See discussions, stats, and author profiles for this publication at: http://www.researchgate.net/publication/7341474
`
`Pharmacokinetics and pharmacodynamics of
`multiple sublingual buprenorphine tablets in
`dose-escalation trials
`
`ARTICLE in THE JOURNAL OF CLINICAL PHARMACOLOGY · MARCH 2006
`
`Impact Factor: 2.47 · DOI: 10.1177/0091270005284192 · Source: PubMed
`
`CITATIONS
`24
`
`DOWNLOADS
`272
`
`VIEWS
`593
`
`9 AUTHORS, INCLUDING:
`
`Domenic A Ciraulo
`Massachusetts General Hospital
`
`124 PUBLICATIONS 3,425 CITATIONS
`
`Eugene Somoza
`University of Cincinnati
`
`99 PUBLICATIONS 1,578 CITATIONS
`
`SEE PROFILE
`
`SEE PROFILE
`
`Ofra Sarid-Segal
`Boston University
`
`27 PUBLICATIONS 684 CITATIONS
`
`SEE PROFILE
`
`Available from: Domenic A Ciraulo
`Retrieved on: 11 August 2015
`
`TEVA EXHIBIT 1014
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`The Journal of Clinical
`Pharmacology
`
`http://jcp.sagepub.com/
`
`
`
`
`Pharmacokinetics and Pharmacodynamics of Multiple Sublingual Buprenorphine Tablets in
`Dose-Escalation Trials
`Domenic A. Ciraulo, Robert J. Hitzemann, Eugene Somoza, Clifford M. Knapp, John Rotrosen, Ofra Sarid-Segal, Ann Marie
`Ciraulo, David J. Greenblatt and C. Nora Chiang
`J Clin Pharmacol
` 2006 46: 179
`DOI: 10.1177/0091270005284192
`
`The online version of this article can be found at:
`
` http://jcp.sagepub.com/content/46/2/179
`
`Published by:
`
`
`http://www.sagepublications.com
`
`On behalf of:
`
`American College of Clinical Pharmacology
`
`
`
`
`
`
` can be found at:The Journal of Clinical Pharmacology
`
`Additional services and information for
`
`
`Email Alerts:
`http://jcp.sagepub.com/cgi/alerts
`
`
`
`Subscriptions:
`http://jcp.sagepub.com/subscriptions
`
`
`Reprints:
`http://www.sagepub.com/journalsReprints.nav
`
`http://www.sagepub.com/journalsPermissions.navPermissions:
`
`
`
`
`Downloaded from
`
`jcp.sagepub.com
`
` at CALIFORNIA DIGITAL LIBRARY on April 18, 2011
`
`TEVA EXHIBIT 1014
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`
`
`10.1177/0091270005284192CIRAULO ET ALBUPRENORPHINE TABLET PHARMACOKINETICSPHARMACOKINETICS AND PHARMACODYNAMICS
`
`
`
`
`
`PHARMACOKINETICS AND PHARMACODYNAMICS
`
`Pharmacokinetics and Pharmacodynamics
`of Multiple Sublingual Buprenorphine Tablets
`in Dose-Escalation Trials
`
`Domenic A. Ciraulo, MD, Robert J. Hitzemann, PhD, Eugene Somoza, MD,
`Clifford M. Knapp, PhD, John Rotrosen, MD, Ofra Sarid-Segal, MD,
`Ann Marie Ciraulo, RN, David J. Greenblatt, MD, and C. Nora Chiang, PhD
`
`In this investigation, the pharmacokinetic and pharmacody-
`namic properties were determined of multiple doses of sub-
`lingual tablets containing either buprenorphine alone or bu-
`prenorphine and naloxone. Subjects were experienced opiate
`users who received escalating doses (4-24 mg) of buprenor-
`phine either alone or in combination with naloxone. Peak
`concentration (Cmax) and area under the concentration-time
`curves (AUCs) increased for both buprenorphine and na-
`loxone with escalating doses. Significant differences were
`found across the range of doses administered for dose-
`adjusted Cmax for both tablet formulations and for the dose-
`adjusted AUCs for the buprenorphine-naloxone tablets. For
`both formulations, the maximal buprenorphine-induced de-
`
`creases in respiratory rate and pupil diameter did not vary
`significantly across doses. Several of the subjective effects of
`buprenorphine did not increase as the dose of buprenor-
`phine administered was increased. These findings are con-
`sistent with the ceiling effect associated with the partial ago-
`nist actions of buprenorphine. They also indicate a lack of
`dose proportionality for buprenorphine sublingual tablets, at
`least during the times at which levels of this agent are highest.
`
`Keywords: Opioid dependence; partial agonist; naloxone;
`sublingual
`Journal of Clinical Pharmacology, 2006;46:179-192
`©2006 the American College of Clinical Pharmacology
`
`Buprenorphine is a partial µ-opioid receptor agonist
`
`that is an effective agent for agonist therapy for her-
`oin addiction1-9 and for the management of withdrawal
`from heroin and other opioids.10-14 Buprenorphine has
`only 15% bioavailability when orally ingested because
`
`From the Division of Psychiatry, Boston University School of Medicine,
`Boston, Massachusetts (Dr D. A. Ciraulo, Dr Knapp, Dr Sarid-Segal, Ms
`A. M. Ciraulo); Boston Veterans Affairs Healthcare System, Boston, Massa-
`chusetts (Dr D. A. Ciraulo, Dr Sarid-Segal); the Department of Behavioral
`Neuroscience, Oregon Health Sciences University, Portland (Dr
`Hitzemann); Cincinnati Addiction Research Center, University of Cincin-
`nati and Cincinnati VA Medical Center, Cincinnati, Ohio (Dr Somoza); the
`Department of Psychiatry, New York University School of Medicine and VA
`New York Harbor Healthcare, New York, New York (Dr Rotrosen); Depart-
`ment of Pharmacology and Experimental Therapeutics, Tufts University
`School of Medicine, Boston, Massachusetts (Dr Greenblatt); and the Na-
`tional Institute on Drug Abuse, Bethesda, Maryland (Dr Chiang). Submit-
`ted for publication May 5, 2005; revised version accepted October 25,
`2005. Address for reprints: Domenic A. Ciraulo, Boston University School
`of Medicine, Doctors Office Building, Suite 914, 720 Harrison Avenue,
`Boston, MA 02118.
`DOI: 10.1177/0091270005284192
`
`it is subject to extensive first-pass metabolism by the
`liver.15-17 To reduce this problem, sublingual formula-
`tions with improved bioavailability have been devel-
`oped. The bioavailability of buprenorphine when ad-
`ministered sublingually in an ethanol solution is
`approximately 50%.18 As a practical alternative to liq-
`uid formulations, sublingual buprenorphine tablets
`have been developed for use in the treatment of opioid
`dependence. The bioavailability of an 8-mg buprenor-
`phine tablet is approximately 35% to 50% lower than
`an equivalent dose of this drug in an ethanol solu-
`tion.19-21 Results from multiple-dose studies, however,
`indicate that the relative bioavailability ranges be-
`tween 63% to 80% for the tablet versus solution bu-
`prenorphine formulations.21-23
`Buprenorphine can produce mood-elevating effects
`similar to those associated with the use of other µ-
`opioid receptor agonists24 and consequently there is a
`potential for patients who are receiving buprenorphine
`tablets for maintenance therapy (ie, agonist) to self-
`administer this drug by injection by dissolving the tab-
`lets. The addition of the opioid antagonist naloxone to
`
`J Clin Pharmacol 2006;46:179-192
`
`179
`
`Downloaded from
`
`jcp.sagepub.com
`
` at CALIFORNIA DIGITAL LIBRARY on April 18, 2011
`
`TEVA EXHIBIT 1014
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`CIRAULO ET AL
`
`buprenorphine tablets should lower the risk of diver-
`sion to intravenous use. Two sublingual formulations
`are now available, buprenorphine alone (Subutex),
`which may be tolerated better for induction, and bu-
`prenorphine with naloxone (Suboxone, 4:1 ratio of free
`bases), to deter diversion for intravenous misuse.
`The parenteral administration of combinations of
`buprenorphine and naloxone to opioid-dependent
`subjects produces effects that are similar to those asso-
`ciated with opioid withdrawal.25-27 In contrast, the
`combination of buprenorphine and naloxone when ad-
`ministered sublingually either in an ethanol solution28
`or in tablet form27 does not precipitate withdrawal in
`opioid-dependent individuals. There is evidence that
`buprenorphine-naloxone tablets are effective as main-
`tenance therapy for individuals with a history of heroin
`dependence.29
`The pharmacodynamic effects produced by the sub-
`lingual administration of buprenorphine in combina-
`tion with naloxone have been characterized in a lim-
`ited number of studies. The results of these studies
`suggest that sublingually administered naloxone has
`no effect on the pharmacodynamic actions of bupren-
`orphine. An 8-mg dose of buprenorphine when admin-
`istered in solution form either alone or in combination
`with naloxone produced significant increases in sev-
`eral subjective responses, including “high,” “good
`drug,” and “drug liking” effects.28 In nondependent
`opioid abusers, buprenorphine and naloxone when ad-
`ministered in a 4-to-1 ratio in tablet form produced in-
`creases in opioid agonist effects, both subjective and
`physiologic, that were similar to those seen after the ad-
`ministration of buprenorphine alone.30
`Like the buprenorphine-alone tablets, buprenorphine-
`naloxone tablets can be administered on an alternate
`day or thrice-weekly schedule for opioid maintenance
`therapy. Doses of buprenorphine as high as 24 mg must
`be given to maintain patients during the weekend,29,31
`thus requiring the use of multiple 8-mg tablets. The
`pharmacokinetic properties of buprenorphine-alone
`and buprenorphine-naloxone tablets for doses as high
`as 16 mg have been reported in 2 recent studies.32,33 In
`one study conducted in healthy subjects pretreated
`with naltrexone, buprenorphine plasma levels in-
`creased in proportion to increases in the dose of
`buprenorphine administered.32 In contrast, in a second
`study, this relationship between buprenorphine con-
`centrations and dose was not found when this agent
`was administered to experienced opioid users.33 Data
`concerning the kinetics of a 24-mg dose of bupren-
`orphine delivered in multiple tablet form has not yet
`been reported. We present here the findings of 2 studies
`in which the pharmacodynamic effects, pharmaco-
`
`180 • J Clin Pharmacol 2006;46:179-192
`
`kinetics, and dose proportionality of tablets containing
`buprenorphine alone (study 1) and the combination of
`buprenorphine and naloxone (study 2) were examined
`for doses of buprenorphine ranging as high as 24 mg.
`The findings of these 2 studies with respect to the
`pharmacokinetic and pharmacodynamic parameters
`measured are compared to assess whether there are any
`clinically important differences in these parameters
`between the buprenorphine-alone and buprenorphine-
`naloxone tablets.
`
`METHODS
`
`Study Design
`
`The data presented here were compiled from 2 studies.
`These studies examined the pharmacodynamic effects,
`pharmacokinetics, and dose proportionality of tablets
`containing buprenorphine alone (study 1) and the
`combination of buprenorphine and naloxone (study 2).
`Both were open-label, single-dose, 4-period, dose-
`ascending studies consisting of four 3-day treatment
`sessions. Sublingual dosing occurred in both studies
`on the morning of drug-challenge days followed by a
`72-hour observation period. Subjects from both studies
`stayed as inpatients during the observation period.
`Study sites for study 1 were Tufts University School of
`Medicine and the Cincinnati Veterans Affairs (VA)
`Medical Center and for Study 2, the Northport Veterans
`Affairs Medication Development Research Unit. Staff
`from all sites participated in centralized training of
`procedures by National Institute of Drug Abuse (NIDA)
`program staff.
`
`Subjects
`
`Subjects were healthy volunteers, between the ages of
`21 and 45 (study 1) or 55 (study 2) years, weighed
`within 15% of ideal body weight, and had no oral cav-
`ity pathology. Although subjects were required to be
`experienced opiate users, they could not be physically
`dependent on opiates or meet Diagnostic and Statisti-
`cal Manual of Mental Disorders (fourth edition; DSM-
`IV) criteria for dependence on drugs other than opiates,
`nicotine, and caffeine. To establish that they where not
`physically dependent on opioids, all subjects were re-
`quired to have negative urine toxicology screens and
`no signs of withdrawal prior to administration of
`buprenorphine.
`The exclusion criteria for both studies were also
`similar. Subjects were excluded from the studies if they
`had a diagnosis of drug dependence (other than on nic-
`otine, caffeine, or opiates) defined as physiological ab-
`
`Downloaded from
`
`jcp.sagepub.com
`
` at CALIFORNIA DIGITAL LIBRARY on April 18, 2011
`
`TEVA EXHIBIT 1014
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`BUPRENORPHINE TABLET PHARMACOKINETICS
`
`stinence syndrome in the presence of a negative urine
`toxicology, had a history of significant medical or psy-
`chiatric illness that might impede their participation,
`or had clinically significant laboratory measurements in
`hematology, serum chemistries, and urinalysis at screen-
`ing. Subjects were excluded from the buprenorphine-
`alone study if they positively screened for HIV. Vol-
`unteers could not receive medication (other than oral
`contraceptives) on a regular basis for medical condi-
`tions, nor could they have any condition or history
`considered by the investigator(s) to place the subjects
`at increased risk.
`Study 1 was approved by the institutional review
`boards of the Boston Veterans Affairs Medical Center,
`Tufts New England Medical Center, the University of
`Cincinnati Medical Center, and the Cincinnati VA
`Medical Center Research and Development Commit-
`tee. Approval for study 2 was given by the Subcommit-
`tee on Human Subjects at the Veterans Affairs Medical
`Center in Northport, New York. All participants pro-
`vided written informed consent.
`
`Experimental Session
`
`Procedures during experimental sessions were identi-
`cal in both studies except for a few minor differences
`that included slightly different sampling schedules
`(see below). All subjects received the same treatment
`sequence as the other subjects in their study. Subjects
`were not permitted to eat, drink, or smoke for 1 hour be-
`fore and after administration of the medication. The
`sessions began at approximately 8:00 AM on the single-
`dose day of each treatment period, preceded by a light
`breakfast given about 1.5 hours prior to dosing. Pre-
`dose values were obtained for all physiological as-
`sessments (heart rate, blood pressure, and respiratory
`rate), pupil diameter, subjective measures, and plasma
`concentrations.
`The medication was administered sublingually un-
`der supervision of research staff, and the actual time of
`dosing was recorded. Subjects were instructed to hold
`the tablet(s) in place without swallowing until told to
`do so by the observer. When they felt that the tablet had
`dissolved, subjects were to indicate this by a hand sig-
`nal. At 5 minutes postdose, the sublingual area was ex-
`amined briefly with a flashlight and a 6-power lens to
`determine whether any portion of the tablet remained.
`If a portion remained, the subject was instructed to con-
`tinue holding the tablet sublingually until 10 minutes
`postdose or until the tablet had completely dissolved.
`If the subject indicated dissolution, the sublingual area
`was again examined, and the swallowing time was re-
`corded. During the 72-hour observation period, study
`
`personnel performed blood draws for pharmacokinetic
`assays, recorded physiologic and subjective measures,
`and monitored subjects closely for any adverse events.
`
`Study Medication
`
`In both studies, sublingual tablets were produced by
`Reckitt and Coleman and supplied by NIDA. The
`strength of the tablets was expressed as free base con-
`tent of buprenorphine or buprenorphine and naloxone.
`In study 1, buprenorphine hydrochloride in 2-mg and
`8-mg tablets was administered so as to equal doses of 4
`mg (2 × 2 mg), 8 mg (1 × 8 mg), 16 mg (2 × 8 mg), and 24
`mg (3 × 8 mg). In study 2, tablets contained combina-
`tions of buprenorphine (2 mg)/naloxone (0.5 mg) and
`buprenorphine (8 mg)/naloxone (2 mg), thereby keep-
`ing a consistent ratio of 4:1. The combination treatment
`doses studied were 4 mg/1 mg, 8 mg/2 mg, 16 mg/4 mg,
`and 24 mg/6 mg of buprenorphine-naloxone.
`
`Blood Sample Collection
`
`In the buprenorphine-alone study, 6-mL blood samples
`were collected from a venous catheter prior to dosing
`and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60,
`and 72 hours after dosing for each treatment period. In
`the buprenorphine-naloxone study, blood samples
`were obtained prior to dosing and at 0.25, 0.5, 0.75, 1,
`1.5, 2, 3, 4, 6, 8, 10, 12, 24, 30, 36, 48, 60, and 72 hours
`after dosing. Blood samples were collected in Vacu-
`tainer tubes that contained sodium heparin. Plasma
`was separated from blood samples and was then kept
`frozen at a minimum of –20°C until assayed.
`
`Physiologic and
`Subjective Measures
`
`Physiologic measures. In both studies, vital signs
`(heart rate, sitting blood pressure, and respiratory rate)
`were measured after the subject had been in a supine
`position for at least 10 minutes and only when at least
`30 minutes had passed after the most recent cigarette or
`coffee intake. In study 1, this was done prior to dosing
`and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72
`hours after dosing. In study 2, these measures were
`taken prior to dosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4,
`6, 8, 10, 12, 24, 30, 36, 48, 60, and 72 hours after dosing.
`For measuring pupil diameter, both studies used dim
`light conditions with an automated noncontact moni-
`tor system predose and in study 1, at 0.5, 1, 3, 4, 6, 8, 24,
`48, and 72 hours and in study 2, at 1, 3, 6, 24, 48, and 72
`hours postdose. Prior to drug administration, saliva pH
`was measured using a pH meter.
`
`PHARMACOKINETICS AND PHARMACODYNAMICS
`
`181
`
`Downloaded from
`
`jcp.sagepub.com
`
` at CALIFORNIA DIGITAL LIBRARY on April 18, 2011
`
`TEVA EXHIBIT 1014
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`CIRAULO ET AL
`
`Subjective measures. In Study 1, subjects were in-
`structed to rate their current condition at predose and
`at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, 48, and 72 hours after
`dosing using the following symptom scales: Global In-
`toxication and Withdrawal Rating, Opiate Visual Ana-
`log Scale, and Opiate Agonist Scale. For Global Intoxi-
`cation and Withdrawal, subjects rated their feelings on
`a scale ranging from 0 (no effect) to 100 (maximal ef-
`fect), based on the feelings they experienced after tak-
`ing opiate drugs. The Opiate Visual Analog Scale in-
`volved rating each of 4 drug effects (“good” drug effect,
`“bad” drug effect, drug liking, and sickness) by making
`a vertical mark along a line marked at opposite ends as
`not at all and maximal. Last, the Opiate Agonist Scale
`allowed subjects to rate the degree to which they expe-
`rienced each of 16 typical opiate-like effects on a scale
`ranging from 0 (no effect) to 4 (maximal effect). Items
`evaluated were nodding, heavy or sluggish feeling, dry
`mouth, good mood, energetic, upset stomach, itchy
`skin, relaxed, coasting, talkative, pleasant sickness,
`drive, carefree, drunken, friendly, and nervous. The
`maximum possible score was 64.
`In study 2, subjects were instructed to rate their cur-
`rent condition at predose and at 0.25, 0.5, 0.75, 1, 1.5, 2,
`3, 4, 6, 8, 10, 12, 24, 30, 36, 48, and 72 hours after dos-
`ing. The same 3 symptom scales were used as in study
`1, in addition to a fourth scale, the Opiate Withdrawal
`Scale (to assess naloxone effects). Instructions for
`Global Intoxication and Withdrawal Ratings and the
`Opiate Agonist Scale were identical in both studies.
`However, in study 2, the categories of effect for the Opi-
`ate Visual Analog Scale were good drug effect, bad drug
`effect, and high effect. (Drug liking and sickness were
`not included in the buprenorphine-alone study, and
`high effect was unique to the buprenorphine-naloxone
`study.) The additional scale in the buprenorphine-
`naloxone study, the Opiate Withdrawal Scale, asked
`subjects to rate the degree to which they experienced
`each of 21 typical opiate-like withdrawal symptoms on
`a scale ranging from 0 (no effect) to 4 (maximal effect).
`Items evaluated were muscle cramps, flushing, painful
`joints, yawning, restlessness, watery eyes, runny nose,
`chills or gooseflesh, sick to stomach, sneezing, abdomi-
`nal cramps, irritable, backache, tense and jittery, sweat-
`ing, depressed, sleepy, shaky or tremulousness, hot or
`cold flashes, bothered by noise, and skin clammy and
`damp. The maximum subject-rated total opiate with-
`drawal score possible was 84.
`
`Safety Measures
`
`In each study, subjects were monitored throughout the
`entire study period by study staff for adverse experi-
`
`182 • J Clin Pharmacol 2006;46:179-192
`
`ences or untoward and unintended medical occur-
`rences. An adverse event was defined as any physical
`or clinical change experienced by the subject after the
`administration of the first dose of study medication.
`Adverse events were rated as being mild, moderate,
`severe, and serious. A serious adverse experience
`was defined by protocol as an experience that is fatal
`or life threatening, is permanently disabling, requires
`inpatient hospitalization (or prolongation of hospi-
`talization), or is a congenital anomaly, cancer, or
`overdose.
`
`Analytic Methods
`
`Plasma samples for the buprenorphine-alone study were
`analyzed at the Center for Human Toxicology at the
`University of Utah. A sensitive liquid chromatography/
`mass spectrometry/mass spectrometry (LC/MS/MS)
`method with a 0.1-ng/mL limit of qualification (LOQ)
`was used to determine the plasma concentration of
`buprenorphine. Mass spectrometry in this experiment
`was performed using a Finnigan model TSQ-7000 tri-
`ple quadrapole mass spectrometer with an electron-
`spray ionization interface to the liquid chromatograph.
`MS was operated in the selected reaction monitoring
`mode. Buprenorphine-d4 was used as an internal stan-
`dard. Quadrupole Q1 was set to pass only ions at m/z
`468 and 472, which correspond to the protonated mol-
`ecules of buprenorphine and buprenorphine-d4, re-
`spectively. These ions were caused to undergo colli-
`sion-induced dissociation. Product ions at m/z 396 and
`400 were selectively monitored with quadrupole Q3.
`In the buprenorphine-naloxone study, this analysis
`took place at the Drug Study Unit of the University of
`California, San Francisco, where the LC/MS/MS
`method was also used for analysis of buprenorphine
`and naloxone levels. An API III PE-detector was used
`for the analysis. The analytic procedure was validated
`for the linear concentration range of 0.05 ng/mL to 20.0
`ng/mL for both buprenorphine and naloxone. In this
`study, the LOQ was 0.05 ng/mL. Oxybutynin was used
`as an internal standard. Mass scanning was performed
`in the multiple reaction monitoring mode (buprenor-
`phine: 450-418 m/z, naloxone: 328-268 mz, and oxy-
`butynin 358-142 m/z).
`In the buprenorphine-alone study, the percentage
`coefficient of variation (%CV) for calculated concen-
`trations for all runs of buprenorphine calibrators did
`not exceed 11.0%. For quantitation of control samples
`in analytic runs in this study, the %CV ranged between
`0.4 and 8.6. For all runs in the buprenorphine-
`naloxone study, the %CV for back-calculated concen-
`trations of standard buprenorphine calibrators ranged
`
`Downloaded from
`
`jcp.sagepub.com
`
` at CALIFORNIA DIGITAL LIBRARY on April 18, 2011
`
`TEVA EXHIBIT 1014
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`BUPRENORPHINE TABLET PHARMACOKINETICS
`
`from 4.42 to 7.78, while for naloxone calibrators, they
`ranged from 5.74 to 9.85.
`
`Pharmacokinetics
`
`The following parameter values were estimated: peak
`plasma concentration (Cmax), time of occurrence
`(Tmax) of peak plasma concentration, and area under
`the plasma concentration-time curve from predose to
`the time point of the last measurable concentration
`(AUC0-t) for buprenorphine. In study 2, which exam-
`ined the buprenorphine-naloxone combination, the
`area under the curves for naloxone were estimated
`from predose to 6 hours after dosing (AUC0-6) and from
`predose to infinity (AUC0−∞).
`The Cmax and Tmax estimates were derived from
`the observed plasma concentration-time data. The lin-
`ear trapezoidal method was used to calculate the val-
`ues of AUC0-t for buprenorphine and AUC0-6 for
`naloxone. For naloxone, linear regression analysis of
`the terminal phase of the plot of logarithmic (ln) con-
`centration versus time was used to determine λz (esti-
`mated terminal slope). Area under the curve to infinity
`(AUC0-∞) for naloxone was obtained using the equation
`
`AUC0-∞ = AUC0-6 + Ct/λz,
`
`where Ct is the concentration of naloxone at the last
`measurable time point.
`Dose-adjusted values were used to evaluate the dose
`proportionality for the buprenorphine formulations
`used in the present investigations. Values for Cmax and
`AUC0-t (and AUC0-∞ for naloxone) were divided by the
`buprenorphine dose to determine dose-adjusted values
`for these measures (CmaxDA and AUCDA). These dose-
`adjusted values provide measures of Cmax and AUC0-t
`on a per-milligram basis. They would be expected to re-
`main equal as the dose of buprenorphine is increased if
`plasma concentrations of this drug increase propor-
`tionately with elevations in the dose of buprenorphine
`administered.
`
`Statistical Analyses
`
`Physiologic and subjective measures were analyzed for
`subjects for whom plasma drug samples and pupil size
`measures were available. Data for Opioid VAS scales
`(ie, Sick, Liking, and High scales) that were not ob-
`tained in both studies are not presented here. In calcu-
`lation of the total Opiate Agonist score in both studies
`and the total opiate withdrawal score in study 2, if no
`more than 1 of the individual scales were missing, the
`
`missing individual scale was treated as 0; otherwise,
`the total score was treated as being missing.
`Maximal effect (Emax) and Tmax (from 0 to 72
`hours) were determined at each dose level for physio-
`logic and subjective measures. Mean baseline scores
`and change from baseline values were determined for
`physiologic measures.
`The mean ages of the 2 study groups were compared
`using a 1-way ANOVA. Pharmacokinetic data were an-
`alyzed using mixed-models 2-way repeated-measures
`analysis with dose as the within-subject factor and
`treatment as a between-group factor (Proc Mixed).34 A
`separate mixed-models 1-way repeated-measures anal-
`ysis was performed for each treatment group to confirm
`the presence or absence of dose-related differences.
`Pairwise comparison differences for within-group least
`mean squares were performed using the Tukey test.
`A mixed-models 2-way repeated-measures analysis
`was used to examine treatment effects and treatment ×
`dose interactions for differences between baseline and
`maximal effect for physiological effects. Dose effects
`were assessed using a 1-way mixed-models analysis for
`each treatment group. To demonstrate the physiologic
`effects of buprenorphine at each dose level, baseline
`and Emax values were compared using a 1-way gen-
`eral linear models analysis for each group. One-way
`ANOVAs were used to compare baseline values for pu-
`pil diameter and respiratory rate at each dose level.
`Bonferroni adjustments were made to adjust P values
`for multiple between-group comparisons of baseline
`and multiple within-group comparisons for change
`from baseline values obtained for physiological effects.
`Data for ordinal scales used to assess subjective drug
`effects were first converted into ranks and analyzed in
`the Proc Mixed procedure using the ANOVAF option
`(SAS version 8.02).35 In this and in the analyses de-
`scribed above, P values less than .05 were considered to
`be significant. Subjects in the 2 studies described were
`not physically dependent on opioids, and only mini-
`mal changes were produced by buprenorphine admin-
`istration in the withdrawal scales used in these 2 stud-
`ies. Consequently, no attempt was made to assess dose
`effects for these scales.
`
`RESULTS
`
`Subject Characteristics
`
`Twenty-eight subjects were enrolled in the buprenor-
`phine-alone study and 16 in the buprenorphine-naloxone
`study. Data were analyzed for 23 and 15 subjects in the
`buprenorphine-alone and the buprenorphine-
`
`PHARMACOKINETICS AND PHARMACODYNAMICS
`
`183
`
`Downloaded from
`
`jcp.sagepub.com
`
` at CALIFORNIA DIGITAL LIBRARY on April 18, 2011
`
`TEVA EXHIBIT 1014
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`CIRAULO ET AL
`
`Table I Mean ± SD for Pharmacokinetic Parameters for the Buprenorphine-Alone (BUP) and
`Buprenorphine-Naloxone (BUP + NX) Tablets
`
`Kinetic Parameter
`
`Cmax, ng/mL
`
`CmaxDA, ng/mL per mg
`
`Tmax, h
`
`AUC0-t, h•ng/mL
`
`AUCDA, h•ng/mL per mg
`
`Dose, mg
`
`4
`8
`16
`24
`4
`8
`16
`24
`4
`8
`16
`24
`4
`8
`16
`24
`4
`8
`16
`24
`
`BUP
`
`2.00 ± 0.87
`2.65 ± 1.05
`4.42 ± 2.05
`5.41 ± 3.42
`0.50 ± 0.22
`0.33 ± 0.13
`0.28 ± 0.13
`0.23 ± 0.14
`1.09 ± 0.54
`1.15 ± 0.49
`0.94 ± 0.27
`0.92 ± 0.45
`9.37 ± 5.35
`19.92 ± 12.67
`34.94 ± 20.61
`48.81 ± 31.07
`2.34 ± 1.34
`2.49 ± 1.58
`2.18 ± 1.29
`2.03 ± 1.29
`
`BUP + NX
`
`2.33 ± 0.80
`3.53 ± 1.16
`5.83 ± 2.09
`6.44 ± 2.10
`0.58 ± 0.20
`0.44 ± 0.14
`0.36 ± 0.13
`0.27 ± 0.09
`0.96 ± 0.34
`1.04 ± 0.39
`1.08 ± 0.92
`0.96 ± 0.42
`13.09 ± 4.39
`23.23 ± 8.08
`39.38 ± 13.23
`47.55 ± 18.82
`3.27 ± 1.10
`2.90 ± 1.01
`2.46 ± 0.83
`1.98 ± 0.78
`
`naloxone studies, respectively. For the buprenorphine-
`alone study, the analysis included findings for 16 men
`and 7 women. In the buprenorphine-naloxone study,
`the analysis was performed on results for 14 men and 1
`woman. The buprenorphine-alone study included 21
`white and 2 African American subjects, while the
`buprenorphine-naloxone study consisted of 7 white, 4
`African American, and 4 Hispanic subjects. The mean
`age of subjects analyzed in the buprenorphine-alone
`study was 34.5 (SD = 7.8) years, while it was 38.1 (SD =
`6.8) years for the buprenorphine-naloxone study. The
`mean age of subjects in each group did not differ signif-
`icantly between the 2 studies, F(1, 36) = 2.76, P = .11.
`Data were included for 2 subjects in the buprenorphine-
`naloxone study who did not complete the entire study
`(1 subject received 4- and 8-mg doses, the other 4-, 8-,
`and 16-mg doses). Not included for data analysis were
`results for 6 subjects who started the first sessions be-
`cause plasma samples and pupil diameter measures
`were not obtained. Of these subjects, 5 were in study 2.
`Reasons for subjects’ failing to complete the study in-
`cluded the following: (1) subject requested termination
`(because of start of new job; n = 2); (2) request for termi-
`nation, reason unspecified; n = 1; (3) termination due to
`adverse events (severely reduced heart rate after ad-
`ministration of a 4-mg dose of buprenorphine alone;
`
`n = 1); (4) no venous access (n = 1); and (5) termination
`due to violation of site policies (n = 1).
`In the buprenorphine-alone study, 3 subjects met
`DSM-IV criteria for opiate dependence, but none were
`physically dependent on opiates. Four subjects in the
`buprenorphine-naloxone study met criteria for opiate
`dependence; again, none were physically dependent.
`
`Pharmacokinetics
`
`Mean values for pharmacokinetic parameters for
`buprenorphine determined for each dose of this drug
`tested in the 2 studies are presented in Table I. Data
`were available for 23 subjects for the buprenorphine-
`alone study. Values for 14 subjects were used to deter-
`mine means for 4- and 8-mg doses in the buprenorphine-
`naloxone study. Means in this study for the 16-mg and
`24-mg doses were based on results obtained for 13 and
`12 subjects, respectively. Because of the fluctuation of
`buprenorphine plasma levels in the terminal phase,
`the terminal exponential rate constant, half-life, and
`AUC0-∞ could not be estimated with certainty and are
`not presented here.
`Mean plasma concentrations of buprenorphine over
`the 72-hour trial period for each of the 4 test doses of
`this agent administered are shown in Figure 1 for study
`
`184 • J Clin Pharmacol 2006;46:179-192
`
`Downloaded from
`
`jcp.sagepub.com
`
` at CALIFORNIA DIGITAL LIBRARY on April 18, 2011
`
`TEVA EXHIBIT 1014
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`BUPRENORPHINE TABLET PHARMACOKINETICS
`
`1 (the buprenorphine-alone study) and study 2
`(buprenorphine-naloxone study). At 72 hours, the
`mean plasma concentrations of buprenorphine were
`above the LOQ level for the buprenorphine-alone
`study for the 16-mg and 24-mg doses, while for the
`buprenorphine-naloxone study, they were above the
`LOQ level at the 8-mg, 16-mg, and 24-mg doses.
`In comparing the results from the 2 studies, treat-
`ment effects approached significance for Cmax, F(1,
`35) = 3.47, P = .07, and CmaxDA, F(1, 35) = 3.24, P = .08,
`but were not significant for AUC0-t, F(1, 35) = 0.29, P =
`.59, AUCDA, F(1, 35) = 1.32, P = .26, or Tmax, F(1, 35) =
`0.0, P = .95. Treatment × dose interactions were not sig-
`nificant for Cmax, F(3, 102) = 0.67, P = .57; CmaxDA, F(3,
`102) = 0.59, P = .62; AUC0-t, F(3, 102) = 0.57, P = .63; or
`Tmax, F(3, 103) = 0.56, P = .64. This interaction did ap-
`proach significance for AUCDA, F(3, 102) = 2.33, P = .08.
`These results suggest that there are not marked differ-
`ences in pharmacokinetic properties of buprenor-
`phine between the buprenorphine-alone and the
`buprenorphine-naloxone tablets, although there was a
`trend for buprenorphine plasma levels to be slightly
`higher in the buprenorphine-naloxone group.
`Inspection of plasma concentration curves suggests
`that buprenorphine plasma levels increased with dose
`but not in proportion to dose (see insets in Figure 1).
`The finding that the dose effects f