Bioequivalence, Dose-Proportionality, and Pharmacokinetics of
`
`
`
`
`Naltrexone after Oral Administration
`
`MARVIN C. MEY ER, Ph.D., ARTHUR B. STRAUGHN, Pharm.D., MAN-WAI LO, Ph.D.,
`WILLIAM L. SCHARY, Ph.D., and CHARLES C. WHITNEY, Ph.D.
`
`weighed between 60 and 93 kg. All subjects provided writ­
`
`
`
`
`Healthy male volunteers (N =24) participated in a
`
`
`
`
`
`
`
`ten informed consent. Two of the initial subjects withdrew
`
`
`
`four-way crossover study to compare the rate and extent
`
`
`
`from the study for medical reasons unrelated to the study
`
`
`
`of absorption of naltrexone after administration of 50
`
`
`and were replaced by two additional subjects.
`
`mg tablets as 50, 100, and 200 mg doses and a 10 mg/ml
`
`
`
`
`reference syrup. A high-performance liquid chromato­
`Drug Administration and Study Protocol
`
`
`
`
`graphic method was employed to measure naltrexone
`
`
`Study dosage forms, provided by Du Pont Pharmaceuti­
`
`
`
`and 6-/3-naltrexol in plasma and urine. Compared to the
`
`
`
`cals, consisted of tablets containing 50 mg of naltrexone
`
`
`
`syrup, the 50 mg tablets were absorbed more slowly but
`
`
`
`
`equally well. There was excellent linearity between the
`
`
`
`hydrochloride (Lot No. 820947) and a syrup containing 10
`
`administered dose and the area under the plasma con­
`
`
`mg/ml of naltrexone hydrochloride (Lot No. NI-2-08031),
`
`
`centration-time profile, as well as total urinary recovery
`
`
`
`which was supplied to Du Pont by the National Institute on
`
`
`of both drug and metabolite. The mean half-lives for
`Drug Abuse.
`
`
`
`naltrexone and /3-naltrexol were approximately 4 and 12
`After an overnight fast, each subject received either
`
`
`
`
`
`hours, respectively. The fraction of drug reaching the
`
`
`naltrexone tablets as single doses of 50 mg, 100 mg, or 200
`
`
`
`systemic circulation was estimated to be 5% of the ad­
`
`
`mg, or 10 ml (100 mg) of the syrup. The tablets were taken
`
`
`
`ministered dose because of extensive first-pass metabo­
`
`
`with 180 ml of water; syrup was administered by an oral
`
`lism. Less than 1 % of the dose was excreted in the urine
`
`
`
`
`syringe and followed by 180 ml of water. All subjects were
`
`
`as naltrexone after 48 hours, while 25% was recovered
`
`
`required to remain upright for at least 1 hour after drug
`
`
`
`as unconjugated /3-naltrexol. The renal clearance of
`
`
`administration. Water intake was unrestricted throughout
`
`
`
`naltrexone and /3-naltrexol was approximately 127
`
`
`ml/min and 283 ml/min, respectively. The total systemic
`
`the study. No food was permitted for 4 hours after dosing.
`
`
`
`clearance for naltrexone was approximately 94 L/hr.
`
`
`A standard meal was provided 4 hours and 9-10 hours after
`
`
`(J Clin Psychiatry 45 (9, Sec.2):15-19, 1984)
`
`
`
`dosing. All 24 subjects who completed the study received
`
`
`
`each of the 4 dosage forms, administered according to a
`
`
`
`
`completely balanced crossover design with a 7-day interval
`
`
`
`
`Naltrexone is an effective narcotic antagonist which is
`
`
`
`
`between each dose. Subjects were instructed to refrain from
`
`
`
`
`employed in the treatment of opiate dependence. In the
`
`
`
`taking other drugs during the study, if possible. One subject
`
`
`
`study reported here, data were collected to determine the
`
`
`
`
`required two aspirin tablets, one subject took two acet­
`
`
`
`rate and extent of absorption of a 50 mg tablet formulation
`
`
`
`aminophen tablets, and one subject took Afrin Nasal Spray
`
`
`
`
`compared with a reference syrup, and to establish the rela­
`
`
`
`and four doses of aspirin. All subjects were confined to the
`
`
`tionship between the amount of drug administered and the
`study site for 12 hours after each dose.
`
`
`amount of drug absorbed. In addition, the pharmacokinetics
`
`
`
`of naltrexone after oral administration were determined and
`Sample Collections
`
`
`
`
`compared with the results of earlier studies, which were
`Blood samples (10 ml) were obtained via indwelling
`
`
`
`based on only 5 to 6 subjects.
`
`
`
`catheters or dir:_ect venipuncture prior to each dose, and 20
`
`
`minutes, 40 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and
`
`32 hours after each dose. Plasma was separated by centrifu­
`
`
`
`gation and frozen until assay. Urine samples were collected
`Subjects
`
`
`just before drug administration and pooled for periods of 0-
`
`
`
`
`Twenty-four healthy, white, male volunteers were given
`
`
`6, 6-12, 12-24, 24-32, and 32-48 hours after dosing. All
`
`
`
`
`a medical history, physical examination, and laboratory
`
`
`
`samples were refrigerated until a 20-ml aliquot was with­
`
`
`
`
`evaluation, including blood chemistry, hematology, and uri­
`drawn and frozen for later assay.
`
`
`
`nalysis. The subjects ranged in age from 22 to 33 years and
`Assay Method
`Naltrexone and its major metabolite, 6-/3-naltrexol,
`
`
`From the University of Tennessee College of Pharmacy (Drs. Meyer
`
`
`
`
`
`
`were determined in plasma extracts (pH 9 extraction into
`
`
`
`and Straughn) and Du Pont Pharmaceuticals (Drs. Man-Wai Lo, Schary,
`and Whitney).
`
`
`toluene/isopropanol and back-extracted into acid) by re­
`
`
`
`Reprint requests to: Marvin C. Meyer, Ph.D., College of Pharmacy,
`
`
`
`versed-phase high-performance liquid chromatography
`
`
`
`
`University of Tennessee Center for the Health Sciences, Memphis, TN
`
`
`
`(HPLC) with electrochemical detection and an octyl
`38100.
`
`METHOD
`
`1-3
`
`15
`
`ALKERMES EXHIBIT 2028
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`Page 1 of 5
`
`

`

`
`
`J CUN PSYCHIATRY 45:9 (Sec. 2) - SEPTEMBER 1984
`
`MEYER ET AL.
`
`
`
`FIGURE 1. Mean Plasma Concentrations of Naltrexone (N = 24)
`
`FIGURE 2. Mean Plasma Concentrations of 6-13-Naltrexol
`
`
`(N =24)
`
`40U
`
`---· 1 x 50 mg tablet
`- 2 x 50 mg tablets
`••••· 100mgsyrup
`-- 4 x 50 mg tablets
`
`·---1 x SO mq tablPt
`- ! , ::>U mg tablPh
`-- 4, "JO mq tablet<,
`
`
`
`····· 100 mq syrur
`
`16
`
`20
`
`24
`
`28
`
`3?
`
`Hours
`
`
`30
`� 21 I I
`r
`°' I \
`-"- 24 I \
`�
`I I
`"' 21 i ,
`�
`I \
`� 18 I
`\
`u
`I
`u
`\
`\
`§
`
`<1)
`c
`;!
`�
`',
`,
`'°
`6 i \ ',
`c I\
`E
`'
`Cl)
`I
`a:
`ro
`.............. _________ :_-=:::-.. :-..: .. -----
`
`o
`12
`16
`20
`24
`----------�
`� � .-- --'-'� ....,... � � --,,-- � -----�
`0 .,....__����
`
`\
`\
`\
`
`\
`
`....
`',
`
`.......
`
`',
`
`Hours
`
`__,
`
`the study. The time to maximum plasma concentration
`column (Beckman Ultrasphere). Iritraday assay coefficients
`
`
`
`
`
`of (T MAx) was the time at which the highest concentration
`
`
`of variation (CV) for naltrexone were 22.5% at 0.2 ng/ml
`
`and 0.26% at 100 ng/ml; for naltrexol the CV were 11.8%
`
`
`
`naltrexone or naltrexol was observed during the sampling
`procedure.
`
`
`at 1 ng/ml and 6.1 % at 200 ng/ml. Interday assay CV over
`Cumulative amounts of unconjugated naltrexone and
`
`
`
`
`
`4-5 weeks for naltrexone were 10.9% at 0.5 ng/ml and
`
`
`
`naltrexol excreted in the urine were calculated from the
`
`
`0.46% at 100 ng/ml; for naltrexol the CV were 22.5% at 3
`
`
`
`concentrations and volumes of each urine sample. In those
`
`
`
`recoveries wereng/ml and 0.51 % at 500 ng/ml. Extraction
`
`
`
`few cases where urine samples were not collected, concen­
`
`
`96% for naltrexone, 45% for naltrexol, and 88% for the
`
`
`trations were estimated from plots of the log of excretion
`
`
`
`internal standard, an N-cyclopentylmethyl analog of
`
`
`
`rate versus the midpoint of the collection period.
`
`
`
`
`nalbuphine. Both naltrexone and naltrexol were stable in
`
`(ClR) observed for each of the four
`The renal clearance
`
`frozen plasma for at least 4 weeks. The limits of detection
`
`were 0.2 ng/ml for naltrexone and 0.5 ng/ml for naltrexol,
`
`
`
`
`dosages was estimated from the four mean values for the
`
`
`
`total amount of naltrexone or naltrexol recovered at 48
`using 2 ml of plasma.
`
`The urine assay was essentially the same as the plasma
`
`
`
`hours from urine, divided by the corresponding mean
`
`
`
`assay, except that naltrexone and 6-/3-naltrexol were deter­
`
`
`
`
`AUCo-oo.4 The fraction of administered dose reaching the
`
`
`
`mined separately in two HPLC systems because of the large
`
`
`systemic circulation (f) was also estimated from the mean
`
`data, using the method of Vaughan.' The total clearance
`
`
`differences in the concentrations of the two components.
`
`(CIT) was estimated from the mean data, using the relation­
`
`
`
`lntraday urine assay CV for naltrexone ranged from 0.53%
`6
`
`to 3.88% over the concentration range of 1 to 20 µg/ml.
`ship CIT
`
`
`= tD/AUCo-oo, where Dis the administered dose.
`
`
`The dose-proportionality relationship was determined by
`
`
`The intraday assay CV for naltrexol ranged from 0.21 % to
`
`
`
`using linear regression for both individual and mean data
`
`
`2.01 % at 5-100 µg/ml. Interday assay CV over 9 weeks for
`
`
`for the AUCo-oo of naltrexone and naltrexol, as well as the
`
`naltrexone were 9.8% at 0.05 µg/ml and 1.3% at 1 µg/ml;
`
`total 48-hour urine recovery of both substances.
`
`for naltrexol the CV were 5.6% at 5 µg/ml and 0.63% at
`
`
`
`100 µg/ml. Extraction recoveries were greater than 92 %
`
`
`for naltrexone and 86% for naltrexol, and 100% for the
`
`
`
`
`internal standard. Both naltrexone and naltrexol were stable
`Bioavailability
`
`in frozen urine for at least 19 weeks. The limits of detection
`
`
`Figures 1 and 2 illustrate the mean plasma concentra­
`
`
`were 0.01 µg/ml for both naltrexone and naltrexol in 0.2 ml
`of urine.
`
`
`
`tions for naltrexone and naltrexol, respectively, after each
`
`
`of the four doses. As previously observed,
` the naltrexol
`
`plasma concentrations were about 10-to 30-fold greater
`Pharmacokinetic Analysis
`
`
`
`
`than the corresponding naltrexone concentrations. Table 1
`
`The area under the plasma concentration-time curve
`
`
`summarizes the mean values for the peak plasma concentra­
`
`
`
`from zero to infinity (AUCo-oo) was calculated by summing
`
`tion ( CMAX), the time of peak concentration (T MAX), the area
`
`
`
`the area determined by the linear trapezoidal rule and the
`
`under the plasma concentration-time curve to 32 hours
`
`
`
`extrapolated area (obtained by dividing the last measured
`(AUC0_32) and extrapolated
`
`to infinite time AUCo-oo, and
`
`
`plasma level by the terminal rate c6nstant). The apparent
`
`
`the total urinary recovery (Emg) for both naltrexone and
`
`
`) was determined by linear regres­
`
`
`elimination half-life (T112
`naltrexol.
`
`
`
`sion of the terminal log-concentration data points. The
`One objective was to determine how well the tablet was
`
`
`
`maximum plasma concentration value (CMAX) was the high­
`
`
`
`absorbed, with the syrup used as a reference standard at a
`
`
`
`
`est concentration of naltrexone or naltrexol observed during
`
`RESULTS
`
`1•1
`
`16
`
`Page 2 of 5
`
`

`

`
`
`J CLIN PSYCHIATRY 45:9 (Sec. 2) - SEPTEMBER 1984
`
`PHARMACOKINETICS
`
`
`
`
`
`
`
`TABLE 1. Mean Bioavailabilit Parameters for Naltrexone and 6-{3-Naltrexol
`
`j
`�
`
`Naltrexone
`8.55 4.84 19.59
`CMAX(ng/ml)
`0.95 0.39
`0.99
`TMAX(hr)
`AUC().32 (ng,hr/ml) 22.74 13.81 47.42
`AUC0_oo(ng,hr/ml) 24.82 14.56 49.76
`r; Urine (mg)
`0.13 0.06
`0.33
`6-{3-Naltrexol
`CMAX(ng/ml) 99.3 30.23 206.77
`1.0
`0.91 0.37
`TMAX(hr)
`AUC.,.,,(ng,hr/ml)
`642.7 189.1 1152.9
`765.0 244.6 1381.1
`AUC0-oo(ng,hr/ml)
`11.78 2.55 24.73
`r; Urine (mg)
`
`17.91 20.73 9.80 36.10 19.54
`0.57 0.35
`0.55
`1.05 0.45
`36.95 51.97 26.08 104.32 76.42
`37.07 54.88 28.07 108.82 75.85
`0.37 0.22
`0.26
`0.66 0.38
`
`78.08 206.15 77.77 444.31 140.2
`0.6
`0.54
`0.49
`1.08 0.43
`282.8 1202.0 257.7 2617.0 441.1
`301.1 1411.6 328.8 3066.6 543.2
`4.33 24.63 4.50 52.81 9.16
`
`
`
`TABLE 2. Linear Regression For Dose-Proportionality
`Mule" also noted an approximately proportional increase in
`
`
`
`
`
`naltrexone and naltrexol plasma concentrations during
`
`
`
`chronic administration of naltrexone with doses of 100-800
`mg/day.
`
`Individual data
`
`(N=96)
`Slope 0.55 0.00351 15.56 0.275
`Intercept -4.71 -0.0377-77.75 -2.267
`0.34 0.39
`0.86 0.89
`
`17
`
`1'8'9
`
`r2
`
`Mean data
`(N=4)
`Slope 0.621 0.00382 17.30 0.305
`Intercept-3.532 -0.0183-102.42-2.47
`0.998 0.992 0.997 0.999
`
`r2
`
`Pharmacokinetics
`Pharmacokinetic parameters were derived from the
`
`
`
`
`mean data, and the mean terminal half-lives were deter­
`
`
`mined from individual subject data (Table 3). The mean
`
`
`
`
`half-lives for the elimination of naltrexol ranged from 12.2
`
`
`to 13.9 hours for the 4 doses. Other workers have reported
`1
`
`
`
`naltrexol half-lives ranging from 7.?3 to 12.7 hours.
`The
`100 mg dose. Since there were no significant differences
`
`
`
`mean half-lives for naltrexone ranged from 3.7 to 4.8
`
`
`(p > . 05) between the tablet and the syrup in terms of A UC
`
`
`
`hours; the lack of significant differences among the half­
`
`
`or I:mg for naltrexone or naltrexol, it can be concluded
`that
`
`
`lives for the 4 doses further indicated a lack of dose depen­
`
`
`an equivalent amount of drug is absorbed from both dosage
`
`
`
`dency in the elimination process. The estimated half-lives
`
`forms. The only significant difference (p s .05) noted in
`
`
`
`
`were quite variable within each subject. The highest mean
`
`
`this comparison was for the T MAX values, with the syrup
`
`
`
`half-life (N =4 doses) for any subject was 6.5 hours
`
`
`
`
`
`(1.72-11.65 hours) and the lowest mean half-life was 2.27
`
`
`
`
`being absorbed slightly more rapidly than the tablet. The
`
`
`
`
`mean 48-hour urinary recovery of naltrexone and naltrexol
`
`
`
`
`
`hours (1.6-2.9 hours). Earlier reports in small numbers of
`
`was less than 1 % and about 25 % , respectively, which is
`
`
`
`subjects indicated a wide range of half-lives for naltrexone:
`1"8'9
`
`
`A mean of 1.1 hours has been obtained from urinary excre­
`
`
`
`similar to previously reported data.
`
`tion data;8 means have been reported of 2. 7 hours and 8.9
`Dose Proportionality
`
`
`hours after intravenous and oral administration, respec­
`
`
`tively, 3 and 10.3 hours and 9. 7 hours after acute and chronic
`
`
`
`
`Since naltrexone appears to exhibit a substantial first­
`1
`
`
`
`pass metabolism and is primarily eliminated from the body
`
`
`oral administration, respectively.
`
`There are several possi­
`
`
` it is important to determine if the ob­
`by metabolism,
`
`
`
`
`ble causes for the apparent difference in reported half-lives.
`1
`
`
`
`
`served systemic availability is proportional to the adminis­
`
`aoininistered 100 mg oral doses of naltrex­
`
`Verebey et al.
`
`
`
`tered dose. In the absence of such proportionality (which
`
`
`
`one to 4 male postaddict subjects and observed an apparent
`
`
`could result if one or more metabolic steps were saturable),
`
`
`biexponential decay in naltrexone plasma concentrations.
`
`
`
`
`They reported initial and terminal half-lives of 2-4.1 hours
`
`
`
`the adjustment of a patient's dosage regimen for optimal
`
`
`
`
`and 7.3-14.7 hours, respectively. Similar data are shown in
`
`
`
`response could be more difficult. Fortunately, there is an
`
`
`
`
`Figure 3 for those subjects with the longest half-life for a
`
`
`
`
`
`excellent linear relationship between the administered dose
`given dose.
`
`
`and the mean AUCo-00 or urinary recovery (Emg) for both
`It is possible that some enterohepatic recycling could
`
`
`
`
`
`naltrexone and naltrexol (Table 2). The lower correlation
`
`
`
`
`account for the prolonged phase, since the curvature in the
`
`
`
`
`coefficients for naltrexone from individual subject data
`
`
`
`plots occurs after the evening meal. Some evidence for en­
`
`
`
`
`result from the considerable intersubject variability and
`
`
`
`
`terohepatic recycling of naltrexone in the guinea pig has
`
`
`
`from much lower plasma concentrations for naltrexone than
`
`
`been reported by Ludden et al.10 It is also possible that the
`
`
`for' naltrexol. These data clearly show that the systemic
`
`
`
`
`terminal portion of the curves with the longest apparent
`
`
`
`availability and renal elimination of both naltrexone and its
`
`
`half-lives is seen when the plasma concentrations are ap­
`
`
`
`major metabolite, naltrexol, are linearly related to the ad­
`
`
`proaching the limi£ of assay sensitivity. Thus, if endogenous
`
`
`ministered dose over the range of 50-200 mg. Verebey and
`
`Page 3 of 5
`
`

`

`
`
`J CUN PSYCHIATRY 45:9 (Sec. 2) - SEPTEMBER 1984
`
`MEYER ET AL.
`
`
`
`TABLE 3. Pharmacokinetic Parameters for Naltrexone and Naltrexol
`
`
`
`
`
`Total
`Clearance HaH·LHe ( :t SD)"
`Nettrexone Naltrexol Naltrexone
`
`Naltrexone Naltrexol
`Sysamlc
`(hr)
`(hr)
`A�llabHlty(f)
`pose
`(L/hr)•
`(mUmln) (mUmln)
`3.57±2.62
`92.9
`12.24± 2.43
`256.5
`0.051
`107.0
`One 50 mg tablet
`13.89± 10.84
`3.37 ± 2.06
`298.4
`94.3
`137.4
`0.052
`Two 50 mg tablets
`12.58± 4.02
`3.93±3.00
`290.7
`95.5
`0.058
`138.8
`100 mg syrup
`12.83± 2.02
`4.83±2.36
`126.1
`287.0
`93.0
`0.056
`Four 50 mg tablets
`
`'Calculated using mean data.
`
`
`
`"Calculated using individual subject data.
`
`0
`
`
`
`FIGURE 3. Plasma Naltrexone Time Profiles for lwo Subjects with Longest and Shortest Half-Life after Each Oral Dose
`
`
`
`
`
`
`
`4C,
`30
`
`= 20
`E
`
`CJ) 10
`5 8
`c 6
`2 4
`� 3
`c
`u c
`0 d
`u 6
`"'
`E
`
`a:
`
`100 mg Tablets
`
`Sub1ect 24
`� 1 53 hr)
`(T '·
`,
`
`Sub1ect 7
`(T ,.
`= 10 00 hr)
`,
`
`--------------------
`
`50 mg Tablet
`
`I
`
`= E ,,,
`i·
`I\
`a, "
`E:
`c:
`2
`.;
`
`'
`'
`
`''
`
`cl
`
`u
`
`E
`
`
`' '
`Sub1ect 13
`' '
`IT, =1406hr)
`'
`'
`, ____
`-------
`
`Sub1ect 26
`(T ,,, � 1 4 7 hr)
`
`0
`
`4
`
`8
`
`12 16 20 24
`
`0
`
`4
`
`8 12
`
`16 20
`
`24
`
`Hours
`
`Hours
`
`20
`
`E 10
`01 B
`c 6
`c 4
`.2 3
`�
`
`1
`u c 8
`0 6
`u
`
`100 mg Syrup
`
`',
`' ' '
`' '
`'
`'
`' '
`, _______ -
`
`Sub1ect 17
`
`(T v= 1 52 hr)
`,
`
`Sub1ect 19
`= 11 87 hr)
`iT,1,
`------------------
`
`80
`60
`
`40
`E
`30
`a, ?O
`5 10
`c 8
`2
`� 4
`c 3
`u c: 1
`
`0
`u
`
`"' 6
`E 4
`"' 3
`"'
`a:
`
`200 mg Tablets
`
`Subject 8
`(T 't, = 11 .65 hr)
`------
`------------------
`
`Sub1ect 10
`(T,1,= 1 59 hr)
`
`0
`
`4
`
`8
`
`12 16 20 24
`
`0
`
`4
`
`8
`
`12
`
`16 20 24
`
`Hours
`
`Hours
`
`(Table 3) are based on mean data that have been corrected
`
`
`
`components are also present in low concentration, they
`
`for a 20% protein-binding." There was no effect of dose on
`
`
`
`
`would have little effect on the quantitation of the initial high
`
`
`
`plasma concentrations, but could affect the accurate mea­
`
`
`
`the renal clearance values. Those for naltrexone were
`
`
`
`surement of the terminal phase concentrations. A study of
`
`
`somewhat higher than the mean 66. 7 ml/min (16.5-107
`
`
`
`the plasma concentrations of naltrexone and naltrexol after
`
`
`
`
`ml/min) reported by Verebey et al.' for 4 subjects, and the
`
`
`
`values gave no indication of net renal secretion or reabsorp­
`
`
`a single 100-mg dose and daily chronic 100-mg doses of
`
`
`
`tion of naltrexone. Renal clearance values for naltrexol
`
`
`
`
`naltrexone suggested no significant accumulation of
`
`
`naltrexone.' Further, while there was an increase in peak
`
`
`were similar to the mean of 318 ml/min (243-405 ml/min)
`
`
`
`
`
`reported by Verebey et al.,' suggesting renal tubular secre­
`
`
`
`naltrexol concentrations during chronic administration,
`
`
`
`tion of this metabolite. The fraction of administered dose
`
`trough levels after 24 hours (just before each additional
`
`
`
`
`reaching the systemic circulation (t) indicated that approxi­
`
`
`dose) were quite similar for naltrexol after acute and
`
`
`
`mately 95% of the dose was subject to first-pass metabo­
`
`
`
`chronic dosing. Even if the true elimination half-life of
`
`
`lism. Previous estimates have indicated a value of 80% for
`
`
`
`
`naltrexone was similar to that of naltrexol (i.e., approxi­
`
`
`
`first-pass metabolism in a study of 4 postaddict subjects.
`2 In
`
`
`
`
`mately 12 hours), the administration of naltrexone as a sin­
`
`
`addition, Wall et al. 3 determined the plasma concentrations
`
`
`
`gle daily dose should not result in significant accumulation
`
`
`of naltrexone after a 1 mg intravenous dose and a 50 mg
`
`of the drug or the metabolite in the plasma.
`
`
`
`
`oral dose in 5-6 healthy subjects and reported that the AUC
`
`
`The renal clearance data for naltrexone and naltrexol
`
`18
`
`Page 4 of 5
`
`

`

`
`
`J CUN PSYCHIATRY 45:9 (Sec. 2) - SEPTEMBER 1984
`
`PHARMACOKINETICS
`
`Headache
`,,
`Nausea
`Constipation
`Lightheadedness
`Tiredness
`Faintness
`Dreams
`
`Abdominal cramping
`Body aches
`Lack of appetite
`Malaise
`Fatigue
`Diplopia
`Drowsiness
`
`1
`5
`2
`2
`3
`2
`1
`1
`1
`2
`2
`1
`1
`1
`
`REFERENCES
`1.Verebey K, Volavka J, Mule SJ, et al: Naltrexone: Disposition, me­
`
`
`
`
`
`
`
`tabolism, and effects after acute and chronic dosing. Clin Pharmacol
`
`Ther 20:315-328, 1976
`2.Kogan MJ, Verebey K, Mule SJ: Estimation of the systemic availabil­
`
`
`
`
`
`
`ity and other pharmacokinetic parameters of naltrexone in man after
`
`
`acute and chronic oral administration. Res Commun Chem Pathol
`after the oral dose was 60% that of the intravenous dose.
`
`
`
`Pharmacol 18:29-34, 1977
`3.Wall ME, Brine DR, Perez-Reyes M: Metabolism and disposition of
`
`
`
`
`
`
`
`The apparently greater systemic availability of naltrexone
`
`
`
`
`naltrexone in man after oral and intravenous administration. Drug
`
`
`after oral administration in that study3 could be the result of
`
`
`Metab Dispos 9:369-375, 1981
`
`
`
`different subject populations, differences in assay specific­
`4.Wagner JG: Fundamentals of Clinical Pharmacokinetics. Hamilton,
`
`
`
`
`
`IL, Drug Intelligence Publications, 1975
`
`
`
`ity, or the large difference between the intravenous and oral
`
`
`
`
`5.Vaughan DP: Estimation of biological availability after oral drug ad­
`
`
`
`doses. Further, it was not clear whether the same subjects
`
`
`
`
`andby urinary excretion ministration when the drug is eliminated
`
`
`received both the intravenous and the oral doses.
`
`
`
`metabolism. J Pharm Pharmacol 27:458-461, 1975
`
`
`
`6. Gibaldi M, Perrier D: Pharmacokinetics, 2nd ed. New York, Marcel
`
`
`
`Total systemic clearance of naltrexone was also esti­
`Dekker, 1982
`5 The
`mated from mean data with the method of Vaughan.
`7.Verebey K, Mule SJ: Naltrexone, 6-13-naltrexol and 2-hydroxy-3-
`
`
`
`
`
`calculated values approximate liver blood flow and indicate
`
`
`
`
`
`methoxy-6-13-naltrexol plasma levels in schizophrenic patients after
`
`
`
`large oral doses of naltrexone. In National Institute for Drug Abuse
`
`
`
`that naltrexone can be classified as a highly extracted drug.
`
`
`
`(NIDA) Research Monograph 27. Washington DC, US Government
`
`
`
`The contribution of renal clearance to total clearance was
`
`Printing Office, 1979
`
`
`
`about 8 % , which is in agreement with a urinary recovery of
`8.Cone EJ, Gorodetzky CW, Yeh SY: The urinary excretion profiles of
`
`
`
`
`
`
`
`naltrexone in man. Drug Metab Dispos 2:506-512, 1974
`
`
`
`approximately 7% of total systemically available drug after
`
`
`
`
`
`9.Dayton HE, Inturrisi CE: The urinary excretion profiles of naltrexone
`a dose of 100 mg.
`
`
`
`in man, monkey, rabbit and rat. Drug Metab Dispos 4:474-478, 1976
`
`
`There was considerable inter-and intrasubject variabil­
`
`
`
`10.Ludden TM, Bathala MS, Malspeis L, et al: Elimination of radioac­
`
`
`ity noted in the pharmacokinetic parameters and in the
`
`
`
`
`
`tivity following administration of [15, 16-'Hl naltrexone to rats and
`
`
`
`guinea pigs. Drug Metab Dispos 6:321-328, 1978
`
`
`
`plasma naltrexone and naltrexol concentrations. This has
`
`
`
`
`11.Ludden TM, Malspeis L, Baggot JD, et al: Tritiated naltrexone bind­
`
`been observed by others1.1 and is not unexpected
`for a drug
`
`
`
`
`
`ing in plasma from several species and tissue distribution in mice. J
`
`
`that is subject to extensive first-pass metabolism.
`
`Pharm Sci 65:712-716, 1976
`
`"
`;
`
`f':
`
`Subject Responses
`
`Side effects were reported by the subjects, with nausea
`
`
`
`being the most common (Table 4). There were no dose­
`
`
`
`
`
`dependent trends in the numbers of subjects reporting one
`
`or more side effects (50 mg tablet, N=3; two 50-mg tab­
`lets, N =2; 100-mg syrup, N =4; and four 50-mg tablets,
`
`
`
`N =4). No subject withdrew from the study because of side
`effects.
`
`19
`
`Page 5 of 5
`
`