Pharmacokinetics of Gammahydroxybutyrate (GHB) in
`Narcoleptic Patients
`
`Martin B. Scharf, Allen A. Lai, Barb Branigan, Robin Stover, and David B. Berkowitz
`
`The Center For Research In Sleep Disorders, Cincinnati, Ohio; The Tri-State Sleep Disorders Center,
`Cincinnati, Ohio
`
`Summary: Sodium gamma-hydroxybutyrate (GHB) is an endogenous compound that has been under investigation in
`the management of narcolepsy for about two decades. The data confirm that GHB treatment decreases daytime sleepi-
`ness and episodes of cataplexy, sleep paralysis, and hypnagogic hallucinations. The current study evaluated the phar-
`macokinetics of GHB, given twice in one night to six narcoleptic patients who had been chronically taking GHB night-
`ly on a similar basis. Results confirmed earlier reports and showed nonlinear pharmacokinetics. Maximum concentra-
`tions were reached in 40–6.2 and 35.7–7 minutes after the first and second dose respectively. Mean AUCinf was
`17731.6–4867 mg/mL/m. Mean GHB T1/2 was 53–19 minutes. GHB elimination appears to be capacity-limited in some
`patients when administered at a fixed dose of 3 g twice nightly at a 4-hour interval.
`Key words: Cataplexy; narcolepsy; GHB; pharmacokinetics
`
`SODIUM GAMMA-HYDROXYBUTYRATE (GHB), or
`sodium 4-hydroxybutyrate, is an endogenous compound
`with hypnotic properties that is found in many tissues of
`the body. The neuropharmacologic effects of GHB include
`increases in brain acetylcholine, increases in brain
`dopamine, inhibition of GABA ketoglutarate transaminase,
`and depression of glucose utilization but not oxygen con-
`sumption in the brain. GHB is converted to succinate and
`then metabolized via the Krebs cycle by a dehydro-
`genase.l-4 Clinical trials have shown that GHB increases
`delta sleep and improves the continuity of sleep in normal
`and narcoleptic subjects. A variety of neuropharmacologic
`mechanics of action have been reported, but none has been
`conclusively established.l
`Studies have evaluated the effects of GHB in the treat-
`ment of narcolepsy.5-10 The results of these studies all con-
`
`Accepted for publication February, 1998
`
`Address correspondence and requests for reprints to Martin B. Scharf, PhD,
`1275 E. Kemper Road, Cincinnati, OH 45246
`
`firm that GHB treatment substantially reduces the signs
`and symptoms of narcolepsy, ie, daytime sleepiness, cata-
`plexy, sleep paralysis and hypnagogic hallucinations. Our
`own experience with GHB has resulted in over 15 years of
`nightly clinical use in over 120 narcoleptic patients, and
`has provided over 750 patient years of safety and efficacy
`data attesting to the value of this compound in the manage-
`ment of narcolepsy.
`The pharmacokinetics of GHB have been investigated
`in normal healthy males and in alcohol-dependent patients
`after oral administration.11,12 In alcohol-dependent patients,
`consistent with its rapid onset and short pharmacological
`effect, the data indicated that both GHB absorption into and
`elimination from the systemic circulation were rapid pro-
`cesses.11
`Virtually no unchanged drug could be recovered in the
`urine. There were preliminary indications that the pharma-
`cokinetics of GHB might be nonlinear or dose-dependent.11
`In the healthy volunteers study, the pharmacokinetics of
`three rising GHB doses (12.5, 25, and 50 mg/kg) were
`investigated. The apparent area under the curve (AUC)
`increased disproportionately with dose; the dose-normal-
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`Ranbaxy Ex. 1013
`IPR Petition - USP 9,050,302
`
`

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`ized peak concentrations, however, decreased with increas-
`ing doses, while the corresponding peak times increased.l2
`These findings confirmed that both the oral absorption and
`elimination processes of GHB were capacity-limited,
`though the degree of dose dependency was moderate. The
`present study was designed to investigate the pharmacoki-
`netics of two consecutive doses of GHB in narcoleptic
`patients (who on a regular basis ingested the first dose of
`this medication prior to bedtime and the second dose from
`2.5 to 4.9 hours later).
`The objective of this study was to assess the pharma-
`cokinetics of GHB after oral administration of two consec-
`utive single doses of GHB (3 g/dose, 4 hours apart) to nar-
`coleptic patients who have been chronically maintained on
`a similar regimen of nightly GHB use.
`
`METHODS
`
`This pharmacokinetics study was conducted as an
`open-label, single-center investigation in six narcoleptic
`patients. Each patient was determined to be in stable health,
`and had previously received a diagnosis of narcolepsy (1 or
`more years of medical history based on a nocturnal
`polysomnogram [PSG]and a valid score from a multiple
`sleep latency test [MSLT]). Each had a longstanding histo-
`ry of moderate-to-severe cataplexy, and had been receiving
`GHB nightly on a chronic basis. None were taking antide-
`pressants, hypnotics, sedatives, antihistamines, or anticon-
`vulsants, though a stable regimen of methylphenidate
`(immediate-release or sustained-release) was allowed. The
`investigator ensured that there would be at least an 8-hour
`washout period for GHB prior to the treatment period.
`Patients were screened at least 1 day prior to the treatment
`phase, and passed a prestudy physical examination which
`included hematology, blood chemistry, urinalysis, and vital
`signs measurements prior to the commencement of the
`treatment phase. All patients were hospitalized from
`approximately 4 hours prior to first GHB dosing (around
`20:00) until the end of the treatment period (around 10:00
`the next morning). Patients ate their dinner at the clinical
`research unit soon after arrival and fasted until breakfast
`next morning. The investigator or his designee prepared the
`oral solution for dosing within 30 minutes prior to the first
`oral administration to individual patients. The contents of
`one twin-pouch containing 3 g of GHB in powder and
`excipient form was emptied into a dosing cup (provided by
`the sponsor) to which 2 ounces of water was added. After
`replacing the lid of the dosing cup (also provided by the
`sponsor), the dosing cup was gently shaken to dissolve the
`GHB and excipient in water. The GHB solution was ingest-
`ed in its entirety. Likewise, the second GHB dosing solu-
`tion was prepared in the same manner and was ingested in
`entirety 4 hours after the first GHB dose. Before oral
`administration of the first GHB dose, an indwelling
`
`catheter was placed in an arm vein, and a baseline blood
`sample was collected. Each patient then ingested a 3 g dose
`of GHB right at bedtime. Another 3 g GHB dose was
`administered 4 hours after the first dose. Twenty-one
`sequential blood samples were collected over 12 hours
`(starting at 10 minutes after the first dose and ending at 8
`hours after the second dose). Upon completion of the treat-
`ment phase, a follow-up physical examination which
`included the measurement of vital signs was performed on
`each patient within 48 hours after the last blood sample.
`All six patients took some nonstudy medications
`(Synthyroid, Premarin, Lovastatin, Fluvastatin, furo-
`semide, potassium, hydrochlorothiazide, lansoprazole, and
`verapamil). None of these were expected to interfere with
`the metabolism of GHB or effect the results of the study.
`Plasma samples were analyzed for GHB by the
`Department of Bioanalytical Chemistry, Covance (previ-
`ously known as Hazleton Corning), Madison, Wis. A gas
`chromatographic method with mass selective detection
`(GC-MSD) was used in the analysis. This method has a
`limit of quantification (LOQ) of 7.02 mg/mL.
`Pharmacokinetic parameters were determined for indi-
`vidual sets of plasma GHB concentration vs time data using
`the noncompartmental routine in WinNonlin Version 1.1.
`The peak GHB concentrations (Cmax) were observed val-
`ues. Apparent terminal half-life (T1/2) was obtained by log-
`linear regression analysis of the terminal phase of concen-
`tration vs time curves. The apparent area under the curve
`(AUCinf) and the area under the first moment curve
`(AUMCinf) were calculated by the linear trapezoidal rule up
`to the last determined concentration and included extrapo-
`lated areas to time infinity. Apparent oral clearance (CL/F)
`was calculated as dose/AUCinf. Volume of distribution
`(Vlz/F) was determined by taking the ratio between CL/F
`and z (elimination rate constant). Mean residence time
`(MRT) was estimated from the ratio between AUMCinf and
`AUCinf.
`
`RESULTS
`
`Six narcoleptic patients completed the study. Four
`patients were male and two were female; all six patients
`were Caucasian. Their mean age was 50.7 years. Their
`mean body weight was 87.6 kg. Five patients had been
`maintained on GHB nightly for over 10 years, and one
`patient had been receiving GHB nightly for 2 years. One
`patient had multiple sclerosis; however, the attending
`physician judged that it would not interfere with the objec-
`tive of this study. All patients ingested the two GHB doses
`as scheduled. The GHB doses per kg body weight ranged
`from 26.4 to 52.4 mg/kg.
`Individual patient plasma-GHB concentration data sets
`following two consecutive 3 g GHB doses at a 4-hour inter-
`val are depicted graphically in Figs. 1-6. It is of interest to
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`Patient 101
`
`Patient 102
`
`Figure 1
`
`Figure 2
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`Patient 103
`
`Patient 104
`
`Figure 3
`
`Figure 4
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`Patient 105
`
`Patient 106
`
`Figure 5
`
`Figure 6
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`Table 1.(cid:151)Summary of GHB pharmacokinetic parameters
`
`Dose 1
`
`Dose 2
`
`Cmax
`(mmg/ml)
`62.8
`59.7
`27.4
`30.1
`102.0
`
`Statistic
`MEAN
`MEDIAN
`STD
`MIN
`MAX
`
`Tmax
`(min)
`40.0
`36.0
`6.2
`36.0
`48.0
`
`Cmax
`(mmg/ml)
`91.2
`92.0
`25.6
`47.5
`125.0
`
`Tmax
`(min)
`35.7
`36.0
`7.0
`24.0
`46.0
`
`N=6
`
`T 1/2
`(min)
`53.0
`54.2
`19.3
`26.9
`71.4
`
`LAMBDAz
`(1/min)
`0.15
`0.14
`0.01
`0.01
`0.03
`
`AUCinf
`AUClast
`(mmg/ml.min) (mmg/ml.min)
`16455.8
`17731.6
`16170.6
`18050.2
`4602.8
`4867.0
`11302.1
`11813.2
`22408.4
`23287.3
`
`AUCext
` (%)
`7.1
`5.4
`4.1
`3.8
`13.6
`
`Vz/F
`CL/F
`(ml/min/kg) mL/kg
`4.2
`307.0
`4.4
`262.8
`1.0
`96.2
`2.5
`216.0
`5.6
`439.1
`
`MRT
`(min)
`248.8
`243.3
`56.1
`176.0
`330.3
`
`Table 2.(cid:151)Listing of GHB pharmacokinetic parameters
`
`Cmax
`(mmg/ml)
`102
`
`Tmax
`(min)
`36
`
`Cmax
`(mmg/ml)
`125
`
`Tmax
`(min)
`24
`
`LAMBDAz
`(1/min)
`0.02
`
`T 1/2
`(min)
`41.4
`
`AUClast
`(mmg/ml.min)
`22408.4
`
`AUCinf
`(mmg/ml.min)
`23287.3
`
`AUCext
` (%)
`3.8
`
`Vz/F
`CL/F
`(ml/min/kg) mL/kg
`4.5
`268.8
`
`Patient #
`101
`
`102
`
`103
`
`104
`
`105
`
`106
`
`52.6
`
`30.1
`
`40.1
`
`85.2
`
`66.8
`
`48
`
`36
`
`36
`
`36
`
`48
`
`86.7
`
`47.5
`
`96.9
`
`87.1
`
`104
`
`36
`
`46
`
`36
`
`36
`
`36
`
`0.01
`
`0.01
`
`0.02
`
`0.03
`
`0.01
`
`71.4
`
`71.2
`
`39.8
`
`36.9
`
`67
`
`19325
`
`12888.9
`
`11302.1
`
`13016.1
`
`19794.3
`
`21641.3
`
`14923.7
`
`11813.2
`
`13547.3
`
`21176.7
`
`10.7
`
`13.6
`
`4.3
`
`3.9
`
`6.5
`
`4.1
`
`4.3
`
`4.5
`
`5.6
`
`2.5
`
`418.5
`
`439.1
`
`256.8
`
`216
`
`243
`
`MRT
`(min)
`207.9
`
`291.7
`
`330.3
`
`232.2
`
`176.2
`
`254.4
`
`note that in three out of six patients (patients #102, #103,
`and #106), plasma GHB concentrations did not decline
`from the first Cmax to zero concentration before the second
`GHB dose was administered at hour 4. Upon achievement
`of the second Cmax, the semi-logarithmic plot of concentra-
`tion vs time data in patients #102, #103, and #105 exhibit-
`ed a convex decline profile. Such a decline pattern sug-
`gested nonlinear pharmacokinetics. The highest plasma
`GHB concentration observed in the study was 125.0
`mg/mL, which occurred in subject 101 after the second 3 g
`GHB dose.
`Noncompartmental pharmacokinetic parameter esti-
`mates are summarized in Table 1, and individual patient
`parameter estimates are listed in Table 2. The mean (– SD)
`observed maximum GHB concentrations (Cmax) were
`62.8–27.4 mg/mL and 91.2–25.6 mg/mL for the first and
`second GHB doses, respectively. The corresponding mean
`observed times to maximum concentrations were 40–6.2
`and 35.7–7 minutes after the first and second GHB doses,
`respectively.
`The mean apparent AUCinf was 17731.6–4867
`(cid:181)g/mL.min. The mean CL/F was 4.2–1 mL/min/kg and the
`mean Vlz/F was 307–96.2 mL/kg. The mean MRTinf was
`
`248.8–56.1 minutes. The mean apparent GHB T1/2 estimat-
`ed by linear regression of log [C] vs time data of the termi-
`nal phase of the second GHB dose was 53–19.3 minutes.
`
`DISCUSSION
`
`GHB is present in the mammalian brain and other tis-
`sues. In the brain, highest GHB concentration is found in
`the hypothalamus and basal ganglia, and GHB is postulat-
`ed to function as a neurotransmitter.13 The level of GHB in
`human systemic circulation has not been reported in the lit-
`erature. Hence, baseline (0 hour) plasma samples were ana-
`lyzed for GHB concentrations. The GC-MSD method used
`in the present study had a limit of quantification (LOQ) of
`7.02 (cid:181)g/mL, and analysis of the baseline plasma samples
`showed that the endogenous levels of GHB are substantial-
`ly below this quantification limit.
`Values of mean Tmax (~40 minutes after dosing) and
`T1/2 (~50 minutes) suggest that the GHB solution adminis-
`tered to narcoleptic patients in this study was readily
`absorbed and rapidly eliminated. In three out of six
`patients, the drug was essentially gone from the systemic
`circulation by hour 4 after the first GHB dose, whereas in
`the remaining three patients, residual GHB levels of 15
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`(cid:181)g/mL were still detected at hour 4.
`The convex nature of the decline of plasma GHB con-
`centrations in three patients after achievement of the sec-
`ond Cmax indicated that elimination of GHB from the sys-
`temic circulation in these three patients is capacity limited.
`Nevertheless, it should be noted that plasma GHB concen-
`trations were no longer detectable by hour 6 after the sec-
`ond GHB dose (10 hours after the first GHB dose). The
`mean apparent oral clearance found in this study was 4.2
`–1.0 mL/min/kg and appeared to be comparable to the
`apparent oral clearance of 5.3–2.2 mL/min/kg reported in
`the literature for a group of alcohol-dependent patients
`who were administered a dose of 50 mg/kg.11 While it
`appeared that the GHB dose (ranging from 26.4 to 52.4
`mg/kg with a mean of 36.5 mg/kg) in the present study was
`lower than the comparison GHB dose (50 mg/kg) adminis-
`tered to the alcohol-dependent patients, it should be noted
`that each patient in the present study was administered two
`consecutive GHB doses at 4-hour interval, and residual
`GHB levels were detected in three out of six patients
`immediately prior to the second GHB dose. The GHB
`pharmacokinetic nonlinearity
`in alcohol-dependent
`patients easily can be observed from the apparent oral
`clearance, which increased to 8.1–4.8 mL/min/kg when the
`GHB dose is reduced to 25 mg/kg dose.11
`In the present
`study, the nonlinearity was less obvious because each nar-
`coleptic patient received two consecutive fixed 3 g doses
`regardless of body weight.
`The mean apparent elimination half-life of GHB in the
`six narcoleptic patients was determined to be 53–19 min-
`utes, longer than that in alcohol dependent patients after a
`50 mg/kg GHB dose.11 The lengthening of GHB elimina-
`tion half-life observed in this study was partially caused by
`the wider spacing in sampling time points. However,
`capacity limited elimination of this drug in some of the
`narcoleptic patients also could have contributed to this pro-
`longation.
`GHB appears to have a pharmacokinetic shortcoming
`in that its elimination from the body is capacity limited in
`some patients when the drug is administered at a fixed reg-
`imen of 3 g twice nightly at 4-hour intervals. However,
`from a therapeutic perspective, GHB offers an advantage
`in the treatment of narcolepsy because by the time a patient
`wakes up in the morning (ie, 8 to 10 hours after the first
`GHB dose), all GHB, including that from the second dose,
`will have been eliminated from the systemic circulation.
`GHB was well tolerated by narcoleptic patients in this
`study. No adverse experience was reported.
`The results of this study may help explain the unique
`side effect profile seen with this compound. To date, the
`most prominent side effect observed has been episodes of
`sleepwalking. While quite rare, no other side effect has
`appeared to be directly due to the drug(cid:146)s effects. The fact
`
`that sleepwalking normally occurs out of slow-wave sleep
`and is most prevalent in children (in whom slow-wave
`sleep is quite prominent) suggests that the event may be
`secondary to the induction of this sleep stage. However, in
`our clinical experiences, the vast majority of sleepwalking
`events have tended to occur with the second dose rather
`than the first, despite the fact that both clearly induce slow-
`wave sleep. The possibility that capacity-limited elimina-
`tion contributes to higher blood levels after the second
`dose may explain the phenomenon.
`Finally, the extremely short half-life of GHB may
`explain why patients generally awaken fully alert and
`refreshed. A clear rebound insomnia or alertness occurs
`with drug elimination, which can be quite positive for
`patients with narcolepsy. Unfortunately, however, with
`some patients, drug effects may wear off prematurely, leav-
`ing the patient wide awake either long before their second
`scheduled dose or before their planned awakening time.
`We have dealt with this clinically by either adjusting the
`dose, adding a third dose, or adding a sedating short-acting
`hypnotic.
`The results of this study confirm and extend the find-
`ings of GHB kinetics in alcoholic patients. Despite the fact
`that these patients had a long history of nightly GHB use,
`these kinetics of the drug were similar to GHB-na(cid:239)ve
`patients. Despite this, further studies should be carried out
`in na(cid:239)ve narcoleptic patients.
`
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