ALCOHOLISM: CLINICAL AND EXPERIMENTAL RESEARCH
`
`Vol. 30, No. 3
`March 2006
`
`Single- and Multiple-Dose Pharmacokinetics of
`Long-acting Injectable Naltrexone
`
`Joi L. Dunbar, Ryan Z. Turncliff, Qunming Dong, Bernard L. Silverman, Elliot W. Ehrich, and
`Kenneth C. Lasseter
`
`Background: Oral naltrexone is effective in the treatment of alcohol dependence; however, a
`major limitation of its clinical utility is poor patient adherence to the daily dosing schedule. A bio-
`degradable, long-acting naltrexone microsphere formulation was developed to achieve continuous
`naltrexone exposure for 1 month in the treatment of alcohol dependence.
`Methods: The single- and multiple-dose safety and pharmacokinetics of a long-acting naltrexone
`microsphere preparation were evaluated in healthy subjects. One group of subjects (n 5 28) received a
`single dose of oral naltrexone 50 mg followed by a single gluteal intramuscular (IM) injection of long-
`acting naltrexone 190 or 380 mg or placebo. A different group of subjects (n 5 14) received oral
`naltrexone 50 mg daily for 5 days, followed by IM long-acting naltrexone 380 mg or placebo every 28
`days for a total of 4 doses. A 7-day washout period separated oral and IM administrations. Blood
`samples were collected to determine plasma concentrations of naltrexone and the primary metabolite,
`6b-naltrexol.
`Results: After a single IM injection of long-acting naltrexone 380 mg, naltrexone plasma concen-
`trations were measurable in all subjects for at least 31 days postdose. The pharmacokinetics were
`proportional to the dose and multiple dose observations were consistent with single dose observa-
`tions. Mean apparent elimination half-lives for naltrexone and 6b-naltrexol ranged from 5 to 7 days.
`Exposure to 6b-naltrexol was reduced with IM injection compared with that oral administration. No
`serious adverse events occurred.
`Conclusions: This study demonstrated that the long-acting naltrexone formulation was well tol-
`erated, displayed predictable pharmacokinetics, and resulted in no meaningful drug accumulation
`upon multiple dosing. Intramuscular administration avoids first-pass metabolism and changes the
`exposure ratio of 6b-naltrexol to naltrexone compared with oral administration. By providing con-
`tinuous exposure to naltrexone for several weeks following IM injection, this long-acting naltrexone
`formulation may offer therapeutic benefit to those patients who experience difficulty adhering to the
`daily administration schedule necessitated by oral naltrexone therapy.
`Key Words: Naltrexone, Extended-Release Preparation, Pharmacokinetics, Long-acting
`Injectable.
`
`O RAL NALTREXONE WAS approved by the
`
`United States Food and Drug Administration in
`1994 for the treatment of alcohol dependence after the
`medication was shown to reduce the number of drinking
`days, reduce craving for alcohol, and reduce the risk of
`relapse in alcohol-dependent patients (O’Malley et al.,
`1992; Volpicelli et al., 1992). Naltrexone, an opioid antag-
`onist, is thought to exert its therapeutic benefit by reducing
`the reinforcing subjective or behavioral response to
`
`From Alkermes Inc (JLD, RZT, QD, BLS, EWE), Cambridge,
`Massachusetts; and SFBC International (KCL), Miami, Florida.
`Received for publication May 23, 2005; accepted October 28, 2005.
`This study was supported by Alkermes Inc.
`Reprint requests: Joi Dunbar, Alkermes Inc., 88 Sidney Street,
`Cambridge, MA 02139; Fax: 617-252-0799; E-mail:
`joi.dunbar@
`alkermes.com
`Copyright r 2006 by the Research Society on Alcoholism.
`
`DOI: 10.1111/j.1530-0277.2006.00052.x
`
`480
`
`alcohol (Davidson et al., 1999; McCaul et al., 2001). More
`recently, the effects of naltrexone have been explored using
`clinical laboratory models (Drobes et al., 2003; O’Malley
`et al., 2002). Researchers in these studies found that
`naltrexone reduced the amount of alcohol consumed in
`non–treatment-seeking alcoholics. An extension of these
`findings suggests that the reduction in alcohol consump-
`tion may be somewhat dependent on the pattern of alcohol
`consumption (Anton et al., 2004).
`Although oral naltrexone has been shown to be effective
`in the treatment of alcohol dependence, a major limitation
`of its clinical utility has been poor patient adherence to
`the daily dosing schedule (Volpicelli et al., 1997). Reasons
`for nonadherence include poor motivation, cognitive
`impairment (Rinn et al., 2002), and adverse effects of
`the medication, which may result in interrupted therapy
`or premature discontinuation (Croop et al., 1997; Oncken
`et al., 2001; Rohsenow et al., 2000). Nonadherence may
`also result from the ability of alcohol to disrupt behavioral
`control and an individual’s capacity to recognize that
`
`Alcohol Clin Exp Res, Vol 30, No 3, 2006: pp 480–490
`
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`PHARMACOKINETICS OF LONG-ACTING INJECTABLE NALTREXONE
`
`481
`
`(Leshner,
`requiring treatment
`he/she has an illness
`2003). Thus, alcohol dependence itself contributes to the
`adherence difficulties encountered by individuals who
`suffer from the disease. The National Institute on Alcohol
`Abuse and Alcoholism (NIAAA) raised concerns about
`adherence on the basis of its extensive review of the liter-
`ature, concluding that patient adherence to the oral
`naltrexone regimen appears to be a crucial factor in
`the pharmacological treatment of alcohol dependence
`(Litten et al., 2005). Additionally, at least 3 reports have
`found that only those
`subjects who maintain a
`high rate of adherence with daily oral naltrexone obtain
`greater drinking reductions and reduced relapse than
`with placebo (Chick et al., 2000; Monti et al., 2001;
`Volpicelli et al., 1997). A recent review has also identi-
`fied the need for ‘‘strategies to improve adherence to
`naltrexone treatment’’ (Srisurapanont and Jarusuraisin,
`2005).
`One strategy to improve adherence to naltrexone treat-
`ment involves use of a long-acting formulation that would
`provide continuous exposure to naltrexone for several
`weeks following a single administration. Extended release
`preparations of naltrexone have been in development for a
`number of years. One method of achieving extended
`release is to embed or encapsulate naltrexone in a biode-
`gradable polymer comprising lactic and/or glycolic acid.
`Once injected or implanted, the polymer in these prepara-
`tions slowly degrades to its monomer constituents and
`releases naltrexone into the surrounding tissue. The mon-
`omer constituents are further metabolized and eliminated
`as carbon dioxide and water. The pharmacokinetics of
`several such preparations have been described following
`subcutaneous
`implantation or
`injection in humans
`(Chiang et al., 1984; Galloway et al., 2005; Heishman
`et al. 1993; Hulse et al., 2004a, 2004b; Kranzler et al.,
`1998).
`A long-acting naltrexone formulation that releases
`naltrexone for 1 month was developed using Medisorbs
`technology, an injectable, microsphere-based sustained
`release drug delivery system (Bartus et al., 2003). In this
`long-acting formulation, naltrexone microspheres (100
`mm) are manufactured using a polylactide-coglycolide
`(PLG) polymer and administered by deep intramuscular
`(IM) injection. Recently, a double-blind, randomized,
`placebo-controlled,
`clinical
`trial demonstrated this
`formulation, in conjunction with psychosocial treatment,
`significantly reduced heavy drinking among treatment-
`seeking alcohol-dependent patients during 6 months of
`therapy (Garbutt et al., 2005).
`Described here are results of a clinical study evaluating
`the pharmacokinetics and tolerability of single and multi-
`ple doses of a long-acting naltrexone formulation based on
`the Medisorbs delivery system in healthy subjects. For
`comparative purposes,
`the pharmacokinetics of oral
`naltrexone following single and multiple doses were also
`evaluated.
`
`Subjects
`
`METHODS
`
`Nonsmoking men and women aged 18 to 50 years were eligible for
`enrollment provided they were in good health as determined by phys-
`ical examination, electrocardiogram (ECG), clinical laboratory eval-
`uations, and medical history. An equal number of men and women
`were enrolled and randomized across treatments. Subjects were ex-
`cluded if they had a history of alcohol and/or opioid dependence or
`anticipated the need for narcotic analgesia during the study period.
`Women of child-bearing potential were required to have a negative
`serum pregnancy test result before receiving study medication and
`were to use appropriate contraception throughout the study. All
`subjects were required to refrain from other prescription or over-
`the-counter medications (with the exception of prescription oral
`contraceptives) for 2 weeks before and throughout the study.
`
`Study Design
`
`This was a single-center, randomized, double-blind, parallel-
`group study in 2 panels of subjects (A, B). Subjects received either
`single or multiple doses of both oral naltrexone and long-acting
`naltrexone or placebo for long-acting naltrexone according to the
`scheme in Fig. 1.
`All subjects in Panel A (n 5 28) received a single dose of oral
`naltrexone 50 mg on day 1. Following a 7-day wash-out period, sub-
`jects received either a single IM injection of long-acting naltrexone
`190 mg (n 5 12) or 380 mg (n 5 12) or placebo (n 5 4). Subjects
`remained in the Clinical Research Unit (CRU) for 24 and 48 hours,
`after oral and IM treatments, respectively. All subjects in Panel B
`(n 5 14) received oral naltrexone 50 mg daily for 5 days. Subjects
`arrived at the CRU in the morning for administration of the first
`4 doses and were admitted to the CRU in the evening before the fifth
`oral dose. Beginning 7 days after the last oral dose, subjects received a
`total of 4 doses of IM long-acting naltrexone 380 mg (n 5 12) or
`placebo (n 5 2) administered every 4 weeks. Subjects were confined to
`the CRU for 48 hours following the first and fourth IM injections; the
`second and third injections were administered on an outpatient basis.
`The study protocol was reviewed and approved by an independent
`institutional review board before subject enrollment and was con-
`ducted in accordance with principles originating in the Declaration
`of Helsinki. Written informed consent was obtained from each study
`participant after having been informed of the purpose of the study,
`participation conditions, and risks and benefits.
`Dose Administration. Oral naltrexone (ReVias, Dupont Pharma,
`Wilmington, DE) was administered with 240 mL water following an
`overnight fast; food was permitted 4 hours after oral drug adminis-
`tration. Long-acting naltrexone microspheres (Alkermes, Cam-
`bridge, MA), containing 34% w/w naltrexone, were supplied as a
`dry powder and suspended in an aqueous diluent before gluteal IM
`injection (2 mL for the 190-mg dose and 4 mL for the 380-mg
`dose). Placebo for long-acting naltrexone contained only the PLG
`polymer. The diluent volume used for placebo administration was
`matched to the volume of the corresponding active treatment. Repeat
`injections were administered to alternating sides of the buttocks.
`Blood Sample Collection. Venous blood samples (4 mL) were
`obtained predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 36,
`and 48 hours following the first oral dose in Panel A and the fifth oral
`dose in Panel B. For IM administration, blood samples were collected
`predose, 1, 2, 4, 8, 12, 24 hours and 1.5, 1.75, 2, 3, 5, 7, 10, 14, 17, 21, 24,
`28, 31, 35, 42, 49, and 56 days after the first dose in Panel A and the
`fourth dose in Panel B. Additional blood samples were obtained from
`subjects in Panel B over the 28 days following the first IM dose and
`immediately before the second and third injections. The samples were
`collected into ethylenediaminetetraacetic acid (EDTA)-containing tubes
`and centrifuged for 15 minutes. The resulting plasma was transferred to
`polypropylene storage tubes and stored at 20 1C until analysis.
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`482
`
`DUNBAR ET AL.
`
`Study Day:
`
`1
`
`8
`
`64
`
`Panel A
`Single Dose
`(n = 28)
`
`Oral NTX
`50 mg
`
`LA-NTX190 mg, LA-NTX
`380 mg or placebo
`
`1
`
`5
`
`12
`
`40
`
`68
`
`96
`
`152
`
`Panel B
`Multiple Dose
`(n = 14)
`
`Oral NTX
`50 mg daily x 5 Doses
`
`LA-NTX 380 mg or placebo
`every 28 days x 4 Doses
`
`Washout period
`
`PK sampling period
`
`Oral Naltrexone
`LA-NTX
`
`Fig. 1. Study design. NTX, naltrexone; LA-NTX, long-acting naltrexone.
`
`Assessment of Safety and Tolerability. Subjects were monitored
`throughout the study for the occurrence of clinical and/or laboratory
`side effects. Reported adverse events were evaluated by the investi-
`gator and graded by intensity (mild, moderate, or severe) and rela-
`tionship to study drug. Intramuscular injection sites were evaluated
`at each visit following IM drug administration. Twelve lead electro-
`cardiogram (ECG) measurements were obtained at times bracketing
`the anticipated time of maximal plasma naltrexone concentrations
`following both routes of administration. QT intervals were adjusted
`for heart rate using Bazzet’s correction (QTcB) and Fridericia’s cor-
`rection (QTcF) (Funck-Brentano and Jaillon, 1993).
`
`Analytical Methodology
`
`Naltrexone and 6b-naltrexol plasma concentrations were deter-
`mined using a validated high-performance liquid chromatographic
`(HPLC) assay with tandem mass spectrometry detection. Human
`plasma (500 mL) containing naltrexone, 6b-naltrexol, and the inter-
`nal standard (naloxone) was mixed with an organic solvent under
`alkaline conditions. Following centrifugation, the upper organic
`layer was removed and evaporated to dryness before reconstitution
`in mobile phase. An aliquot of the reconstituted sample was injected
`onto a SCIEX API 3000 LC-MS/MS. Peak areas for the following
`product ion reactions were measured m/z 342! 324 for naltrexone,
`m/z 344! 326 for 6b-naltrexol, and m/z 328! 310 for the internal
`standard. Quantitation was performed using weighted (1/x2) linear
`least squares regression analyses generated from fortified plasma
`calibration standards prepared immediately before each run.
`The assay was validated for a range of 0.200 to 100 ng/mL for
`naltrexone and 0.500 to 250 ng/mL for 6b-naltrexol. Accuracy, based
`on the absolute deviation of the theoretical concentration of quality
`control samples assayed during sample analysis, ranged from 0.5%
`to 5.5% for naltrexone and 6b-naltrexol. Precision, expressed as the
`percent coefficient of variation (%CV) for quality control samples
`assayed during sample analysis, was o12% for both analytes.
`
`Pharmacokinetic Analyses
`
`Pharmacokinetic parameters for naltrexone and its major meta-
`bolite, 6b-naltrexol, following single and multiple oral and long-
`acting naltrexone doses were calculated for each subject using
`standard noncompartmental methods (WinNonlin Professional Ver
`4.01, Pharsight Corporation, Mountain View, CA). The maximum
`plasma concentration (Cmax) and the time of its occurrence (tmax)
`were obtained directly from the concentration–time data. Following
`single oral and IM doses, area under the curve (AUC1) was
`calculated using the linear trapezoidal method up to the last
`
`measured concentration plus the remaining extrapolated area, deter-
`mined as the ratio of the last measured concentration and k, where k
`is the terminal elimination rate constant estimated from the log–
`linear portion of the concentration–time curve according to the anal-
`ysis software algorithm. Area under the curve over a dosing interval
`(AUC1 day for oral and AUC28 days for IM) was calculated following
`multiple oral and IM doses. Elimination half-life (t1/2) was calculated
`as ln(2)/k. The metabolite:parent ratio was calculated as the ratio of
`6b-naltrexol AUC (AUC1, AUC28 days, or AUC1 day) to the corre-
`sponding naltrexone AUC.
`
`Statistical Analyses
`
`Naltrexone and 6b-naltrexol pharmacokinetic parameters were
`analyzed with respect to dose proportionality, time dependency,
`accumulation, and achievement of steady state. Dose proportionality
`(evaluated using Cmax and AUC1 following single doses of long-
`acting naltrexone 190 and 380 mg), time invariance (evaluated using
`AUC and t1/2 following a single dose compared with steady state),
`and accumulation (evaluated using AUC28 days following the fourth
`IM dose compared with AUC28 days following the first IM dose) were
`assessed using an analysis of variance (ANOVA) model with treat-
`ment as a fixed effect and subject as a random effect. The ratio of
`geometric least squares means (obtained by exponentiating the dif-
`ference between log-transformed parameters) and 90% confidence
`intervals (CIs) were determined. Results were interpreted in the con-
`text of whether or not the CIs included the value of 1.0 (2.0 in the
`case of dose proportionality). Statistical tests were performed using
`the mixed effects model (PROC MIXED) procedure in SAS, version
`8.2.
`Achievement of steady state following IM dosing was assessed by
`using concentrations before Doses 2, 3, and 4 and 28-days postdose
`following Dose 4. The 90% CI for the slope of the linear regression
`through the log-transformed values was estimated. A CI, that
`contained 0 indicated that steady state was achieved.
`The effect of gender on AUC28 days and Cmax was explored using
`an ANOVA model including gender as a fixed effect and subject as
`random effect.
`
`RESULTS
`
`Subject Demographics and Baseline Characteristics
`
`The extended elimination half-life of naltrexone result-
`ing from administration of the long-acting preparation
`made a cross-over study design impractical; therefore, the
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`PHARMACOKINETICS OF LONG-ACTING INJECTABLE NALTREXONE
`
`483
`
`this study were
`single and multiple dosing arms of
`conducted in different panels of subjects. Demographic
`information on enrolled subjects is presented in Table 1.
`Within each panel, an equal number of men and women
`were enrolled; however, they were not matched for weight,
`age, or race. A total of 42 subjects (Panel A, n 5 28; Panel
`B, n 5 14) were enrolled in the study, and 40 subjects
`completed all evaluations. Two subjects in Panel B who
`discontinued the study early (1 was lost to follow-up and
`1 withdrew consent) were not replaced. In subjects who
`received a single dose of long-acting naltrexone 380 mg
`(Panel A), males weighed approximately 15% more on
`average [76 (67–90) kg; mean (range)] than females [66
`(56–71) kg]. In this same group, males were approximately
`10 years younger on average [31 (24–42) years old] than
`females [41 (34–44) years old].
`
`Single-Dose Pharmacokinetics of Long-Acting Naltrexone
`
`Mean naltrexone and 6b-naltrexol plasma concentra-
`tions versus time following a single dose of long-acting
`naltrexone 190 and 380 mg are illustrated in Fig. 2.
`Naltrexone located at or near the surface of the micro-
`spheres was immediately released, resulting in an initial
`peak in plasma concentrations at 1 to 2 hours after dosing.
`Concentrations declined approximately 12 hours postdose
`and began to increase again 1 day postdose as naltrexone
`embedded deeper in the microspheres was released, result-
`ing in a second peak approximately 2 days after dosing.
`Beginning around Day 14, plasma naltrexone concentra-
`tions declined in a log–linear fashion and were measurable
`in all subjects, although at least 31 days following admin-
`istration of 190- and 380-mg doses. Mean concentrations
`remained 41 ng/mL for longer than 35 days at the 380-mg
`dose level. At both dose levels, the concentrations of
`6b-naltrexol exceeded those of naltrexone, but the shape
`of the profile was similar.
`Plasma pharmacokinetic parameters for naltrexone and
`6b-naltrexol following a single dose of long-acting naltrex-
`one are summarized in Table 2. Dose-related increases for
`AUC1 were observed, however, Cmax did not differ
`substantially between the 190- and 380-mg doses. Owing
`to the shape of the concentration profile and the sample
`collection schedule, it is possible that the true Cmax was not
`captured in some subjects at the 380-mg dose. Peak
`naltrexone concentrations were achieved at a median of
`2 days following injection, but were delayed in 2 subjects in
`the 190-mg dose group (17 and 24 days). Time of occur-
`rence of Cmax for the metabolite typically occurred 1 day
`later than the parent, although in 2 subjects in the 190-mg
`dose group and 4 subjects in the 380-mg dose group, tmax
`occurred 14 days or later after dosing. With the exception
`of 2 subjects, 6b-naltrexol was detected in the plasma at
`the first sampling timepoint (1 hour postdose), indicating
`prompt formation of the metabolite. Considering the rapid
`generation of 6b-naltrexol, the 24-hour delay typically
`
`Table 1. Demographics of Study Participants
`
`LA-NTX
`
`Panel Aa (mg)
`
`Panel Bb (mg)
`
`Variable
`
`190
`
`380
`
`380
`
`Allc
`
`Gender, n (%)
`Male
`Female
`Age (years)
`Mean (SD)
`Range
`Weight (kg)
`Mean (SD)
`Range
`Race, n (%)
`Hispanic
`Caucasian
`African American
`
`6 (50)
`6 (50)
`
`6 (50)
`6 (50)
`
`6 (50)
`6 (50)
`
`21 (50)
`21 (50)
`
`36.3 (8.8)
`20 to 49
`
`35.8 (7.5)
`24 to 44
`
`39.1 (7.4)
`23 to 48
`
`36.9 (7.9)
`20 to 49
`
`75.7 (8.5)
`59 to 89
`
`71.0 (8.7)
`56 to 90
`
`69.3 (10.8)
`54 to 85
`
`72.2 (9.2)
`54 to 90
`
`9 (75)
`2 (16.7)
`1 (8.3)
`
`11 (92)
`0 (0)
`1 (8)
`
`11 (92)
`0 (0)
`1 (8)
`
`37 (88)
`2 (5)
`3 (7)
`
`aSubjects also received a single dose of oral naltrexone 50 mg.
`bSubjects also received oral naltrexone 50 mg daily for 5 days.
`cIncludes 6 subjects who received placebo injections.
`LA-NTX, long-acting naltrexone; SD, standard deviation.
`
`observed for tmax was possibly an artifact of the sample
`collection schedule. Elimination half-lives (t1/2) for both
`naltrexone and 6b-naltrexol were approximately 7 days
`following single dose administration of 190 mg and
`approximately 5 days following single dose administration
`of 380 mg. Exposure to 6b-naltrexol was approximately
`2-fold higher than the corresponding naltrexone exposure.
`
`Multiple-Dose Pharmacokinetics of Long-Acting
`Naltrexone
`
`Mean plasma concentrations of naltrexone and 6b-
`naltrexol following administration of the first and fourth
`long-acting naltrexone 380-mg doses to subjects in Panel B
`are shown in Fig. 3. The concentration profiles following
`the first and fourth doses to subjects in Panel B were con-
`sistent with the profile following a single dose to subjects in
`Panel A. Summary statistics of pharmacokinetic parame-
`ter values are listed in Table 3. Estimated naltrexone and
`6b-naltrexol t1/2 following multiple doses of long-acting
`naltrexone 380 mg to subjects in Panel B were in general
`agreement with those estimated following single dose
`administration to subjects in Panel A. Naltrexone and 6b-
`naltrexol concentrations immediately before subsequent
`doses (i.e., 28 days after each dose of long-acting naltrex-
`one) were relatively constant. A linear regression through
`these data points indicated that steady state was achieved
`at the end of the first dosing interval (naltrexone, slope
`0.001, 90% CI 0.004, 0.002; 6b-naltrexol, slope 0.000,
`90% CI 0.004, 0.003)
`
`Statistical Analysis of Dose Proportionality, Time
`Invariance, Accumulation, and Gender Effects
`
`Table 4 summarizes the statistical analysis of naltrexone
`and 6b-naltrexol dose proportionality, time invariance,
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`484
`
`DUNBAR ET AL.
`
`Fig. 2. Mean plasma concentration of naltrexone (top) and 6b-naltrexol (bottom) following single dose administration of long-acting naltrexone 190 (&) and
`380 (*) mg. Left panel: Days 0 to 56; right panel: Days 0 to 5.
`
`accumulation, and gender effects following long-acting
`naltrexone administration. Naltrexone and 6b-naltrexol
`pharmacokinetics appeared dose proportional between
`the 2 dose levels, with Cmax exhibiting greater variability
`compared with AUC. Pharmacokinetic parameters did
`not change upon repeat dosing, as the AUC and t1/2
`estimates following multiple doses were in agreement with
`those from a single dose. Dosing of the long-acting prep-
`aration every 28 days resulted in minimal accumulation of
`naltrexone and 6b-naltrexol (13 and 11%, respectively).
`Maximum plasma concentration for naltrexone and
`6b-naltrexol was approximately 30% lower in females;
`however, AUC was similar between the genders.
`
`Single- and Multiple-Dose Pharmacokinetics of Oral
`Naltrexone
`
`Mean naltrexone and 6b-naltrexol plasma concentra-
`tions versus time following a single oral dose of naltrexone
`50 mg are depicted in Fig. 4. The concentration profiles for
`both analytes following multiple oral doses were similar to
`the profiles following a single dose. After oral dosing, peak
`concentrations of naltrexone were approximately 1/10th
`of those observed for 6b-naltrexol (Table 5). Elimination
`of 6b-naltrexol was slower compared with naltrexone.
`Little or no accumulation of naltrexone or 6b-naltrexol was
`observed after daily oral dosing. Area under the curve of
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`PHARMACOKINETICS OF LONG-ACTING INJECTABLE NALTREXONE
`
`485
`
`Table 2. Pharmacokinetic Parameters for Naltrexone and 6b-Naltrexol Fol-
`lowing Single Dose Administration of Long-acting Naltrexone (Panel A)
`
`Naltrexone
`
`6b-Naltrexol
`
`Pharmacokinetic
`parameter
`
`190 mg
`n 5 12
`
`380 mg
`n 5 12
`
`190 mg
`n 5 12
`
`380 mg
`n 5 12
`
`Tenderness and induration at the injection site were
`reported in 3 subjects over a period of 2 to 23 days after
`receiving the first IM dose of long-acting naltrexone. All
`injection site–related events were not considered clinically
`significant and resolved without sequelae.
`
`Cmax (ng/mL)
`tmax (days)a
`AUC1
`(ng d/mL)
`t1/2 (days)
`6b-naltrexol:
`naltrexone
`AUC1 ratio
`
`19.4 (33)
`14.1 (56)
`12.9 (36)
`10.2 (65)
`2.0 (1.75, 24) 2.0 (1.5. 2.0) 3.0 (2.0, 24) 3.0 (2.0, 21)
`71.8 (13)
`144 (21)
`175 (15)
`329 (24)
`
`7.36 (41)
`
`4.95 (25)
`
`7.11 (23)
`2.44
`
`5.70 (24)
`2.28
`
`aMedian (range).
`Mean (% CV) values are reported; AUC, area under the curve.
`
`the metabolite was 420-fold higher than that of the parent
`drug, indicative of extensive first-pass hepatic metabolism.
`
`Tolerability
`
`The study treatments were generally well tolerated
`following both parenteral and oral administration. Six of
`36 subjects (17%) who received long-acting naltrexone
`reported a total of 7 adverse events, which were consider-
`ed to be possibly drug related. All events were mild in
`severity. The most commonly reported event was dizzi-
`ness, which occurred in 2 subjects; all other events were
`reported in 1 subject each. In addition, 2 of the 36 subjects
`reported 3 events, which were considered probably not
`drug related,
`including 1 report of moderate diarrhea
`following the fourth dose. There was no apparent relation-
`ship between the frequency of adverse events and the
`number of injectable doses administered. Furthermore,
`there was no relationship between the occurrence of an
`adverse event and the dose administration time. Adverse
`events occurred across the period of 30 minutes to 12 days
`postinjection, with only 1 report (dry mouth) occurring
`on the same day as the observed peak drug concentration
`in plasma. No adverse events were reported in subjects
`who received placebo microspheres. Ten of the 42 subjects
`(24%) reported a total of 17 events following oral
`naltrexone administration. All events were mild and
`considered possibly drug related. The most commonly
`reported events were nausea (5 subjects), somnolence (4),
`and dizziness (2).
`No clinical adverse event was serious and no subject
`discontinued because of a clinical adverse event. No
`laboratory adverse events were reported. There were no
`clinically meaningful changes in physical examinations,
`vital signs, or ECGs. In addition, scatterplots of absolute
`and change from baseline values for QT, QTcB, and QTcF
`versus naltrexone concentration revealed no relationship
`between interval
`length and naltrexone concentration
`(data not shown).
`
`DISCUSSION
`
`Extended-release preparations of the opiate antagonist
`naltrexone have been developed to alleviate the require-
`ment for daily dosing necessitated by the oral formulation.
`The primary purpose of this study was to characterize
`the single and multiple dose pharmacokinetics of a long-
`acting naltrexone microsphere formulation based on the
`Medisorbs drug delivery technology. Results from this
`study showed measurable naltrexone plasma concentra-
`tions for at least 1 month, as well as dose proportional and
`time invariant pharmacokinetics of naltrexone and its
`major human metabolite, 6b-naltrexol,
`following IM
`administration of long-acting naltrexone.
`The minimum effective therapeutic plasma concentra-
`tion for naltrexone is not well understood. Previous studies
`with naltrexone have demonstrated that plasma concent-
`rations approximately 2 ng/mL completely antagonize the
`effects of 25 mg intravenous heroin (Verebey et al., 1976).
`Other investigations suggest plasma concentrations of less
`than 1 ng/mL are sufficient to antagonize heroin-induced
`effects (Chiang et al., 1984; Comer et al., 2002). Oral
`naltrexone is effective with once daily dosing, despite
`the fact that plasma concentrations are not detectable
`24 hours after a dose. It has been suggested that naltrex-
`one continues to inhibit brain opioid receptors in the
`absence of measurable plasma concentrations of naltrex-
`one (Lee et al., 1988). Although the plasma concentration
`necessary for the effective treatment of alcohol dependence
`has not been definitively established, long-acting naltrex-
`one 380 mg administered every 28 days demonstrated a
`significant reduction in the event rate of heavy drinking in
`624 alcohol-dependent subjects compared with placebo
`(Garbutt et al., 2005).
`This study enrolled only healthy nonsmoking adults,
`most of whom were Hispanic, under 50 years of age,
`reported no other medical conditions and were not receiv-
`ing any concomitant medications. Therefore, the study
`population may not reflect the alcohol-dependent popula-
`tion at large. The influence of race, smoking status, or age
`on the pharmacokinetics of long-acting naltrexone, was
`not explored in this study.
`The mechanism of naltrexone release from the injected mi-
`crospheres is multiphasic and dependent predominantly on
`polymer hydration and erosion. In the present study, the first
`plasma peak on Day 1 is the result of drug diffusion from the
`surface of the microspheres; the second peak on Day 2 is
`primarily because of polymer hydration. The sustained
`release (over 30 days) is due to polymer erosion, the rate
`of which is influenced primarily by polymer composition
`
`AMN1080
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`

`

`486
`
`DUNBAR ET AL.
`
`Fig. 3. Mean plasma concentration of naltrexone (top) and 6b-naltrexol (bottom) following the first (&) and fourth (*) doses of long-acting naltrexone 380
`mg. Left panel: Days 0 to 28; right panel: Days 0 to 5.
`
`(i.e., ratio of lactide to glycolide), polymer molecular
`weight, and drug loading (Lewis, 1990). Biodegradation
`of the polymer provides sustained plasma concentrations
`
`following long-acting naltrexone
`several weeks
`over
`administration and eliminates the daily rise and fall of plasma
`concentrations observed with oral naltrexone dosing.
`
`Table 3. Pharmacokinetic Parameters for Naltrexone and 6b-Naltrexol Following the First and Fourth Doses of Long-acting Naltrexone 380 mg (Panel B)
`
`Pharmacokinetic Parameter
`
`Cmax (ng/mL)
`tmax (days)a
`AUC28 days (ng d/mL)
`t1/2 (days)
`6b-Naltrexol:naltrexone AUC28 days ratio
`
`Mean (% CV) values are reported.
`amedian (range).
`nd, not determined.
`
`Naltrexone
`
`6b-Naltrexol
`
`Dose 1 n 5 12
`
`25.0 (51)
`2.0 (1.75, 24)
`138 (7.7)
`nd
`
`Dose 4 n 5 10
`
`28.0 (44)
`2.0 (1.75, 3.0)
`160 (15)
`4.73 (28)
`
`Dose 1 n 5 12
`
`24.5 (43)
`3.0 (3.0, 24)
`264 (28)
`nd
`1.91
`
`Dose 4 n 5 10
`
`34.2 (38)
`3.0 (2.0, 3.0)
`337 (22)
`5.13 (21)
`2.11
`
`AMN1080
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`

`

`PHARMACOKINETICS OF LONG-ACTING INJECTABLE NALTREXONE
`
`487
`
`Table 4. Summary of Statistical Results for Long-acting Naltrexone
`Pharmacokinetics
`
`Analyte
`
`Naltrexone
`
`6b-Naltrexol
`
`Comparison
`
`Ratioa
`
`90% confidence
`interval
`
`Dose proportionalityb
`AUC1
`Cmax
`Time invariancec
`AUC
`t1/2
`Accumulationd
`Gendere
`AUC28 days
`Cmax
`Dose proportionality
`AUC1
`Cmax
`Time invariance
`AUC
`t1/2
`Accumulation
`Gender
`AUC28 days
`Cmax
`
`1.975
`1.455
`
`1.124
`0.951
`1.134
`
`1.039
`0.677
`
`1.843
`1.565
`
`0.896
`0.908
`1.114
`
`1.042
`0.742
`
`1.756, 2.222
`0.991, 2.135
`
`0.982, 1.287
`0.772, 1.172
`1.048, 1.226
`
`0.823, 1.313
`0.469, 0.979
`
`1.590, 2.137
`1.075, 2.279
`
`0.754, 1.065
`0.755, 1.092
`1.043, 1.191
`
`0.822, 1.321
`0.536, 1.027
`
`aObtained by exponentiating the difference in LS means of the log
`transformed parameters.
`bEvaluated following a single dose of 380 mg compared with 190 mg
`(Panel A).
`cEvaluated at steady state (Panel B) compared with a single dose
`(Panel A).
`dEvaluated following the