Published under the auspices of the
`International Council on Alcohol and Addictions
`
`AMN1012
`IPR of Patent No. 7,919,499
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`

`

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`DRUG AND ALCOHOL DEPEND~"~2 o ~~·~~ ~i
`
`Vol. 16 (1985)
`
`AMN1012
`IPR of Patent No. 7,919,499
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`

`

`©ELSEVIER SCIENTIFIC PUBLISHERS IRELAND LTD., 1985
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`AMN1012
`IPR of Patent No. 7,919,499
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`

`

`Drug and Alcohol Dependence, 16 (1985) 1-8
`Elsevier Scientific Publishers Ireland Ltd.
`
`1
`
`CLINICAL EVALUATION OF A NALTREXONE SUSTAINED-RELEASE
`PREPARATION
`
`C.N. CHIANG*•a, L.E. HOLLISTER b, H.K. GILLESPIEb and R.L. FOLTzc
`a Division of Preclinical Research, National Institute on Drug Abuse, 5600 Fishers Lane,
`Rockville, MD 20857, b Veterans Administration Medical Center, Palo Alto, CA arid
`cc enter for Human Toxicology, University of Utah, Salt Lake City, UT 84112 (U.S.A.)
`(Received March 20th, 1985)
`
`SUMMARY
`
`A clinical evaluation of the naltrexone bead, a biodegradable sustained-
`release dosage form of 3.0 mg in weight containing 70% naltrexone in a
`copolymer of lactic and glycolic acids, was carried out in 4 healthy normal
`males. Subjects were given an intravenous dose of 10 mg naltrexone and
`approx. 1 week later a 63-mg dose of naltrexone by subcutaneous adminis-
`tration of the beads. Challenge doses of 15 mg morphine were given to each
`subject during the study for the assessment of narcotic blockade effects of
`naltrexone. For a 2-4-week period after bead administration, relatively
`constant plasma levels were maintained at 0.30-0.46 ng/ml for naltrexone
`and were 0.64-1.07 ng/ml for naltrexol. Urine levels for unchanged and
`conjugated naltrexone were 79-215 ng/ml and for naltrexbl were
`315-500 ng/ml. From kinetic analysis, an average of 2.4-2.7% of implanted
`dose was absorbed each day from the administration of the beads. Opiate
`effects of morphine challenges were mitigated during the 2-4-week period
`after administration of naltrexone beads.
`
`Key words: Naltrexone- 30-Day sustained-release dosage form- Clinical
`evaluation- Opiate antagonism effect- Pharmacokinetics - ·· Plasma and
`urine concentrations - N altrexol
`
`INTRODUCTION
`
`Naltrexone, a potent narcotic antagonist [1], was recently approved by
`the Food and Drug Administration (FDA) for the treatment of narcotic
`· addiction. By blocking opiate euphoric effects, naltrexone provides protection
`for postaddicts from opiate use or readdiction. It has been reported [2,3],
`
`*To whom correspondence should be sent at: Division of Preclinical Research, National
`Institute on Drug Abuse, Room 10-A-13, 5600 Fishers Lane, Rockville, MD 20857, U.S.A.
`
`0376-8716/85/$03.30
`© 1985 Elsevier Scientific Publishers Ireland Ltd.
`Printed and Published in Ire}and
`
`~.·
`
`t.
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`t
`1· ;;
`t;
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`~·
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`2
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`that patients were opiate-free as long as they were on naltrexone and patients
`who stayed on naltrexone treatment longer were able to continue longer
`periods opiate free after treatment. An oral dose of 50 mg daily or
`100 mg Monday, Wednesday and 150 mg Friday is generally required in the
`treatment. As naltrexone provides no euphoric effects and there are no
`observable pharmacological consequences from not taking the drug, patient
`compliance for taking the drug everyday or three times every week over a
`long period of time is a problem [ 4]. One solution for improving patient
`compliance is the development of sustained-release dosage forms to alleviate
`the need for taking frequent medication. A biodegradable bead containing
`70% naltrexone was developed [5] to provide narcotic blockade effect for
`a 1-month period. Preliminary pharmacokinetic studies in humans [ 6]
`demonstrated that relatively constant plasma levels of naltrexone were
`maintained for a 1-month period following subcutaneous administration of
`the naltrexone bead sustained-release dosage form. A clinical evaluation was
`therefore carried out to assess both the opiate antagonism effects of this
`dosage form and the feasibility of a sustained-release dosage form for treat-
`. ment of narcotic addiction.
`
`MATERIALS AND METHODS
`
`Materials
`Naltrexone beads and naltrexone HCl solution (10 mgjml) were provided
`by the National Institute on Drug Abuse. The naltrexone bead, a solid
`sphere of 1.5 mm in diameter and 3.0 mg in weight, is composed of 70%
`naltrexone in a physical mixture with a copolymer of 90% L (+)-lactic acid
`and 10% glycolic acid [5].
`
`Clinical protocols
`Protocoll. Two healthy normal males (M1 and M2) were given intravenous
`(i.v.) doses of 10 mg naltrexone solution. Approximately 1 week later both
`subjects were also given a 63-mg dose of naltrexone implantation of 30
`naltrexone beads dispersed in a circle of approx. 2 inches in diameter in the
`interscapular area. The beads were not removed after the study. Challenge
`doses of 15 mg morphine were given intramuscularly on week 1 and week
`4 after bead implantation for both subjects M1 and M2 and on week 8 and
`week 12 for subject M2. Following morphine challenges, subjects were
`observed for opiate effects on subjective states, pupillary diameters and
`hyperemia in the conjunctivas. Subjects were also asked to describe their
`feelings. Blood samples were drawn at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6 ? 8,
`10, 12 and 24 hand urine samples were collected for 1 day after the intra-
`venous dose of naltrexone. After bead implantation, blood sarp.ples were
`drawn approx. 4, 8, 12 and 24 h after dosing on the first day and daily
`during week 1, every other day during week 2, and every third day during
`weeks 3 and 4. Urine samples were collected daily throughout 4 weeks.
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`3
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`Urine samples were hydrolyzed· with ~-glucuronidase, to liberate conjugated
`naltrexone and naltrexol, and then assayed for total naltrexone and naltrexol.
`Gas chromatography-mass spectrometric method was used for the analysis
`of naltrexone and naltrexol concentrations in plasma and urine samples. The
`assay sensitivity was 0.1 ngjml for both naltrexone and naltrexol [7].
`Protocol II. This protocol was similar to I except that subjects received
`additional 15 -mg challenge doses of morphine prior to the subcutaneous
`administration of naltrexone beads. The pharmacological responses observed
`for this challenge dose of morphine served as a baseline for the evaluation
`of the extent of narcotic blockade effects of the beads. Briefly, two healthy
`normal males (M3 and M4) were given 10-mg intravenous doses of naltrexone
`and approx. 1 week later, subcutaneous implants of 30 beads (63 m.g nal-
`trexone) in the interscapular area as described in I. The beads were surgically
`removed from the implant site on day 14. An initial15-mg intramuscular
`dose of morphine sulfate was given prior to implantation of the naltrexone
`beads. Additional challenge doses of·15 mg morphine and placebo (distilled
`w·ater) were given in a double-blind fashion on days 5 and 7 for week 1 and
`days 12 and 14 for week 2 following the bead administration. After morphine
`challenges, subjects were observed for opiate effects on subjective states,
`pupillary diameters, hyperemia in the conjunctivas and were also asked to
`describe their feelings. Blood and urine samples were collected at times
`specified in I for the IV naltrexone. After bead implantation, blood samples
`were collected at 4, 8 and 24 h during the first day and daily from day 2 to
`day 14 urine samples were collected daily. Naltrexone and naltrexol con-
`centrations in plasma and urine samples were quantitated by the method
`described in I. Additional blood samples were also taken at 2 h after challenge
`doses and quantitated for morphine concentrations by a gas chromato-
`graphy -mass spectrometric method [ 8] . During the study, subjects kept a
`diary to record any effects that might be attributable to the treatment.
`
`RESULTS
`
`Pharmacokinetics
`Following an i.v. dose of naltrexone, plasma naltrexone levels declined
`rapidly and fell to levels below assay sensitivity within 24 h. Plasma levels
`of metabolite naltrexol reached peaks rapidly in 15-30 min and then
`declined at a much slower rate than that of naltrexone. Terminal plasma
`half-lives or naltrexone, estimated from the terminal log-linear portion of
`the plasma concentration-time curve, were about 2 h. N altrexone plasma
`clearances calculated as dose divided by area under plasma concentration-
`time curve (AUC) ranged from 2.0 to 3.7 1/min.
`Representative plasma and urine levels of both naltrexone and metabolite
`naltrexol after subcutaneous implantation of a 63-mg dose of naltrexone are
`shown in Fig. 1 for subject M3. Relatively constant plasma levels were
`maintained for naltrexone at 0.3-0.6 ngjml and for naltrexol at
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`Subject M3
`
`800
`
`6oo
`
`400
`
`200
`
`0~------------------------------------------------
`
`4
`
`E d>
`E.
`Q3
`> Q)
`
`_J
`
`Q) c
`:§
`
`E
`........
`0> c
`Q3
`> Q)
`_J
`ro
`E CJ) ro
`0:
`
`Time (Day)
`Fig. 1. Plasma concentration-time curve (bottom) and urine concentration-time curve
`(top) for Subject M3 after naltrexone bead implantation for naltrexone (o) naltrexol U~ ).
`
`0.5-0.9 ng/ml throughout a 2-week period. Urine levels of naltrexone and
`naltrexol fluctuated throughout the experiment. Data for both naltrexone and
`naltrexol of all subjects were summarized in Table I. Plasma levels are
`reported as averages from day 2 until the end of the experiment. Average
`plasma levels were similiar for all subjects with a range 0.30-Q.46 ngjml
`for naltrexone and 0.64-1.07 ngfml for naltrexol. Average urine levels
`for unchanged and conjugated naltrexone were 78.9-214.6 ng/ml and for
`naltrexol were 315.1-500.2 ngjml. The amount of naltrexone absorbed
`fr<:>m the subcutaneous implants was calculated as AUC X clearance, where
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`5
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`TABLE I
`SUMMARY OF EXPERIMENTAL DATA OF NALTREXONE AND NALTREXOL
`'~'OLLOWING A 63-mg DOSE OF NALTREXONE BY SUBCUTANEOUS
`IMPLANTATION
`
`Subject Duration
`(days)
`
`Plasma
`
`Urine
`
`Naltrexone Naltrexol
`(ng/ml)
`(ng/ml)
`
`Naltrexoneb
`(ng/ml)
`
`Naltrexolb
`(ng/ml)
`
`% Dosec
`absorbed
`
`M1
`M2
`M3
`M4
`
`30
`27
`14
`14
`
`84.7 ( 54.5) 440.9 (280.7) 81.2
`0.31 (0.14)a 1.07 (0.28)
`0.36 (0.11) 0.64 (0.22) 214.6 (129.5) 500.2 (237.8) 65.2
`0.64 (0.11) 0.75 (0.20) 205.7 (223.9) 327.9 (120.5) 33.0
`78.9 ( 30.3) 315.1 (117.1)
`0.30 (0.08) 0.66 (0.15)
`
`a .Average from day 2 till the end of the experiment numbers in parentheses are S.D.
`hConcentrations of hydrolyzed samples.
`cEstimated from area under plasma concentration-time curve X plasma clearance.
`clearance was estimated from the intravenous study. The estimated dose of
`naltrexone absorbed into the systemic circulation from bead administra~ion,
`Table I, was 81.2% for subject M1 during a 30-day period, 65.5% for subject
`IVI2 during a 27 -day period and 33% for subject M3 during a 2-week period.
`
`Pharmacological evaluation
`Pharmacological responses to a morphine challenge given either before or
`after the bead administration were quite variable among the subjects. A
`summary of the results are presented in Table II. No data on the pharmaco-
`logical responses of 15 mg morphine given prior to the bead implantation
`were available for subjects M1 and M2.
`When morphine challenges were given after the beads implantation, subject
`M1 showed no observable objective effects, no miosis, no hyperemia and did
`not feel any mental effects. Considering the usual response to a 15 mg
`n1orphine in normal subjects, it is conceivable that the no-effect observed
`for subject M1 suggests a complete opiate antagonist effects due to the
`naltrexone implant. A presumably complete suppression of opiate effects for
`1 month after the bead administration is tentatively assigned for subject M1.
`When morphine challenges were given during the 4-week period after the
`bead administration, subject M2 showed very slight hyperemia in conjunctiva
`and miosis (pupillary diam,e~ers reduced from 3 mm to 2 mm), but felt no
`subjective effects. When morphine challenge doses were given on week 8
`and 12 after the beads implantation, the opiate effects of hyperemia and
`miosis were more apparent and subject M2 indicated that he felt the euphoric
`effects. Although no control data is available on the pharmacological effects
`of a 15-mg morphine dose for assessment of opiate blockade effects of the
`beads, comparison of opiate effects during the 12-week period appears to
`indicate that opiate subjective effects were effectively blocked for subject
`M2 during the 1-month period after the bead administration.
`
`...
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`6
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`TABLE II
`SUMMARY OF PHARMACOLOGICAL EVALUATION
`
`Subject
`
`Before beads implantation After beads implantation
`
`M1
`M2
`
`M3
`
`M4
`
`Morphine
`
`Nausea, vomiting
`perspiring, miosis
`Morphine cone.
`17 ng/ml
`Mental and physical
`heaviness, time
`perception distorted
`miosis
`Morphine cone.
`33 ng/ml
`
`Morp~ine
`
`No effects
`Miosis
`No mental effect
`Light-headed
`(on and off)
`Morphine cone.
`19 ng/ml
`Opiate effects
`mitigated
`
`Morphine cone.
`22 ng/ml
`
`Placebo
`
`No effects
`
`No effects
`
`Prior to bead administration, subject M3 experienced severe morphine
`reactions after the morphine challenge including nausea, vomiting, perspira-
`tion, dizziness and miosis (pupillary diameters were reduced from 3.5 mm
`to 3.0 mm.) The plasma morphine concentration at 2 h after this morphine
`dose was 17 ng/ml. After beads implantation, subject M3 did not experience
`any of the severe opiate reactions he had experienced previously except light
`headedness on and off for 4 h after the challenge dose. Morphine concen ~
`tration was 19 ngfml at 2 h after dose. A nearly complete antagonism of
`morphine effects by the bead administration was clearly demonstrated.
`Subject M4 felt mentally and physically sluggish and his time perception
`distorted after the control challenge dose, his pupillary diameters were
`reduced from 2 mm to 1 mm and the plasma morphine concentration was
`33 ngfml at 2 h after administration. When morphine challenge doses were
`given after bead implantation, subject M4 experienced opiate effects similar
`to what he had prior to the bead administration but the intensities were
`mitigated. In this case the morphine concentrations was 22 ng/ml at 2 h
`after administration.
`When challenge doses of placebo were given to subjects M3 and M4, no
`effects were reported. For all subjects, a partial to a presumably complete
`blockade of the opiate effects of a 15-mg morphine challenge was observed
`for a month period following naltrexone beads implantation. The blocking
`of subjective effects appeared more effective than the blocking of physio-
`logical responses. This observation is consistent with that reported by Verebey
`et al. [9] .
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`7
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`Tissue reactions to the implanted beads were reported in a previous
`report [ 6] . In order to minimize tissue reactions, the beads were dispersed in
`a circle of 2 inches in diameter at the implantation site. About 2 weeks after
`the beads administration, there was a mild inflammation reaction at the
`implantation site of subject M2 which subsided during the remaining 10
`weeks. No reaction was observed for subject M1 during the 4-week study
`period. For subject M3 and M4, no reactions occurred during the 2-week
`study period at which time the beads were surgically removed.
`
`DISCUSSION
`
`The pharmacokinetic parameters of naltrexone and naltrexol following
`the i.v. naltrexone bolus and the subcutaneous beads implantation for all the
`subjects were similar to those reported earlier [ 6] . Relatively constant
`plasma levels of naltrexone were maintained during the study period for all
`the subjects following implantation of the beads. An estimated daily dose
`of 1.5-1.7 mg or 2.4-2.7% of the implanted dose was absorbed from the
`site of implantation into the systemic circulation. These data confirm
`observations reported earlier [ 6] that naltrexone is released at relatively
`constant rates over a period of 1 month following the subcutaneous adminis-
`tration of the beads.
`The antagonistic effect of naltrexone to a morphine challenge was quite
`variable among subjects, ranging from partial to a presumed complete
`antagonism, after subcutaneous administration of the naltrexone beads.
`Earlier . reports [ 9] demonstrated that complete narcotic antagonism to a
`25-mg heroin challenge at 24 h after 100 mg daily oral dose of naltrexone, at
`which time the average plasma naltrexone level was 2.4 ngjml. As a daily oral
`dose of 50 mg is effective in treatment, a minimum effective plasma level
`of naltrexone is therefore suggested to be 1 ng/ml. For this preliminary
`evaluation, a safe and possibly minimal effective dose of 63 mg was chosen.
`The resulting average plasma naltrexone level was about 0.30-Q.46 ng/ml
`and opiate effects were partially blocked for some subjects. Since it has
`been suggested that effects of naltrexone are related to plasma levels [ 9] ,
`a dose greater than 63 mg will be required for this dosage form in order to
`maintain clinically -effective levels.
`In summary, the results of this preliminary evaluation indicate that a
`sustained-release dosage form which is capable of maintaining constant
`naltrexone plasma levels for 1 month can be clinically useful if sufficient
`plasma levels of naltrexone are maintained. However, the incidence of
`tissue irritations of the naltrexone beads will preclude the use of this parti-
`cular dosage form in clinical treatment. Nevertheless, the information
`obtained on pharmacokinetic and pharmacodynamics of this sustained
`release form will be valuable for the future development of an improved
`delivery system which is biocompatible and suitable for clinical use for the
`treatment of narcotic addiction.
`.
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`8
`
`ACKNOWLEDGEMENT
`
`We thank Ms. Kim M. McGinnis for analyses of blood and urine samples
`and Mr. Kenneth Davis for analyses of beads. The work was supported by
`National Institute on Drug Abuse Grant No DA-0424 and Contract Nos.
`271-81-3802 and 271-82-3900.
`
`REFERENCES
`
`1 W.R. Martin, D.R. Jasinski and P.A. Mansky, Arch. Gen. Psychiatry, 28 (1973) 784.
`2 R.A. Rawson, F.S. Tennant, Jr. and L.S. Harris (Ed.), Problems of Drug Dependence,
`J.983, NIDA Research Monograph 49, DHHS Publication No. (ADM) 84-1316,
`Washington, DC, 1984, pp. 289-295.
`3 A.M. Washton, M.S. Gold and A.C. Pottash, Advances in Alcohol and Substance
`Abuse, 4 (1984) 89.
`4 P. Renault, Treatment of heroin dependent persons with antagonists: current status,
`in: R.E. Willett and G. Barnett (Eds. ), Naroctic Antagonists: Naltrexone Pharmaco-
`chemistry and Sustained-Release Preparations, NIDA research monograph 28, DHHS
`publication (ADM) No. 81-902, Washington, DC, 1981, pp. 11-12.
`5 A. C. Sharon and D.L. Wise, Development of drug delivery systems for use in treatment
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`N altrexone Pharrpacochemistry and Sustained Release Preparation, NIDA research
`1nonograph 28, DHHS publications (ADM) No. 81-902, Washington, DC, 1981,
`pp. 194-213.
`6 C.N. Chiang et al., Clin. Pharmacol. Ther., 36 (1984) 704.
`7 D.M. Chinn, K.M. McGinnis and R. L. Flotz, Quantitative measurement of naltrexone
`and its major metabolite in plasma and urine, Presented at the Annual Meeting of
`the American Society for Mass Spectrometry, Boston, MA, May 8-13, 1983.
`8 R.L. Foltz, Service Laboratory fo1· Drug Quantification, 11th Quarterly Report,
`NIDA Contract No. 271-82-3900, National Institute on Drug Abuse, Rockville, MD.
`9 K. Verebey et al., Clin. Pharmacal. Ther., 20 (1976) 315.
`
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