CLINICAL
`
`PHARMACOLOGY
`
`an d THERA P E U T I C S
`
`volume 36 number 1·
`
`July 1984
`
`Copyright © 1984 by The C. V. Mosby Company
`
`Table of contents
`
`Commentary 1
`
`Original 5
`articles
`
`Predictability of verapamil steady-state plasma levels from single-dose
`data explained
`John G. Wagner, Ph.D., Ann Arbor, Mich ., College of Pharmacy and Up-
`john Center for Clinical Pharmacology, The University of Michigan Medical
`Center
`
`Simultaneous modeling of bopindolol kinetics and dynamics
`Rudolf Platzer, M .D., Renata L. Galeazzi, M .D., Werner Niederberger,
`Ph.D., and Joachim Rosenthaler, Ph.D. , Bern and Basel, Switzerlimd, De-
`partment of Medicine, University of Bern, Bern, and Department of Biophar-
`maceutics, Sandoz Ltd., Basel
`Data indicate that bopindolol reversibly blocks beta-adrenergic receptors
`
`14
`
`19
`
`Effect of food on blood hydralazine levels and response in hypertension
`Alexander M. M. Shepherd, M .D. , NormqnA . Irvine, M.D. , and Thomas M.
`Ludden, Ph.D. , San Antonio and Austin, Tex., Division of Clinical Pharma-
`cology, Departments of Pharmacology and Medicine, University of Texas
`Health Science Center, San Antonio, and College of Pharmacy, University of
`Texas, Austin
`Food decreases hydralazine levels and blood pressure effect
`
`Effect of nifedipine on serum c!igoxin concentration and renal digoxin
`clearance
`Janice B. Schwartz, M .D., and Philip J. Migliore, M.D., Houston, Tex. ,
`Sections of Cardiology and Clinical Pharmacology/Hypertension, Depart-
`ments of Pathology and Internal Medicine, Baylor College of Medicine
`Data indicate that nifedipine does not alter serum concentration or remit clearance of digoxin
`
`July 1984
`
`Continued on page 2A
`
`page 1A
`
`AMN1025
`IPR of Patent No. 7,919,499
`
`

`

`Kinetics of a naltrexone sustained-release preparation
`
`A biodegradable sustained-release naltrexone bead preparation containing 70% naltrexone in a
`physical mixture with a copolymer of 90% lactic acid and 10% glycolic acid was evaluated in
`three male subjects. Each subject received a 10-mg iv dose of naltrexone HCl and a 63-mg dose
`by subcutaneous implantation of naltrexone beads. Kinetics of naltrexone estimated from the
`intravenous dose indicated a plasma clearance range of 3.1 to 3.4 !/min and a tVz range of 1.7
`to 3 .7 hr. After bead implantation, average plasma naltrexone levels were maintained at 0.3 to
`0.4 ng/ml and naltrexollevels were at 0.4 to 1.0 nglml for a period of approximately I mo,
`during which urine naltrexone and naltrexollevels were about 20 to 30 and 70 to 200 nglml. It
`was estimated that approximately 70% to 77% of the dose was absorbed after bead
`implantation. There were no serious adverse effects other than tissue irritation in two of the
`three subjects.
`
`C. N. Chiang, Ph.D., L. E. Hollister, M.D., Akiri Kishimoto, M.D., and
`G. Barnett, Ph.D.* Rockville, Md., and Palo Alto, Calif.
`Division of Preclinical Research, National Institute on Drug Abuse, Rockville, and Veterans
`Administration Hospital. Palo Alto
`
`Naltrexone, a safe and potent long-acting
`narcotic antagonist, 4• 6 is currently under clini-
`cal investigation for the treatment of narcotic
`addiction. Because. of the need for long-term
`treatment in drug addiction and the problem of
`patient compliance, a sustained-release prep-
`aration that blocks narcotic effects for about a
`month will have an advantage over current oral
`preparations, which require dosing daily or
`three times a week. 6 One of the dosage forms
`developed, 9 biodegradable beads containing
`naltrexone, has been shown in animals to re-
`lease naltrexone and provide pharmacologic ac-
`
`Supponed by National Institute on Drug Abuse Grant No. DA-
`00424 and Contract Nos. 271-81-3802 and 271-82-3900.
`Received for publication June 22, 1984; accepted Aug. 9, 1984.
`Reprint requests to: C. N. Chiang, Division of Preclinical Re-
`search, National Institute on Drug Abuse, Roclcville, MD 20857.
`*Present address: Laboratory of Mathematical Biology, National
`Cancer Institute, Bethesda, MD 20205.
`
`704
`
`ttvtty for 1 mo.3• 8 We report a preliminary
`evaluation of naltrexone beads in man. Since
`the effect of narcotic antagonism was shown to
`correlate with plasma naltrexone levels in
`man, 10 a kinetic study was performed to charac·
`terize plasma and urine levels of naltrexone and
`its metabolite naltrexol after subcutaneous im-
`plantation of naltrexone beads in man.
`
`Methods
`Naltrexone beads and naltrexone HCI (10
`mg/ml) solution were provided by the Nation~
`Institute on Drug Abuse. The naltrexone bead IS
`a solid solution sphere, 1.5 mm in diameter and
`3. 0 mg ill weight, composed of 70% naitrexone
`in a physical blend with a copolymer of 90%
`L( + )-lactic acid and 10% glycolic acid. our
`subjects were three normal healthy men aged 2°
`to 37 yr who were given an intravenous injec·
`tion of 1 0 mg (1 ml) naltrexone and a subcuta·
`
`AMN1025
`IPR of Patent No. 7,919,499
`
`

`

`Vofu!lle 36
`Number 5
`
`Sustained-release naltrexone 705
`
`oeous implant in the interscapular area of 63 mg
`(30 beads) naltrexone. There was at least a 1-wk
`period between treatments. For the intravenous
`dose, blood samples were drawn 0, 0.25, 0.5,
`0.75, 1. 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hr
`after dosing. Urine samples were collected for 1
`day. After bead implantation, blood samples
`were drawn approximately 0, 4, 8, 12, and 24
`hr after dosing on the first day, daily during the
`first week, every other day during the second
`week, and every third day during the third and
`fourth weeks. Urine samples were collected
`daily throughout 4 wk. Beads were surgically
`removed from the implant site approximately a
`month after they were implanted. During the
`study, subjects kept a diary to record any effects
`that might be attributable to the treatment.
`Naltrexone and naltrexol concentrations in
`plasma and urine samples were quantitated by
`gas chromatography/mass spectrometry (Ge-
`MS) with 2H3-naltrexone and 2H3-naltrexol as
`internal standards. 1 Samples were extracted and
`derivatized with 2% methoxyarnine HCl and
`pentaftuoropropionic anhydride to form
`the
`roethoxime bis-pentafluoropropionate deriva-
`tive of naltrexone and the tris-pentafluoropro-
`pionate derivative of naltrexol. The derivatives
`were then analyzed by means of capillary col-
`umn gas chromatography coupled to a Finnegan
`4500 mass spectrometer operated in the nega-
`tive ion chemical ionization mode. Assay sen-
`sitivity was 0.1 ng/ml for naltrexone and nal-
`trexol. The naltrexone content in the beads re-
`moved from each subject was analyzed by GC
`or HPLC.2
`
`Results
`Representative plasma levels of naltrexone
`and naltrexol after an intravenous dose of nal-
`lrexone are shown in Fig. 1 for Subject J. Nal-
`lrexone levels declined biexponentially and fell
`to levels below assay sensitivity at 24 hr. Nal-
`lrexol levels peaked within 1 hr and then de-
`clined at a slower rate than the parent drug.
`Individual plasma data analyzed by nonpara-
`metric kinetics are listed in Table I. The termi-
`nal phase tlh for naltrexone is I. 7 to 3. 7 hr.
`Plasma naltrexone clearance (calculated as dose
`divided by AUC) was 3.1 to 3.4l/rnin. Maxi-
`mum naltrexol plasma levels were reached with-
`
`200
`
`i ... Ill 50
`.s
`1:
`f! .. 1:
`0 ;:
`E .. Ill
`
`Gl
`1.1
`1:
`0
`u
`Ill 20
`
`i
`
`"
`
`"'
`
`"'
`
`"
`
`10
`
`"
`
`3L-----L-----L-----L-----L---~
`0
`5
`10
`15
`20
`25
`Time (hours)
`
`Fig. 1. Plasma concentration-time curves for Sub-
`ject J. after naltrexone, 1 0 mg iv, for naltrexone ( o)
`and naltrexol (L>).
`
`in an hour by all subjects. Maximum metabolite
`plasma levels ranged from 7 to 24 ng/ml and the
`AUC through 24 hr ranged from 67 to 148 ng/
`m1 · hr. Approximately 1% to 2% of the dose
`was excreted as naltrexone in urine in 24 hr.
`Plasma levels of naltrexone and naltrexol
`after subcutaneous implantation of a 63-mg
`dose of naltrexone beads are shown in Fig. 2 for
`Subject J. Naltrexone levels were highest on the
`first day and then fell to relatively constant
`levels of 0.2 to 0.4 ng/ml from day 2 through
`day 31 or the end of the experiment. Naltrexol
`plasma levels were higher than naltrexone
`levels and fluctuated at 0.2 to 0. 7 ng/ml. The
`other two subjects also had higher naltrexone
`and naltrexol plasma levels on the first day, fol-
`lowed by relatively constant values for both
`
`AMN1025
`IPR of Patent No. 7,919,499
`
`

`

`706 Chiang et al.
`
`C/in. Pharmacol. Thtr
`November 19~
`
`300
`
`E
`' "' c
`
`"E
`' "' c
`
`1.0
`
`0 .5
`
`0
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Day
`
`Fig. 2. Plasma concentration-time curve (bottom) and urine concentration-time curve (top) for
`Subject J. after naltrexone bead implantation for naltrexone (o) and naltrexol (6 ).
`
`Table I. Naltrexone and naltrexol kinetics after a 10-mg intravenous dose of naltrexone
`Naltrexone
`
`Naltrexol
`
`Subject
`
`tY;
`(hr)
`
`AUC
`(nglml · hr)
`
`Clp
`(I! min)
`
`C,TUU
`(nglml)
`
`7.3
`3.26
`51.1
`2.4
`J.
`A.
`24.2
`3.36
`49.6
`1.7
`P.
`11.0
`3.07
`54.3
`3.7
`Clp = Plasma clearance; c.,., = maximum concentration; T.,, = time to reach c.,,.
`
`T ""''
`(hr)
`
`0.5
`0.25
`1.0
`
`AUCo.14h'
`(ng/ml · hr)
`
`66.7
`147.4
`95.6
`
`from the second day until the end of the experi-
`ment. A representative curve of naltrexone and
`naltrexol daily urine levels, which fluctuated
`throughout the experiment for all three subjects,
`is shown for Subject J. in Fig. 2. Data for all
`subjects for both naltrexone and naltrexol are
`summarized in Table II. Plasma levels are re-
`ported as the average from day 2 until the end of
`the experiment. For the three subjects, average
`plasma naltrexone levels are similar (range 0.3
`to 0.4 ng/ml), while naltrexol levels varied
`(range 0.4 to 1.0 ng/ml). The AUC values, es-
`timated by the trapezoidal rule from the begin-
`ning until the end of the experiment, were 9.4 to
`
`11.0 ng/ml · day for naltrexone and 14 to 24
`ng/ ml · day for naltrexol. Average urine levels
`were 20 to 30 ng/ml for naltrexone and 70 to
`200 ng/ ml for naltrexol.
`The amount of naltrexone absorbed frorn
`the subcutaneous implants was calculated ~
`AUC x clearance, where clearance was esti-
`mated from the intravenous dose. Naltrexone
`kinetics for clearance and terminal phase tih are
`listed in Table I for a dose of 10 mg and are
`of the same order as those of 1- and 5-rng
`dosesY· 12 These findings suggest no apparent
`dose-dependent kinetics for naltrexone at thes_e
`low doses. As reported in Table ill, approxt·
`
`AMN1025
`IPR of Patent No. 7,919,499
`
`

`

`36
`5
`
`Sustained-release naltrexone 707
`
`fable II. Summary of experimental data for naltrexone and naltrexol after insertion
`of naltrexone beads
`Plasma levels (nglml)
`
`AUC (ng/ml · hr)
`
`Urine levels (nglml)
`
`Naltrexone
`
`Naltrexol
`
`Naltrexone
`
`Naltrexol
`
`Naltrexone
`
`Naltrexol
`
`0.26 (0.09)*
`0.41 (0.13)1
`0.29 (0.16):j:
`
`0.41 (0.14)
`1.00 (0.39)
`0.55 (0.26)
`
`9.4
`10.1
`11.0
`
`14.3
`24.5
`17.4
`
`29.3 (14.4)
`31.6 (14.2)
`20.5 (9.9)
`
`103.2 (57.3)
`200.9 (115.6)
`70.9 (40.0)
`
`•St.andard deviation (in parentheses) of mean values for 32 days.
`!Standard deviation (in parentheses) of mean values for 23 days.
`tStandard deviation (in parentheses) of mean values for 30 days.
`
`Table ill. Estimate of percent recovery of naltrexone dose after subcutaneous bead implantation
`Duration of
`implant (days)
`
`Total(%)
`
`Subject
`
`Dose absorbed* (%)
`
`Dose remainingf (%).
`
`J.
`A.
`P.
`
`32
`23
`30
`
`70
`77
`77
`
`26
`
`16
`
`96
`
`93
`
`•Calculated as AUC X Clp, where AUC is over days of duration and Clp is from intravenous experiment (see Table 1).
`tFrom analysis of beads removed at end of experiment.
`
`mately 70% to 77% of the implanted dose gets
`into systemic circulation and 16% to 26% of the
`dose was recovered from the beads after re-
`moval from the subject at the end of the experi-
`ment. Approximately 100% of the dose was ac-
`counted for in two of the three subjects.
`Most subjects were not aware of any change
`in mood or general function after implantation
`of the beads. In two of the three subjects there
`were varying degrees of local irritation at the
`site of implantation. In one subject, the beads
`were removed after 23 days because they had
`started to extrude. Another subject had a
`marked inflammatory reaction that became in-
`durated but that subsided after the beads were
`removed. The high prevalence of local reaction
`to the beads may prelude the clinical use of this
`particular preparation of beads.
`
`Discussion
`Plasma naltrexone levels were maintained at
`l relatively constant level for approximately a
`IIIonth after subcutaneous implantation of beads.
`Naitrexone is qui~kly absorbed after subcutane-
`OUs injection and shows both high clearance and
`short tVz . 11 The persistent and constant plasma
`levels after bead implantation must
`a result of the slow and relatively constant
`
`release of naltrexone. The high plasma levels on
`the first day after dosing is probably because of
`an initial ''burst'' effect such as was also seen
`in monkeys. 8
`Naltrexone is eliminated mainly by metabo-
`lism, primarily conjugation and oxidation. Be-
`cause of extensive first-pass metabolism, the
`bioavailability of an oral naltrexone dose is ap-
`proximately 40%12 and the ratio of naltrexol to
`naltrexone plasma levels for an oral dose is
`higher than those for intravenous and subcuta-
`neous doses .U· 12 Verebey et al. 10 indicate
`that plasma naltrexol levels are approximately
`1000% those of naltrexone 24 hr after long-
`term, chronic, oral dosing, while we find nal-
`trexol levels are only 100% to 200% those of
`naltrexone after implantation. Although its ac-
`tivity in man needs further investigation, this
`difference may be important, as naltrexol has
`weak narcotic antagonistic activity in animals. 5
`Nearly complete narcotic antagonism to a
`25-mg heroin challenge was reported as long as
`48 hr after a 100-mg oral dose of naltrexone, at
`which time plasma levels were 2 ng/ml for nal-
`trexone and 10 ng/ rnl for naltrexol; partial an-
`tagonism was present at 72 hr.10 Since 25 mg
`heroin is a large challenge, a minimum effective
`concentration of naltrexone for the treatment of
`
`AMN1025
`IPR of Patent No. 7,919,499
`
`

`

`708 Chiang eta!.
`
`Cli11. Pharmacal. Ther
`November 1984
`
`opiate addiction may be lower than 1 ng/ml.
`The opiate blockade effect of naltrexone beads
`was related to dose in monkeys trained for mor-
`phine self-administration. 3 The self-administra-
`tion of morphine was not affected by the beads
`at a dose of 1 mg/kg, was partially blocked at 3
`mg/kg, and was completely blocked above 5
`mg/kg. For a dose of IO mg/kg, naltrexone
`plasma levels are approximate! y 2 ng/ ml. 8
`Since linear naltrexone kinetics are observed, 7
`·naltrexone levels after a 5-mg/kg dose would be
`I ng/ml, suggesting that the minimum effective
`concentration for blocking morphine in mon-
`keys is approximately I ng/ml. This is of the
`order of magnitude of naltrexone plasma levels
`in man after chronic oral dosing.
`Since an estimated minimum effective dose
`was used for preliminary assessment of the ki-
`netics of this dosage form in man, it is clear that
`this dosage form is capable of maintaining con-
`stant naltrexone levels over a 1-mo period. A
`pharmacologic evaluation is currently under-
`way, and preliminary results indicate that the
`opiate effect of a I5-mg morphine intravenous
`injection was blocked by the beads I wk after
`implantation.
`We thank Dr. Foltz and Mr. Chinn for analyses of
`plasma and urine samples and Mr. Kenneth Davis for
`analyses of beads .
`
`References
`I. Chinn DM, McGinnis KM, Foltz RL: Quantita-
`tive measurement of naltrexone and its major
`metabolite in plasma and urine. Presented at the
`Annual Meeting of the American Society for
`Mass Spectrometry, Boston, Mass ., May 8-13,
`1983.
`2. Davis KH: Dosage forms and analysis of abused
`drugs . Annual Report, NIDA contract No . 271-
`81 -3802 . Rockville, Md. , 1983, National Insti-
`tute on Drug Abuse.
`3. Harrigan SE, Downs DA: Pharmacological eval-
`uation of narcotic antagonist delivery systems in
`Rhesus monkeys , in Willet RE , Barnett G,
`editors: Narcotic antagonists: Naltrexone phar-
`macochemistry and sustained-release prepara-
`tions. NIDA research monograph 28 , DHHS
`publication (ADM) No . 81-902. Washington,
`
`D. C. , 1981 , U. S. Government Printing Office
`pp 77-92 .
`'
`4 . Martin WR , Jasinski DR, Mansky PA: NaJ.
`trexone: An antagonist for the treatment of her-
`oin dependence . Effects in man . Arch Gen Psy.
`chiatry 28:784-791 , 1973 .
`5. Misra AL: Current status of preclinical research
`on disposition , pharmacokinetics, and metab0•
`!ism of naltrexone, in Willet RE, Barnett G
`editors: Narcotic antagonists: Naltrexone phar:
`macochemistry and sustained-release prepara.
`tions . NIDA research monograph 28 , DHHS
`publication (ADM) No. 81-902. Washington,
`D. C., 1981 , U. S . Government Printing Office,
`pp 132-146.
`6. Renault P: Treatment of heroin dependent per·
`sons with antagonists: Current status, in Willet
`RE, Barnett G, editors: Narcotic antagonists:
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`release preparations. NIDA research monograph
`28, DHHS publication (ADM) No . 81-902.
`Washington , D. C. , 1981 , U. S. Government
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`7. Reuning RH, Batra VK, Ludden TM, Jao MY,
`Morrison BE, Sams RA, McCarthy DA, Harri·
`gan SE, Ashcraft SB , Bathala MS , Staubus AE,
`Malspeis L: Plasma naltrexone kinetics after in·
`travenous bolus administration
`in dogs and
`monkeys . J Pharm Sci 68:411-416, 1979.
`8. Reuning RH, Liao SHT, Staubus AE, Ashcraft
`SB , Downs DA , Harrigan SE, Wiley JN, Wise
`DL: Pharmacokinetic quantitation of naitrexone
`controlled release from a copolymer delivery
`system. J Pharmacokinet Biopharm 11:369-387,
`1983 .
`9. Sharon AC , Wise DL: Development of drug de·
`livery systems for use in treatment of narcotic
`addiction, in Willet RE, Barnet G, editors: Nar·
`cotic antagonists: Naltrexone pharmacochemis·
`try and sustained-release preparations. NIDA re·
`search monograph 28 , DHHS publication (ADM)
`No. 81-902 , Washington, D. C. , 1981, U. S.
`Government Printing Office, pp 194-213 .
`10. Verebey K, Volavka J, Mule SJ, Resnicks RB:
`Naltrexone: Disposition, metabolism and effects
`after acute and chronic dosing . CuN P HARMA·
`COL THER 20:315-328, 1976.
`II. Wall ME, Brine DR, Cook CE, Perez-Reyes M:
`Naltrexone disposition in man after subcutane·
`ous administration. Drug Metab Dispos 12:
`1206-1211 , 1984.
`12 . Wall ME, Brine DR, Perez-Reyes M: Metabo·
`!ism and disposition of naltrexone in man after
`oral and intravenous administration. Drug Metab
`Dispos 9:370-375 , 1981.
`
`AMN1025
`IPR of Patent No. 7,919,499
`
`