 88
`
`{\V
`
`\
`
`mm _,
`
`4.0
`
`6.0
`
`16.0
`1210
`Scheduled Time (hr)
`
`20.0
`
`24.0
`
`28.0
`
`Tmalmam
`
`i—H Amhim alone
`
`H“. NaGHB plus Ambiou
`
`15
`
`:
`f
`
`0 r
`0.0
`
`,
`
`Table 21
`
`Zolpidem Pharmacokinetic Parameters:
`
`.
`I
`Parameter Mints)
`
`
`
`
`
`
`
`
`
`[251:1thch Mean gamut-t}
`Arabian. Alone
`
`
`
`
`
`
`
`
`
`Arabian With
`
`(13:15}
`
`Xyrem (11215)
`
`
`
`
`
`** Median is reparted for Tmax‘
`
`42
`
`

`

`Table 22: Zolpidem Pharmacokinetic Parameters:
`
`Effect of Xyrem Co-Administration (90% Confidence Intervals)
`
`Least Squares Geometric
`
`
`
`
`Means
`Parameter (units) With Xyrem
`
`Ratio of
`Means
`
`90% Confidence
`Interval
`
`Alone (n=15)
`(n=15)
`
`
`Cmax (Hg/ml)
`90.0
`98.0
`0.92
`0.78 —— 1.08
`
`
`AUCinf(ng‘11r/ml)
`
`368.4
`
`375.8
`
`0.98
`
`0.85 — 1.13'
`
`The systemic exposure to gamma—hydroxybutyrate following co—administration
`with Ambien was equivalent to the systemic exposure when Xyrem was administered
`alone. The gamma—hydroxybutyrate Cmax increased by 6% and AUCinf increased by 3%
`in the presence of Ambien.
`The systemic exposure to zolpidem following co—
`administration with Xyrem was equivalent to the systemic exposure when Ambien was
`administered alone.
`In the presence of Xyrem, the zolpidem Cmax and AUCjnf decreased
`by 8% and 2%, respectively. According to the sponsor, the frequency and severity of
`adverse events was the same when Xyrem and Ambien were administered together as
`when Xyrem was administered alone. One adverse event was experience when Ambien
`was administered alone. All of the adverse events were well tolerated by healthy adult
`volunteers and resolved without sequelae.
`
`Conclusions:
`
`When Xyrem and Ambien were administered together, no clinically significant
`pharmacokinetic changes were observed for either drug. A pharrnacodynamic interaction
`cannot be ruled out, especially when 9 g/day of Xyrem and 10 mg of zolpidem are
`administered. The results of the assay validation may be suspect because the tables
`submitted for this study were identical to the tables in the Modafinil and Vivactil drug
`interaction studies.
`
`9. Protocol OMC- SXB-14: Pharmacokinetic Interaction of GHB with Vivactil
`
`(Protriptyline).
`Title: A Study To Determine The Interaction Potential Of Xyrem® (Sodium Oxybate,
`Sodium y—Hydroxybutyrate) With Vivactil® (Protriptyline Hydrochloride) In Normal
`Healthy Volunteers
`
`Objectives:
`The purpose of this study was to describe the plasma pharmacokinetics of
`
`gamma-hydroxybutyrate ’W
`
`J
`assay) and protriptyline
`' .W
`
`“
`assay) in normal healthy subjects following administration of
`
`43
`
`

`

`In addition, the
`Xyrem and Vivactil alone and in combination after an overnight fast.
`safety and tolerability of sodium oxybate was assessed when administered alone and in
`combination to healthy volunteers.
`
`Study Center:
`
`“HM
`<_____———————~\
`
`Study Design and Methods:
`three-treatment,
`three-period,
`This study utilized a single-center, open-label,
`crossover, randomized design. After qualifying for study entry based on medical history
`and satisfying the inclusion/exclusion criteria, each subject was randomized to one of
`three treatment sequences. All subjects spent the night before dosing at the study facility.
`During the morning of period 1, one third of the subjects ingested 2 x 2.25 g Xyrem 4 h
`apart, following a light breakfast; one third of the subjects ingested one 10 mg Vivactil
`tablet after a light breakfast; and one third of the subjects ingested both 2 x 2.25 g Xyrem
`and a 10 mg Vivactil tablet after a light breakfast. Lunch, dinner and a snack were given
`to the subjects at 5, 9, and 14 h following administration of GHB. There was a 3—week
`washout between periods 1, 2 and 3. During periods 2 and 3, individual subjects crossed
`over to the other treatments according to the sequence to which they had been
`randomized. Serial plasma samples were collected pre—dose and up to 312 h after the
`Vivactil dose,
`in combination treatment, and up to 8 h after Xyrem dosed alone.
`Appropriate samples were analyzed for the determination of pertinent pharmacokinetic
`parameters and evaluation of the effect of co-administration. Throughout the treatment
`phase, each volunteer was monitored for the occurrence of adverse events (AE5) and
`changes in vital signs.
`
`Subjects:
`Twelve healthy volunteers (five male and seven female; 11 Caucasian and one
`Asian; 19 to 55 years of age; 56 to 89 kg in weight) were selected on the basis of general
`good health as confirmed by physical examination, medical history, and clinical
`laboratory evaluations.
`
`Test Product, Dose, and Mode of Administration (Batch No):
`Xyrem was supplied as an oral solution containing 500 mg sodium oxybate
`(gamma-hydroxybutyrate) per milliliter.
`It was supplied by Orphan Medical in bottles of
`180 ml [Lot No: EH75]. Vivactil was supplied as tablets containing 10 mg protriptyline
`hydrochloride (equivalent
`to 8.78 mg protriptyline base) [Lot No: H6740]. The 3
`treatments compared in this study were a divided oral dose of 2 x 2.25 g sodium oxybate
`administered 4 h apart, a single oral dose of one 10 mg Vivactil tablet administered alone
`and the combination of a 10 mg Vivactil tablet and 2 x 2.25 g sodium oxybate. Each
`treatment was administered 2 h after a light breakfast. The doses were started at
`approximately 0800 hours (8 am). Each Xyrem dose was diluted to 60 ml with
`room—temperature water and the dosing cup was rinsed with another 60 ml water. Each
`Vivactil dose was administered with 120 ml water. For the combination treatment the
`
`44
`
`

`

`Vivactil tablet was administered with the 60 ml Xyrem dose and followed by the 60 m1
`dosing cup rinsings.
`
`Criteria for Evaluation:
`
`Pharmacokinetic evaluation included the determination of peak concentration
`(Cmax), corresponding peak times (tmax), area under the curve (AUCinf), oral plasma
`clearance (CL/F), elimination half-life (tug) of gamma—hydroxybutyrate (GHB) and of
`protriptyline when administered alone and in combination. Dose-l Cmax and dose-2 Cmax
`and the corresponding tmax were determined for the 2 portions of each Xyrem dose. Non—
`compartmental methods were used in the determination of various pertinent
`pharmacokinetic parameters. Descriptive statistics (mean, median, standard deviation,
`coefficient of variation, maximum, and minimum) were computed for pertinent
`pharmacokinetic parameters for all treatment groups. The effect of co—administration of
`protriptyline
`hydrochloride
`on
`gamma—hydroxybutyrate
`pharmacokinetics was
`determined by an ANOVA of logarithmically transformed AUCinf, dose-1 Cmax and dose—
`2 Cmax and computation of the 90% confidence interval for the ratio of the mean results
`observed after administration in combination and alone. A non-parametric analysis'
`(Wilcoxon signed rank test) was used in the comparison of tmax values. The effect of co
`administration of Xyrem on protriptyline AUCinf and Cmax were determined in the same
`manner.
`
`Assay Validation:
`The assay used to quantitate GHB and protriptyline was an -——— assay.
`For plasma GHB, the calibration curve was linear for the concentration range from H
`“"7 with a lower limit of quantitation (LLOQ) of 5- The within—day
`
`variability ranged from 2.1 to 6.7% for the QC samples of 15, 75, and 150ug/m1. For the
`accuracy of the method,
`the deviations from the mean were —8.5% for the low QC
`sample, -5.9% for the intermediate QC sample, and -4.7% for the high QC sample.
`For protriptyline, the within-day variability ranged from 4.1 to 9% for the QC
`samples of 0.06, 2.00, and 40 ng/ml. For the accuracy of the method, the deviations from
`the mean were —0.5% for the low QC sample, -1.1% for the intermediate QC sample, and
`—0.9% for the high QC sample. The calibration curve was linear for the concentration
`range from M with a lower limit of quantitation (LLOQ) of
`
`APPEARS This WAY
`0N OREGWAL
`
`45
`
`

`

`Results:
`
`Figure 11: Effect of Vivactil on the Plasma Concentration-Time Profile of GHB
`
`
`
`0.0
`
`1.0
`
`2.0
`
`3.0
`
`4,0
`
`5.0
`
`5‘0
`
`7.0
`
`8.0
`
`9.0
`
`10.0
`
`11.0
`
`:5
`
`E ga5 §5
`
`William
`
`*"H Xymm alone
`
`H". Xymm plus Vivamil
`
`deMMTMwmfl
`
`Table 23
`
`Gamma~8ydroxybutyrate Pharmacokinetic Parameters:
`
`[Arithmetic Mean (iSD)'*]
`
`
`
`Parameter (units)
`
`Xyren Alone
`(naiZ)
`
`Dose—1 CW“
`
`(pg/mL)
`
`55.1 (14 5)
`
`Aucm (ngzr/mL)
`
`173 (72.6}
`
`
`
`
`
`
`
`
`
`
`
`Xyrem With
`Vivactil
`
`55.5 (18.8)
`
`(n=12)
`
`
`
`
`
`
`
`** Median is reported for Tfix
`
`* n=11
`
`There were no significant effects of co~administration of
`
`Vivactil with Xyrem (p20.05).
`
`46
`
`

`

`Table 24: Gamma-Hydroxybutyrate Pharmacokinetic Parameters:
`
`Effect of Vivactil Co-Administration (90% Confidence Intervals)
`
`Least Squares Geometric
`
`Parameter (units)
`
`Means
`
`‘
`.
`.
`With Vivactil
`
`Alone
`
`Ratio of
`
`Means
`
`900/
`0
`Confidence
`Interval
`
`(n=12)
`(n=12)
`
`
`Dose-1 Cmax (Hg/m1)
`52.5
`53.5
`0.98
`0.85 — 1.14
`
`13°56‘7- Cmax (Hg/m1)
`52.7
`62.8
`0.84
`0.64 — 1.09
`
`
`AUCinf (Hg-W“10*
`
`158.8
`
`163.3
`
`0.97
`
`0.89 * 1.07
`
`
`
`*n=ll
`
`Figure 12: Vivactil Plasma Pharmacokinetics Following Co-administration with
`GHB
`
`
`
`Meanl’rotriptylinamammalian(mam
`
`
`
`
`
`
`
`0.0
`
`48,0
`
`96.0
`
`192.0
`144.0
`Scheduled lime {hr}
`
`240.0
`
`285.0
`
`336.0
`
`Treatment m Vimcfil alnm;
`
`H4 Xymm plus Vivaudl
`
`47
`
`

`

`Table 25
`
`Protriptyline Pharmacokinetic Parameters:
`
`{Arithmetic Mean (ism H1
`
`(n=12)
`
`Xyrem (n=12}
`
`
`
`
`
`
`—--
`
`
`
`
`
`
`Table 26: Protriptyline Pharmacokinetic Parameters:
`
`
`Effect of Xyrem Co-Administration (90% Confidence Intervals)
`
`Least Squares Geometric
`
`Parameter units
`
`(
`
`Means
`
`With Xyrem
`
`Alone
`
`Ratio of
`Means
`
`)
`
`90% Confidence
`Interval
`
`(n=12)
`(n=12)
`
`
`0.99 — 1.15
`1.07
`4.51
`4.81
`Cmax (Hg/ml)
`
`
`AUCinf (ng-hr/ml)
`
`377.5
`
`367.7
`
`1.03
`
`0.96 — 1.09
`
`On average, Cmax decreased by 2% and 16% after the first and second portions of
`the Xyrem dose respectively and AUCinf decreased by 3% following co-administration
`with Vivactil The systemic exposure of protriptyline following co—administration with
`Xyrem was equivalent to the systemic exposure when Vivactil was administered alone.
`For protriptyline, the CmX increased by 7% and AUCinf increased by 3% following co-
`administration with Xyrem. Thus, no clinically significant pharmacokinetic changes
`were observed for either drug. According to the sponsor, all of the adverse events were
`mild and well tolerated by healthy adult volunteers and resolved spontaneously without
`sequelae. The frequency of adverse events was greater when Xyrem and Vivactil were
`administered together compared to when Xyrem was administered alone but the severity
`of adverse events was similar. Only one adverse event was experienced when Vivactil
`was administered alone.
`
`48
`
`

`

`Conclusion:
`
`The systemic exposure of human subjects to gamma—hydroxybutyrate when
`Xyrem was administered with Vivactil was equivalent to the systemic exposure when
`Xyrem was administered alone. The results of the assay validation may be suspect
`because the tables submitted for this study were identical to the tables in the Ambien and
`Modafinil drug interaction studies.
`
`10. Protocol OMC SXB-17: Pharmacokinetic Interaction of GHB with Provigil
`Title: A Study To Determine The Interaction Potential Of Xyrem® (Sodium Oxybate,
`Sodium y—Hydroxybutyrate) With Provigil® (Modafinil) In Normal Healthy Volunteers
`
`Objectives:
`The purpose of this study was to describe the plasma pharmacokinetics of
`gamma—hydroxybutyrate ’W
`W assay) and modafinil
`_,_._.——————————-—————————-————-
`
`assay) following single doses of Xyrem and Provigil alone and in combination
`after an overnight fast.
`In addition, the safety and tolerability of sodium oxybate and
`modafinil were assessedalone and in combination.
`
`Study Center: W
`
`m
`
`Study Design and Methods:
`three—treatment,
`three-period,
`This study utilized a single-center, open—label,
`crossover, randomized design. After qualifying for study entry based on medical history
`and satisfying the inclusion/exclusion criteria, each subject was randomized to one of
`three treatment sequences. All subjects spent the night before dosing at the study facility.
`During the morning of period 1, one third of the subjects ingested 4.5 g of Xyrem
`following an overnight fast; one third of the subjects ingested a 200 mg Provigil tablet
`after an overnight fast; and one third of the subjects ingested both 4.5 g of Xyrem and a
`200 mg Provigil tablet after an overnight fast. There was a 7—day washout between
`periods 1, 2 and 3. During periods 2 and 3, individual subjects crossed over to the other
`treatments according to the sequence to which they had been randomized. Serial plasma
`samples were collected pre—dose and up to 48 h following closing for the determination of
`pertinent pharmacokinetic parameters and evaluation of the effect of co-administration.
`
`Subjects:
`Thirteen healthy volunteers (six female and seven male; all Caucasian; 19 to 51
`years of age; 59 to 88 kg in weight) were selected on the basis of general good health as
`confirmed by physical examination, medical history, and clinical laboratory evaluations.
`
`49
`
`

`

`Test Product, Dose, and Mode of Administration:
`Xyrem was supplied as an oral solution containing 500 mg sodium oxybate per
`milliliter.
`It was supplied by Orphan Medical in bottles of 180 ml. (Lot No: EH75).
`Provigil was supplied as tablets containing 200 mg modafinil. (Lot No. 918201) The 3
`treatments compared in this study were a single oral dose of 4.5 g sodium oxybate
`administered alone, a 200 mg Provigil tablet administered alone and the combination of a
`200 mg Provigil tablet and 4.5 g of sodium oxybate. Each treatment was administered
`after an overnight fast. The dose was administered at approximately 0700 hours (7 am.)
`Each Xyrem dose was diluted to 60 ml with room—temperature water and the dosing cup
`was rinsed with another 180 ml water. Each Provigil dose was administered with 240 ml
`water. For the combination treatment the Provigil tablet was administered with the 60 m1
`Xyrem dose and followed by the 180 ml dosing cup water rinsings.
`
`Criteria for Evaluation:
`
`Safety and pharmacokinetic parameters were the primary end-points of this
`pharmacokinetic and drug interaction study.
`Safety evaluations included physical
`examination, vital
`signs measurements
`(blood pressure, pulse,
`respiratory rate),
`electrocardiogram (ECG) assessment, clinical laboratory evaluation, and adverse events
`(AE5) assessment.
`Pharmacokinetic evaluation included the determination of peak
`concentration (Cmax), corresponding peak times (tmax), area under the curve (AUCinf), oral
`plasma clearance (CL/F), elimination half-life (tm) of gamma—hydroxybutyrate and of
`modafinil when administered alone and in combination. Non-compartmental methods
`were used in the determination of various pertinent pharmacokinetic parameters.
`Descriptive statistics
`(mean, median,
`standard deviation, coefficient of variation,
`maximum, and minimum) were computed for pertinent pharmacokinetic parameters for
`all of the treatment groups. The effect of co—administration of modafinil on
`gamma-hydroxybutyrate
`pharmacokinetics was
`determined
`by ANOVA of
`logarithmically transformed AUCinf and Cmax and computation of the 90% confidence
`interval about the ratio’of the mean results observed after administration in combination
`and alone. A non-parametric comparison (Wilcox