APPENDIXB
`
`Naltrexone: Disposition, metabolism, and effects
`
`after acute and chronic dosing
`
`·
`
`The dispo5.ition of naltrexone during acute and chronic administration of JOO-mg oral
`dose was studied in 4 subjects. Following an acute dose the mean (X) peak naltrexone
`plasma level was 43.6 ± 29.9 nglml at I hr and for the major biotransformation
`prodttct, {3-naltrexol, was 87.2 ± 25.0 ng/ml at 2 hr. Twenty-four hours after the dose
`the X levels of naltrexone and {3-naltrexol declined to 2.1 ± 0.47 and 17.6 ± 5.0 ng/ml,
`respectively. Following chronic administration the X peak plasma levels of naltrexone and
`/3-naltrexol rose to 46.4 ± 18.5 and 158.4 ± 89.9 ng/ml at 1 hr, but by 24 hr both
`compounds declined to levels of the same order as in the acute state at 24 hr. Plasma
`levels of naltrexone and {3-naltrexol measured 24 hr after the daily doses of naltrexone
`throu_ghout the study indicated that steady-state equilibrium was rapidly attained and that
`there was no accumulation of naltrexone and beta naltrexol in the plasma after chronic
`treatment on 100 mg oral doses. Bi exponential kinetics were observed for naltrexone and
`{3-naltrexol in the first 24 hr. The half-life of naltrexone and {3-naltrexol decreased
`slightly from the acute to the chronic study from IO .3 ± 3 .3 to 9. 7 ± I. 1 hr and from
`12 .7 ± 2 .6 to JI .4 ± ·2 .0 hr. The plasma levels of naltrexone declined slowly from 24
`through 72 hr from 2 .4 to 1.7 ng/ml, with an apparent half-life of 96 hr. The renal
`clearance data indicate that naltrexone is partially reabsorbed while beta naltrexol is
`actively secreted by the kidney. During acute and chronic naltrexone administration the
`mean fecal excretion was 2.1% and 3.6%, while urinary excretion was 38% and 70% of
`the dose in a 24-hr period. Opiate antagonism to 25 mg heroin challenges was nearly
`complete through 48 hr after naltrexone. At 72 hr the objective responses reappeared to a
`greater extent than the subjective ones. Correlation coefficient (r) between naltrexone
`plasma levels and opiate antagonism was 0.91 and between individual half-life of
`naltrexone and opiate antagonism it was 0.99.
`
`Karl Verebey, Ph.D., Jan Volavka, M.D., Salvatore J. Mule, Ph.D., and
`R. B. Resnick, M.D. Brooklyn and New York, N. Y.
`New York State Office of Drug Abuse Services, Testing and Research Laboratory, and
`Department of Psychiatry, The New York Medical College
`
`Supported by the National Institute on Drug Abuse, Contract No.
`ADM-45-74-133 and Grant No. DA 00073.
`Received for publication March 16, 1976.
`Accepted for publication April 27, 1976.
`Reprint requests to: Dr. K. Verebey, N. Y. S. Office of Drug
`Abuse Services, :resting and Research Laboratory, 80 Hanson
`Place, Brooklyn, N. Y. 11217.
`
`Naltrexone (N-cyclopropylmethylnoroxymor(cid:173)
`phone), a potent narcotic antagonist, is an ex(cid:173)
`perimental drug proposed for the treatment of
`opiate dependence. It was synthetized in 1965
`by Blumberg, Pachter, and Matossian. 3 Animal
`
`~\i,~ :lli-.%-~:S.1S.'®..i~ @.~~· s.~ @.~~wt¢.~,~ ~,~t~l ~~ ~~ @~ ~,i~~~ i,s\.• ~~ ~""-~1S:~'®- ~~ ~i~®S ~~ ~"'~~'..1!:'i(cid:173)
`~t~~~ ~~1!,'~ ~'®o '" ~ ~~~~ ~~~~~,i~~ 1~ ~'@.t~~\~o
`
`ALKERMES EXHIBIT 2017
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`Page 1 of 14
`
`

`

`316 Vere bey et al.
`
`Clinical Pharmacology
`and Therapeutics
`
`Table I. Clinical study protocol for drug administration, sample collection, heroin challenges, and
`pupillary photography
`
`JO
`
`NT
`
`II
`
`NT
`
`12
`
`NT
`
`13
`
`PL
`
`14 I
`
`15:
`NT
`
`NT
`H§
`
`B
`NT
`
`B
`NT
`
`B
`NT
`
`B
`NT
`
`B
`NT
`
`B
`NT
`
`B
`NT
`
`NT
`
`NT
`H:j:
`
`PL
`
`B
`NT
`
`B
`NT
`
`B
`NT
`
`B
`NT
`
`PL
`
`B
`NT
`
`B
`NT
`H§
`
`NT
`H§
`
`B
`
`B
`
`B
`
`B
`
`Subject I I
`c. L.
`
`PL
`H*
`
`2
`
`PL
`
`3
`
`PL
`Ht
`
`E. M.
`
`PL
`
`PL
`
`PL
`H*
`
`B. P.
`
`PL
`
`PL
`H*
`
`p
`PL
`Ht
`
`R. J.
`
`PL
`H*
`
`PL
`
`PL
`Ht
`
`4
`
`5
`
`6
`
`PL
`
`7 I 8 I 9
`
`NT NT NT NT NT
`H:j:
`tV2
`UF
`F24
`p
`p
`B
`B
`B
`B
`PL NT NT NT NT NT
`Ht
`t~
`UF
`F24
`p
`B
`B
`B
`B
`NT NT NT NT NT
`Ht
`t~
`UF
`F24
`p
`p
`B
`B
`B
`B
`PL NT NT NT NT NT
`H:j:
`t~
`UF
`F24
`p
`
`PL
`
`p
`
`B
`
`B
`
`B
`
`B
`
`PL, Placebo dose of naltrexone; NT, I 00 mg oral dose of naltrexone; H ( 15, 25 mg), heroin challenge, 15 mg, 25 mg intravenously, H (24, 48, 72 hr),
`heroin challenge of 25 mg intravenously; 24, 48, and 72 hr after the last naltrexone dose (when NT is noted on the same day the dose was given after the
`challenge); B, blood sample 24 hr after naltrexone: tJ, serial blood samples in a 24-hr period for biological half-life determination; P, pupillary
`photography; UF, fractional urine collection 0-4, 4-8, 8-12, and 12-24 hr; U(24), 24-hr urine collection, F(24), 24-hr fecal collection.
`*15 mg.
`t25 mg.
`:f:24 hr.
`§48 hr.
`
`studies indicated that naltrexone had undetect(cid:173)
`able or minimal agonistic effects and its relative
`opiate antagonistic potency was 40 times that of
`nalorphine and 2 to 3 times that of naloxone. 2•
`17 In man, naltrexone was 17 times as potent as
`naloxone in precipitating acute abstinence. 20
`The time-course of narcotic blockade in rats
`was 3 times as
`long as that achieved by
`naloxone. 1 A slow-release preparation of zinc(cid:173)
`tennate-naltrexone complex in mice maintained
`about 40% opiate blockade for 21 days,
`whereas a similar dose of naltrexone HCl lasted
`only 1 day. 12 Martin and Sandquist reported 21
`to 29 days antagonistic activity of naltrexone
`suspended in small particles of a polylactide
`plastic given intramuscularly to dogs. 22
`The pharmacology and narcotic antagonistic
`activity of naltrexone in man were studied by
`Martin, Jasinsky, and Mansky, 21 Resnick and
`associates, 24 and Volavka and associates. a-1
`
`These investigators found that the greater po(cid:173)
`tency (smaller oral doses) and longer duration
`of action of naltrexone present a definite
`therapeutic advantage over naloxone. No with(cid:173)
`drawal symptoms were observed after the
`abrupt discontinuation of 200-mg daily
`doses given for 3 to 8 wk. 24
`A comparative urinary excretion study of
`naltrexone in man and animals was reported by
`Dayton and
`lnturrisi. 9 Cone5
`isolated and
`identified ,8-naltrexol, the major urinary excre(cid:173)
`tion product of naltrexone in man. The chemis(cid:173)
`try of ,8-naltrexol was investigated in detail by
`Cone, Gorodetzky, and Yeh, 6 Chattargie and
`colleagues, 4 and Malspeis and colleagues. 19
`The quantitative aspects of human urinary dis(cid:173)
`position of naltrexone was studied by Cone,
`Gorodetzky, and Yeh 7 and Verebey, Mule, and
`Jukofsky, 28 both reporting that the major uri(cid:173)
`nary excretion product was ,8-naltrexol and that
`
`~\i,~ :lli~~:s.1S.~i<§: @.~~- s.~ @.~~wt¢.~,~ ~,~i~l ~~ ~%ss ®.~ ~,i~~~ i,s\.• ~~ ~~'1SS.~~'@. ~~ ~i~®S ~"\.~ ~~~~'..1!:'i(cid:173)
`~t~~~ ~<§:.%'~ ~'®o '" ~ ~~~~ ~~~~~".i@.~ is§: ~'@.t~~'~"
`
`Page 2 of 14
`
`

`

`Volume ]0
`Number 3
`
`Naltrexone 317
`
`~6
`NT
`
`17
`
`NT
`
`B
`NT
`H§
`
`NT
`
`PL
`
`B
`NT
`
`B
`NT
`
`B
`NT
`
`/8
`
`19
`
`20
`
`21
`
`NT
`U (24)
`F (24)
`
`NT
`NT
`U (24) U (24)
`F (24)
`
`NT
`t 1h
`UF
`
`22
`
`PL
`
`23
`
`PL
`
`24
`
`25
`
`26
`
`27
`
`H (72 hr)
`
`B
`NT
`
`B
`NT
`U (24)
`F (24)
`
`B
`NT
`U (24)
`F (24)
`
`B
`NT
`U (24)
`F (24)
`
`B
`NT
`U (24)
`F (24)
`
`B
`NT
`U (24)
`F (24)
`
`p
`B
`NT
`NT
`U (24) U (24)
`F (24)
`
`B
`NT
`
`B
`NT
`
`NT
`U (24)
`
`NT
`U (24)
`
`B
`NT
`
`NT
`t 1h
`UF
`
`p
`NT
`t 1h
`UF
`
`p
`
`PL
`
`H (72 hr)
`
`NT NT
`tlf.?
`UF
`
`B
`PL
`
`p
`
`PL
`
`PL
`
`B
`
`H (72 hr)
`
`PL
`
`H (72 hr)
`
`B
`PL
`
`B
`
`B
`
`B
`
`B
`
`B
`
`B
`
`a small quantity of unchanged drug, mainly in
`the conjugated form, was also present in the
`urine.
`The relative narcotic antagonistic potency of
`,B-naltrexol to naltrexone was reported to be
`l: 53 in the rat by Fujimoto and associates.11
`times as potent as
`Naltrexone was 12
`,B-naltrexol in the chronic spinal dog. 7 Re(cid:173)
`cently, Verebey and co-workers26 reported the
`isolation and identification of another human
`urinary metabolite of naltrexone, 2-hydroxy-
`3-methoxynaltrexol, which represents approx(cid:173)
`imately 10% of the urinary excretion products
`of naltrexone. Determination of naltrexone and
`,B-naltrexol in human plasma after therapeutic
`doses was only recently accomplished. 27 Using
`this method, the total disposition of naltrexone
`in conjunction with its pharmacological activity
`was evaluated and the results reported in this
`communication.
`
`Methods
`Subjects. Four male post-addict paid volun(cid:173)
`teers from the New York State Office of Drug
`Abuse Services were the subjects in the study.
`The subjects were admitted
`to a closed
`metabolic ward located at Manhattan State
`
`Hospital. The physical characteristics and drug
`history of subjects were: ( 1) average age, 28 yr
`(24 to 36); (2) average weight, 159 pounds (135
`to 180); (3) average duration of heroin use, 11
`yr ( 6 to 16). The subjects were all heavy
`cigarette smokers and occasional cocaine users.
`Some, but not all, of the subjects occasionally
`used marijuana, LSD, and barbiturates. At the
`beginning of the study all subjects stated that
`they were free of drugs for an average of 3 mo
`(2 to 6). After admission, the subjects were kept
`in the metabolic ward for 1 wk to assure a
`drug-free state. Prior to the study, each subject
`received a thorough physical examination and
`clinical blood chemistry survey; control urine
`and blood samples were collected. The urine
`samples were screened for all common drugs of
`abuse. 23
`Drug administration and protocol sched(cid:173)
`ule. All subjects recei\ed initial and subse(cid:173)
`quently daily oral doses of 100 mg nal(cid:173)
`trexone. The dosage schedule, metabolic sam(cid:173)
`ple collections, and time of heroin challenges
`are presented in Table I. The techniques used in
`this study to measure pupil size and to calculate
`plasma half-lifes have been reported. 29 Heroin
`in aqueous solution was injected intravenously
`
`~t~~~ ~~%'~ ~'®o '" ~ ~~~~ ~~~~~'-.i@.~ i~ ~'@.t~~\~o
`
`~\i,~ :m~~:s.1S.~i~ ~~~· s.~ ~~~wt¢.~,~ ~,~i~l ~~ ~~ ®.~ ~,i~~~ i"-"• ~~ ~""-~~~'@. ~~ ~i~~ ~"\.~ ~"'~~'..~'i(cid:173)
`
`Page 3 of 14
`
`

`

`318 Vere bey et al.
`
`Clinical Pharmacology
`and Therapeutics
`
`Table II. Plasma levels of naltrexone (NT) and beta-naltrexol (/3-0L) (ng/ml) in acute and
`chronic treatment after JOO mg doses of naltrexone
`
`Subject
`
`C. L.
`
`E. M.
`
`B. P.
`
`R. J.
`
`Drug
`NT
`
`{3-0L
`
`NT
`
`{3-0L
`
`NT
`
`{3-0L
`
`NT
`
`(3-0L
`
`Type of
`treatment
`
`Acute
`Chronic
`Acute
`Chronic
`
`Acute
`Chronic
`
`Acute
`Chronic
`
`Acute
`Chronic
`
`Acute
`Chronic
`
`Acute
`Chronic
`
`Acute
`Chronic
`
`Hours
`
`I
`
`2
`
`I 4
`
`I 8
`
`I 12
`
`I 24
`
`47.1
`42.9
`110.8
`114.7
`
`50.3
`28.8
`98.7
`204.0
`
`15.2
`21.9
`52.6
`131. l
`
`32.0
`32.9
`86.7
`96.0
`
`32.4
`21.4
`69.3
`103.4
`
`20.7
`18.0
`49.3
`163.8
`
`8.9
`15.1
`85.1
`68.4
`
`18.6
`20.8
`72.5
`68.8
`
`11.2
`10.8
`40.5
`79.6
`
`7.6
`9.5
`··37.5
`67.1
`
`5.3
`9.1
`33.6
`56.6
`
`8.0
`10.3
`57.6
`53.0
`
`4.7
`7.3
`34.8
`56.7
`
`5.0
`4.9
`25.2
`54.0
`
`3.3
`6.0
`28.9
`44.0
`
`4.3
`7.0
`44.0
`38.6
`
`1.5
`3.5
`18. l
`34.2
`
`2.6
`2.2
`11.7
`21.4
`
`2.3
`3.1
`16.7
`22.4
`
`2.0
`3.1
`23.8
`18.6
`
`1
`
`58.7
`55.5
`129.7
`143.3
`
`64.2
`53.7
`80.8
`288.0
`
`11.2
`18.7
`39.I
`119.3
`
`40.3
`57.6
`81.0
`83.0
`
`over a period of 3 min. Two such injections (15
`and 25 mg) were given before the naltrexone
`treatment. All subsequent heroin injections
`were of 25 mg.
`Sample collections. Following an acute oral
`dose of 100 mg naltrexone, 20 ml of blood was
`collected in tubes containing sodium oxalate at
`times 1, 2, 4, 8, 12, and 24 hr after naltrexone
`for the determination of the acute half-life (t1h).
`The same blood collection schedule was used
`during the maintenance phase of the study for
`the determination of the chronic tyz. The sam(cid:173)
`ples were centrifuged, the plasma obtained and
`frozen at -16° C until analyzed. Single blood
`samples were collected throughout the study,
`24 hr after each dose of naltrexone, to evaluate
`build-up and stabilization plasma levels of drug
`and metabolite during continued naltrexone
`administration. A single blood sample was
`collected just prior to heroin challenges to
`determine the narcotic antagonist blood levels
`at that time. Twenty-four hour urine specimens
`were collected on 3 successive days and feces
`samples on 2 successive days during the chronic
`phase of the study. Fractional urine samples of
`
`O to 4, 4 to 8, 8 to 12, and 12 to 24 hr were
`collected along with the acute and chronic t1h
`blood samples, to allow determination of renal
`clearance values and cumulative urinary excre(cid:173)
`tion patterns. The volumes of urine samples and
`weights of feces were recorded and the samples
`frozen at -16° C until analyzed.
`Analytical methods. The methods used in
`this study have been reported. 27
`• 28 An aliquot
`of plasma and internal standard (naloxone) were
`mixed and extracted into chloroform at pH
`8.5. 27 After a series of purification steps, the
`residue resulting from the evaporation of the
`last organic phase was derivatized with pen(cid:173)
`tafluropropionic anhydride (PFPA). The PFPA
`/3-naltrexol, and
`derivatives of naltrexone,
`naloxone were analyzed on a Hewlett-Packard
`Model 5830A instrument, equipped with a 63Ni
`linear electron capture detector. The column
`was packed with 3% OV-22 and the operating
`column oven temperature was 215° C. For urine
`and feces determinations of naltrexone and
`metabolites a modified method was used. 28
`Bis(trimethylsilyl)-trifluoracetamide (BSTF A)
`derivatives of the weak organic bases were
`
`~\i,~ :lli~~:s.1S.~i<§: @.~~, s.~ @.~~wt¢.~,~ ~,~t~l ~~ ~%ss @~ ~,i~~~ i,s\.• ~~ ~~'1SS.1S:~'@. ~~ ~i~®S ~~~ ~~~~'..1!:'i(cid:173)
`~t~~~ ~<§:.1!,'~ ~'®o '" ~ ~~~~ ~~~~~,i~~ 1<§: ~'@.t~~'~"
`
`Page 4 of 14
`
`

`

`Volume 20
`Number]
`
`2.0
`
`]
`
`1.5
`
`ACUTE
`
`-Naltruone
`-JS-Nalhexol
`
`2.0
`
`1.S
`
`1.0
`
`0.5
`
`0
`
`120
`
`Naltrexone 319
`
`CHRONIC
`
`-Nallrexone
`--JI-Nalbeml
`
`I.LT
`.ri ......... .
`,
`··1 ......... 1
`-i--·----------....... ..
`
`I
`
`0
`
`.§ I '°
`I~·
`1120 -I:
`
`0
`
`160
`
`J O
`
`012 4
`
`8
`
`12
`
`24
`
`012 4
`HOlllS
`
`8
`
`12
`
`Fig. 1. The time-course of naltrexone and J3-naltrexol plasma levels and the corresponding pupillary
`effects after a single IOO-mg dose (acute) and following multiple 100-mg doses of naltrexone
`(chronic). Each point on the graph represents the mean ± SD (n = 4).
`
`the ARCI (Addiction Research Center In(cid:173)
`prepared and anlyzed using a hydrogen flame
`ventory) was used. Table VIII presents a list of
`ionization detector. The column was packed
`questions: ( 1) absolute heroin effects were in(cid:173)
`with 3% OV-17 and the operating column oven
`vestigated by 10 true or false questions, repre(cid:173)
`temperature was 270° C. Feces samples were
`senting commonly reported opiate symptoms
`weighed and homogenized (1: 10 w/v) in 0.1 N
`elicited by intravenous heroin; (2) the relative
`HCl with a Waring blender, and small aliquots
`heroin effects were examined by a comparative
`were extracted, derivatized, and analyzed. 28
`test relating to past heroin experiences, referred
`Objective responses. Respiration rate was
`to as "opiate high"; (3) "liking" is a separate
`measured by a strain-gauge and recorded on a
`entity from
`''highs'' and symptoms and is
`polygraph. Respiratory depression was deter(cid:173)
`strongly influenced by the circumstances under
`mined by calculating the difference between the
`respiratory rate just prior to a heroin challenge
`which the drug is taken. It represents a state of
`and the rate 10 min after heroin administration.
`euphoria, rated on a scale of O to 4 (none to
`Pupillography was performed prior to a heroin
`best); (4) the observers not knowing what was
`administered, placebo 6r drug, also rated the
`challenge and 5 min after heroin administration.
`subjects' state of euphoria during and after
`Pupillary rniosis is expressed as the difference
`challenges on a scale of Oto 5; (5) the econom(cid:173)
`in millimeters between the pre- and post(cid:173)
`ics of heroin appears to provide a numerical
`challenge pupil sizes. Total objective responses
`were determined by summing the respiratory
`subjective measure. The test is based on the
`subject's estimate of the street value in dollars
`and pupillary responses.
`of the heroin or placebo injection.
`Subjective responses. A modified version of
`~\i,~ :lli~~:s.1S.~i<§: @.~~, s.~ @.~~wt¢.~,~ ~,~t~l ~~ ~%ss @~ ~,i~~~ i,s\.• ~~ ~~'1SS.1S:~'@. ~~ ~i~®S ~"\.~ ~"\.~~'..1!:'i(cid:173)
`~t~~~ ~<§:.1!,'~ ~'®o '" ~ ~~~~ ~~~~~,i~~ 1<§: ~'@.t~~'~"
`
`Page 5 of 14
`
`

`

`320 Verebey et al.
`
`Clinical Pharmacology
`and Therapeutics
`
`40
`
`315
`
`fS-NALTREXOL
`
`I
`
`!
`
`JH ---t I I
`\!1
`1
`
`levels of naltrexone were
`Peak plasma
`reached at I hr in the acute and chronic studies,
`averaging 43.6 ± 29.9 ng/ml and 46.3 ± 18.5
`ng/ml, respectively. The levels declined rapidly
`to an average of 2.1 ± 0.47 and 3.0 ± 0.55
`ng/ml by 24 hr after the dose in the acute and
`chronic studies . .B-Naltrexol plasma levels were
`high at 1 hr in the acute study, peaking at 2 hr
`(average of 87.2 ± 25.0 ng/ml). The levels
`declined to an average of 17.6 ± 5.0 ng/ml 24
`hr after the dose. In the chronic study, the
`average peak
`level of
`.B-naltrexol was
`158.4 ± 89.9 ng/ml at 1 hr, and by 24 hr the
`level declined to 24.2 ± 6.9 ng/ml. The simi(cid:173)
`lar 24-hr values in the acute and chronic studies
`for naltrexone and also for .B-naltrexol indicated
`no accumulation of naltrexone and .B-naltrexol
`in the plasma during the daily administration of
`100 mg naltrexone (Fig. 2). The figure shows
`that a steady-state equilibrium was almost in(cid:173)
`stantaneously achieved after the first dose was
`given.
`,8-Naltrexol levels varied more than
`naltrexone day to day. At 24 hr, .B-naltrexol
`concentrations were approximately IO times
`Results
`those of naltrexone.
`Table III shows the apparent t1h values of
`Naltrexone was administered in l 00-mg daily
`oral doses to 4 post-addict volunteers according
`naltrexone and .B-naltrexol in acute and chronic
`treatment. Since naltrexone was administered
`to the study protocol (Table I). The plasma
`orally, the secondary exponential decay repre(cid:173)
`levels of naltrexone and .B-naltrexol were de(cid:173)
`sents the apparent t1h while for .B-naltrexol the
`termined in acute and chronic treatment (Table
`t1h values are estimates since ,8-naltrexol was
`II). Substantial individual variation in the peak
`levels of naltrexone, 1 hr after the dose, was
`not administered in the absence of naltrexone.
`observed especially in the acute study, ranging
`The mean t1h for naltrexone and .B-naltrexol
`between 15.2 and 64.2 ng/ml of plasma.
`slightly declined from the acute to the chronic
`study. Naltrexone t1h was 10.3 ± 3.3 and
`Twenty-four hours after the dose, the individual
`9.7 ± 1.1 hr and ,B-naltrexol t1h was 12.7
`differences were much smaller, ranging be(cid:173)
`± 2.6 and 11.4 ± 2.0 hr in the acute and
`tween 1.5 and 2.6 ng/ml. .B-Naltrexol levels
`chronic studies, respectively.
`were higher than the parent compound at all
`· times, with differences of 1.5- to 10-fold.
`The 24-hr urinary excretion data are shown in
`Fig.
`l shows the average pupillary and
`Table IV. Naltrexone accounted for approxi(cid:173)
`plasma level time-courses of the 4 subjects
`mately 20% of the total ba&e recovered in 24 hr
`determined in the acute and chronic state. The
`in both the acute and chronic study, and it was
`biphasic nature of the pupillary time curve,
`excreted 90% conjugated . .B-Naltrexol was the
`though observed in both acute and chronic
`major urinary excretion product, approximately
`states, should be interpreted with due regard to
`70% of the total base recovered in 24 hr, and
`the great range of individual values (as indi(cid:173)
`was excreted 30% conjugated. The newly
`cated by the large standard deviations). The
`identified metabolite, 2-hydroxy-3-methoxy
`greater degree of papillary constriction in the
`naltrexol, is expressed as .B-naltrexol equiva(cid:173)
`chronic state than in the acute appears to be
`lents because a pure standard was not yet
`significant.
`available. This compound was approximately
`~\i,~ :m~~:s.1S.~i<§: @.~~, s.~ @.~~wt@.~,~ ~,~i~l ~~ ~%ss ®.~ ~,i~~~ i,s\.• ~~ ~~'1SS.1S:~'*- ~~ ~~~®S ~~~ ~~~~,1!:~(cid:173)
`
`I
`
`30 -e 25 p
`i
`! 15
`
`-
`
`20
`
`A.
`
`10
`
`5
`
`0
`
`2
`
`4
`
`6
`
`8 ~ U M
`DAYS
`
`•
`
`~
`
`Fig. 2. Naltrexone and {3-naltrexol plasma levels 24
`hr after each daily I 00-mg dose. The data at day O
`represent the 24-hr period of the acute t'h. Each point
`on the graph represents the mean ± SD (n = 4).
`
`~t~~~ ~<§:.~~ ~'®o '" ~ }"\~~~ *'.~~~~".i@.~ i~ ~'@.\~~'~"
`
`Page 6 of 14
`
`

`

`Volume 20
`Number 3
`
`Naltrexone 321
`
`Table III. tl/2 (in hr)* of naltrexone (NT) and {3-naltrexol ({3-0L)from plasma after JOO mg doses
`of naltrexone
`
`Acute
`
`Chronic
`
`Subject
`
`10
`
`NT
`
`I 20
`
`(3-0L
`
`I 20
`
`JO
`
`NT
`
`I 20
`
`10
`
`{3-0L
`
`I 20
`
`10
`
`C. L.
`10.2
`13.5
`7.3
`3.0
`3.0
`13.8
`E. M.
`10.8
`2.0
`8.1
`2.0
`9.6
`9.5
`B. P.
`14.7
`4.1
`10.7
`5.5
`15.7
`12.3
`R. J.
`12.0
`8.5
`3.0
`9.8
`9.5
`2.1
`Mean± SD 3.0 ± 0.9 10.3 ± 3.3 2.3 ± 1.7 12.7 ± 2.6 3.2 ± 1.6 9.7±1.1 3.1 ± 2.9 11.4 ± 2.0
`
`6.9
`3.5
`2.1
`
`4.1
`2.0
`3.0
`
`*The plasma levels were plotted semilogarithmically against time and the best lit was determined by the least-squares method. In most cases a
`biexponential decay was observed up to 24 hr and thus reported as primary (I°) and secondary (2°) tY.z.
`
`Table IV. Total urinary excretion of naltrexone and metabolites in 24 hr in acute and chronic
`treatment after JOO mg daily doses of naltrexone
`
`Acute base (mg)
`
`--
`
`Naltrexone
`
`Subject
`
`Free
`
`I Total
`
`{3-naltrexol
`
`Free
`
`I Total
`
`2 hydroxy-
`3-methoxy
`naltrexol
`
`Total
`
`Total base
`
`C. L.
`27.35
`18.35
`7.99
`0.81
`25.00
`17.66
`7.00
`0.87
`E.M.
`19.61
`13.77
`5:51
`0.77
`B. P.
`R. J.
`32.74
`26.56
`12.08
`1.43
`Mean± SD 0.97 ± 0.30 8.15 ± 2.82 19.08 ± 5.38 26.18 ± 5.45
`
`4.01
`3.02
`2.71
`4.09
`3.46 ± 0.69
`
`39.35
`35.02
`27.83
`48.91
`37.77 ± 8.81
`
`Chronic base (mg)
`
`Free
`
`Total
`
`Free
`
`Total
`
`Total
`
`Total base
`
`c. L.
`32.03
`43.49
`17.14
`1.25
`24.60
`40.45
`10.21
`0.90
`E.M.
`50.44
`33.81
`0.72
`B. P.
`15.44
`R. J.
`51.41
`25.52
`1.33
`21.56
`Mean± SD 1.05 ± 0.28 16.09 ± 4.82 28.99 ± 4.61 46.45 ± 5.33
`
`8.40
`4.08
`9.68
`8.18
`7.57 ± 2.41
`
`69.03
`54.74
`75.56
`81.15
`70.12 ± I l.39
`
`Table V. ,B-naltrexol-naltrexone
`concentration ratio for the 24-hr urinary
`excretion in acute and chronic treatment
`
`10% of the total base recovered in 24 hr in the
`acute and chronic study and was present only in
`the free form. In the acute study an average of
`38% and in the chronic study 70% of the dose
`was recovered in the 24-hr urine as naltrexone
`and known metabolites. Some increase in the
`urinary excretion of the conjugated bases was
`observed from the acute to the chronic study.
`Naltrexone conjugation increased from 88% to
`94% and
`,B-naltrexol conjugation increased
`from 24% to 38%. The nearly double urinary
`recovery of all the bases in the chronic study
`~\i,~ :lli-.%-~:s.1S.~i<§: @.~~, s.~ @.~~wt@.~,~ ~,~i~l ~~ ~%ss ®.~ ~,i~~~ i,s\.• ~~ ~~'1SS.1S:~'@. ~~ ~i~®S ~'\.~ ~~~~'..1!:'i(cid:173)
`~t~~~ ~<§:.1!,'~ ~'®o '" ~ ~~~~ ~~~~~".i@.~ is§: ~'@.t~~'~"
`
`Subject
`
`c. L.
`E.M.
`B. P.
`R. J.
`Mean± SD
`
`Beta-naltrexol I naltrexone
`
`\
`Acute
`
`Chronic
`
`3.42
`3.57
`3.55
`2.71
`3.31 ± 0.41
`
`2.54
`3.96
`3.26
`3.38
`3.29 ± 0.58
`
`Page 7 of 14
`
`

`

`322 Verebey et al.
`
`Clinical Pharmacology
`and Therapeutics
`
`80
`
`70
`
`ACUTE
`
`CHRONIC
`
`80
`
`_.; ,,,--,-,._.--/
`,~ ...
`.'.~ -·-·-
`
`~ .................... ---· .. ··"·
`, ..
`10
`.. ··········
`,, ... ··----..HIUl'IUll---
`v:_~--·-
`·-·*·
`24
`4
`HOURS
`
`0
`
`8
`
`12
`
`~-/
`..... ···
`......
`,,.,
`/
`/r---
`-·-· .
`4
`
`-
`
`8
`
`_ _J!_af!rUl:lm_ --·
`
`12
`
`24
`
`Fig. 3. Urinary excretion of naltrexone and its metabolites in acute and chronic treatment after
`100-mg oral doses of naltreX:one (n = 4).
`
`Table VI. Renal clearance of naltrexone and beta-naltrexol in acute and chronic treatment
`
`Subject
`
`Acute
`
`Renal clearance*t (ml/min)
`
`Naltrexone
`
`l
`
`Chronic
`
`Acute
`
`C. L.
`E. M.
`B. P.
`R. J.
`Mean± SD
`
`16.5
`75.0
`!07.2
`68.2
`66.7 ± 37.5
`
`27.5
`10.7
`38.5
`42.3
`29.8 ± 14.2
`
`242.7
`340.0
`284.9
`404.6
`318.1 ± 70.1
`
`{3-Naltrexol
`
`I
`
`Chronic
`
`527.3
`256.4
`375.8
`318.2
`369.4 ± 116.0
`
`*Renal clearance equals the slope of the plot of t:.X.u/ ~t vs Cp(t), where ~xu = the change in the amount of free drug excreted in the urine,
`~t = the time interval in min, Cp(t) is the drug plasma concentration at the midpoint of the interval. The intervals Oto 4, 4 to 8, 8 to 12, and 12 to
`24 hr were used in the calculation.
`tNaltrexone plasma concentrations were corrected for protein binding by multiplication of the plasma value by 0.8 (see Reference 18).
`
`(from 37.8% to 70.1 % of the dose) did not
`age clearance value of 67 and 30 ml/min and
`involve any qualitative changes in the propor(cid:173)
`{3-naltrexol is secreted by the kidney tubules,
`tion of naltrexone and its metabolites. In fact
`indicated by the average values of 318 and 369
`the ratios of naltrexone over
`(Table V),
`ml/min. The naltrexone values were corrected
`{3-naltrexol were strikingly similar in the acute
`for plasma protein binding of 20% (Ludden and
`and chronic studies.
`associates 18).
`Availability of plasma level and urinary
`The urinary excretion time-course of nal(cid:173)
`excretion values of free naltrexone and
`trexone and metabolites were similar in the
`,B-naltrexol for the same time periods permitted
`acute and chronic study but the quantities of all
`the calculation of renal clearance for both com(cid:173)
`bases nearly doubled in the chronic state (Fig.
`pounds. Table VI shows the renal clearance
`3). Most of the naltrexone excretion is limited
`data for naltrexone and {3-naltrexol. Naltrexone
`to the first 4 hr after the dose when the plasma
`is partially reabsorbed as indicated by the aver-·
`levels of naltrexone were highest. {3-Naltrexol
`~\i,~ :fil-.%-~:S.1S.'®..i~ @.~~, S.~ @.~~Wi@.~,~ ~,~i~l ~~ ~~ @.~ ~,i~~~ i,s\.< ~~ ~":,.'@S.~'@. ~~ ~i~®S ~'\.~ ~'\.~~'..1S:~(cid:173)
`~:§.~~~ ~~:S.'~ ~'®o '" ~ ~~~~ ~~~~~".i@.~ i~ ~~t~i.'~"
`
`Page 8 of 14
`
`

`

`Volume 20
`Number]
`
`Naltrexone 323
`
`Table VII. Total fecal excretion of naltrexone
`and metabolites in 24 hr in acute and chronic
`treatment after JOO mg oral doses of
`naltrexone
`
`Acute* base (mg)
`
`2-hydroxy-3-
`{3-0L methoxy na/trexol
`
`Subjects NT
`c. L.
`E.M.
`B. P.
`R. J.
`
`0.041 0.264
`0.130 4.921
`0.228 0.306
`0.116 2.204
`
`Mean
`
`0.128 1.924
`
`Chronict
`
`c. L.
`E.M.
`B. P.
`R. J.
`Mean
`
`0.251 2.792
`0.143 4.832
`0.370 1.612
`0.408 2.313
`0.293 2.887
`
`0.087
`0.074
`0.036
`0.110
`
`0.077
`
`0.942
`0.122
`0.491
`0.186
`0.435
`
`Total
`
`0.392
`5.125
`0.570
`2.430
`
`2.129
`
`3.985
`5.097
`2.473
`2.907
`3.615 ·
`
`• A single 24-hr collection.
`tAvcrage of two 24-hr collections after 10 days of treatment with
`100 mg naltrexone daily.
`
`Table VIII. The pharmacological testing
`protocols during and after heroin challenges
`
`Opiate symptoms
`(Reports by the subject about his feelings or
`physiological state.)
`I. Absolute-True and False Questionnaire (IO)
`(a) I feel so good that I know other people can
`tell it.
`(b) My voice sounds different than usual.
`(c) I feel as if something pleasant has just
`happened to me.
`(d) I feel it in my stomach.
`(e) I feel it in my mouth.
`(t) I feel it in my throat.
`(g) I feel it in my head.
`(h) I feel it in my nose.
`(i) My skin itches.
`U) I felt a rush.
`2. Relative- "Opiate High"
`Remember the experience when you had the
`very best high after heroin in your whole life?
`Now let us say we call it a I 00% high.
`Compared with that, how high are you now?
`____ %
`3. "Liking" the relative state of euphoria a scale of
`(0 to 4).
`4. Street value of heroin. How much would you pay
`for this shot if I asked you to pay me now?
`$ ___________ _
`
`TRUE
`
`Opiate signs
`(Measurements or notations of the physiologic state
`of the subject by observers.)
`l. Respiratory rate (No./min)
`2. Pupillary response (mm diameter)
`3. "Liking" the observers' rating of apparent
`euphoria (no change: l, 2, 3, 4, 5, very high)
`4. EEG (frequency and amplitude)*
`5. EKG (pattern)*
`6. Heart rate (No./min)*
`7. Blood pressure (mm Hg)*
`Phannacodynamic parameters
`Plasma levels of opiate antagonist at the time of
`heroin challenge (ng/ml).
`
`•Data not presented in this study.
`
`and 2-hydroxy-3-methoxynaltrexol, however,
`were steadily excreted throughout the 24-hr
`period_
`·
`Table VII shows the fecal excretion data after
`acute and chronic treatment. A total of 2.1 %
`and 3 .5% of the dose was excreted in the feces
`in the acute and chronic states, respectively.
`the major fecal excretory
`,8-Naltrexol was
`product together with small amounts of nal(cid:173)
`trexone and 2-hydroxy-3-methoxy naltrexol.
`Acid hydrolysis of the fecal material did not
`yield larger amounts of any of the compounds,
`indicating the absence of conjugated metabo(cid:173)
`lites.
`Table VIII is a list of tests and questionnaires
`used during heroin challenges. The data ob(cid:173)
`to
`to 9.83 ± 3.16 ng/ml at 48 hr and
`tained through the use of these testing protocols
`3. 75 ± 1.63 ng/ml at 72 hr. The estimated H~
`are presented in Fig. 4. The plasma levels of
`of this terminal phase decline of naltrexone and
`naltrexone and ,8-naltrexol just prior to heroin
`/j-naltrexol was 96 and, 18 hr, respectively. In
`challenges are shown in the first panel. The
`the following panels (2 through 8), the first two
`mean naltrexone levels of 4 subjects declined
`marks on the abscissa represent control re(cid:173)
`very slowly from 2.35 ± 0.34 ng/ml at 24 hr to
`2.03 ± 0.31 ng/ml at 48 hr and to 1. 73 ± 0.15
`sponses to 15 and 25 mg intravenous heroin
`injections, respectively, in the absence of nal(cid:173)
`ng/ml at 72 hr. Decline of ,8-naltrexol plasma
`levels was substantially faster than that of
`trexone. The following three markings on the
`naltrexone, from 24. 95 ± 7 .57 ng/ml at 24 hr
`abscissa represent responses to 25 mg intrave-
`~\i,~ :lli~~:s.1S.~i<§: @.~~, s.~ @.~~wt@.~,~ ~,~i~l ~~ ~%ss ®.~ ~,h~~ i,s\.• ~~ ~~'1SS.1S:~'@. ~~ ~i~®S ~"\.~ ~~~~'..1!:'i(cid:173)
`~t~~~ ~<§:.%'~ ~'®o '" ~ ~~~~ ~~~~~".i@.~ is§: ~'@.t~}~'~"
`
`Page 9 of 14
`
`

`

`324 V erebey et al.
`
`Clinical Pharmacology
`and Therapeutics
`
`25
`
`5
`
`0
`
`. \
`
`\
`\
`
`Plasma level
`(llg,'mlt
`
`18
`
`~ \
`' \
`\
`........
`
`"'-.
`
`"•1!!115111:
`
`•
`•
`
`Opillle high
`Sub;ects' rating
`scale 0-100
`
`12
`
`8
`
`4
`
`0
`
`4
`
`3
`
`2
`
`~mioN(mmt
`
`..
`
`ANpinilory depiwion
`(No./min)
`•
`•
`
`•
`
`•
`
`5
`
`4
`
`3
`
`2
`
`Umg
`~·r.ting
`ec.i.o-o
`
`0
`
`5
`
`4
`
`2
`
`• ..
`
`•
`
`Liking
`Subilda'l'lting
`sc11eo-•
`
`•
`• ••
`
`• v - .
`
`Opiate s,, llptolilS
`(No.dbul-5)
`
`..
`
`H
`
`• •
`
`•
`
`•
`
`Street,,_,. ol heroin
`Subjec:ta'l'Ming
`($)
`
`•
`
`8
`
`8
`
`4
`
`2
`
`8
`
`Fig. 4. The first panel represents the average plasma levels of naltrexone and ,B-naltrexol (n = 4)
`measured just before heroin challenges. The second and third panels represent the objective, and the
`rest of the panels the subjective responses after heroin, 25 mg. intravenously. The first two markings
`on the abscissa are heroin challenge controls in the absence of naltrexone to 15 and 25 mg heroin
`intravenously. The next three markings represent responses to 25 mg heroin intravenously. 24, 48,
`and 72 hr after the last naltrexone dose. For further clarification of the test system, see Table VIII.
`
`Table IX. Correlation coefficients (r) between the t1h of naltrexone and {3-naltrexol and the
`objective, subjective, and total responses to 25 mg heroin intravenously 72 hr after naltrexone
`
`Correlation coefficient ( r)
`
`Chronic
`tVz (2~)
`
`Respiratory
`depression
`
`Pupillary
`constriction
`
`Naltrexone
`Beta naltrexol
`
`-0.97
`-0.76
`
`-0.85
`-0.78
`
`Total
`objective
`effects
`
`-0.99
`-0.82
`
`Total
`subjective
`effects
`
`-0.50
`-0.32
`
`Total
`subjective
`and objectives
`effects
`
`-0.66
`-0.46
`
`nous heroin at 24, 48, and 72 hr after the last
`agonistic responses to heroin slowly began to
`dose of naltrexone (Table I). In the second
`return, a respiratory depression of 1 and 6
`breaths per minute, respectively.
`panel (Fig. 4), data are presented of the respira(cid:173)
`The pupillary miotic effects of heroin are
`tory depression. In the controls, 7 and 10
`shown in panel 3 of Fig 4. Narcotic antagonism
`breaths per minute respiratory depression were
`was nearly complete up to 48 hr, but by 72 hr
`observed following 15 and 25 mg intravenous
`there was a slightly greater pupillary· miosis
`heroin, respectively. Twenty-four hours after
`following heroin than in the control periods.
`the last dose of naltrexone, no respiratory de-.
`pression w