This material may be protected by Copyright law (Title 17 U.S. Code)
`
`
`
`Drug and Alcohol Dependence 70 (2003) S39 S47
`
`Review
`
`DRUG and
`ALCOHOL @
`nspsunsuas
`
`www.elsevier.com/loaatdd rugalcdep
`
`Pharmacokinetics of the combination tablet of buprenorphine and
`naloxone
`
`Dii:i.vion of Trounnenl R¢’.\'(‘(U‘(‘/I and Detrelopniem. National [n.\'liIllI(' on Drug Abuse. 600/ E‘.\'m1live Blvd. Room 4133 Berltawla. MD 2089.". USA
`
`C. Nora Chiang*, Richard L. Hawks
`
`Recehed I9 December 2002: accepted 4 February 2003
`
`Abstract
`
`The sublingual combination tablet fonnulation of buprenorphine and naloxone at a fixed dose ratio of 4:] has been shown to be
`as elfective as the tablet formulation containing only buprenorphine in treating opiate addiction. The addition of naloxone does not
`affect the efficacy of buprenorphine for two reasons: (I ) naloxone is poorly absorbed sublingually relative to buprenorphine and (2)
`the half-life for buprenorphine is much longer than for naloxone (32 vs.
`I h for naloxone). The sublingual absorption of
`bttprenorphine is rapid and the peak plasma concentration occurs 1 h after dosing. The plasma levels for naloxone are much lower
`and decline much more rapidly than those for buprcnorphine. Increasing dose results in increasing plasma levels of buprenorphine.
`although this increase is not directly dose-proportional. There is a large inter-subject variability in plasma buprenorphine levels. Due
`to the large individual variability in opiate dependence level and the large variability in the pharmacokinetics (PK) of
`buprenorphinc. the etTeetive dose or effective plasma concentration is also quite variable. Doses must be titrated to a clinically
`effective level for individual patients.
`Published by Elsevier Science Ireland Ltd.
`
`Keywords.‘ Buprenorphine: .\'alo.\one: Phannacokinetics: Metabolism: Opiate
`
`I. Introduction
`
`A combination tablet containing buprenorphine and
`naloxone at a fixed dose ratio of 4:1 ('2 mg buprenor-
`phine:0.5 mg naloxone and 8 mg buprcnorphine:2 mg
`naloxone) has been approved by the Food and Drug
`Administration (FDA) for treating opiate dependence.
`The daily recommended dose of the combination tablet
`of buprenorphine and naloxone will probably range
`from 4:!
`to 24:6 mg depending on the individual
`patients dependence level (Johnson et al.. this volume).
`Buprenorphine. a long acting mu-opiate partial agonist
`(Jasinski et a1.. I978) has been shown to be effective for
`treating opiate-dependence (Johnson et al., 1992: Fudala
`und Johnson. 1995; Bickel und Amuss. 1995: Ling et ul..
`1998). Naloxone is a short-acting opiate antagonist and
`can precipitate a moderate to severe withdrawal syn-
`drome in opiate-dependent individuals (Jasinski ct al.,
`
`‘ Corresponding author. Tel.: +1-301-443-5280: fax: + l-30l-443-
`2599.
`E-mull ullt/rl’.\'.\'.' ncliiaug@nili.gov (('.N. Chiangl.
`
`1978; 0’Brien et al.. I978). The addition of naloxone to
`the buprcnorphinc tablet is intended to reduce the abuse
`potential of buprenorphine. When buprenorphine and
`naloxone at a 4:1 ratio were given intravenously to
`opiate-dependent
`individuals.
`the combination dose
`precipitated opiate-withdrawal
`signs and symptoms
`(Fudala et al.. 1998: Mendelson et al.. 1999). Taken
`sublingually. the addition of naloxone does not affect
`the efficacy or pharmacological effects of buprenorphine
`(Walsh and Eissenberg. 2003; Harris ct al.. 2000)
`because of the differential in both sublingual absorption
`(40% for buprenorphine vs. 10% for naloxone for the
`solution formulation) (Harris ct al.. 2000) and duration
`of action (1 day for buprenorphine vs.
`1 h for naloxone)
`(Jasinski et at. 19/8: Berkowitz, 1970). Because of its
`
`this combination
`anticipated limited abuse potential.
`formulation is expected to be useful in a broad treat-
`ment setting that includes office-based practice (Bridge
`et a1.. 2003).
`This report summarizes the pharmacokinctics (PK)
`and metabolism data for buprenorphine and naloxone
`focusing specifically on the combination tablet. Data for
`
`03765-8716/03l$ ~ see front matter. Published by Elsevier Science Ireland Ltd.
`doi: I (l.lOl6/S0376-8716((l3)00058-9
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`a buprenorphine solution formulation (typically con-
`taining 30% ethanol) will also be presented since it was
`the formulation used in earlier clinical
`trials. which
`
`provided the basic efficacy data for the buprenorphine
`alone product. These data in turn provided a significant
`portion of the data supporting the safety and efficacy of
`the combination product.
`
`Studies in rats indicate that buprenorphine is rapidly
`distributed to the brain and achieves a concentration
`
`higher than in the plasma (Ohtani et al.. 1995). The red
`blood cell to plasma ratio of buprenorphine is reported
`to be close to unity (Bullingham et al.. 1980). Bupre-
`norphine is highly bound (96%) to plasma proteins in
`humans. primarily to <1- and B-globulin fractions
`(Walter and Inturrisi, I995).
`
`2. Analytical methods
`
`Immunoassay was the method used in most PK
`studies for buprenorphine in the 19805 (Moore, 1995).
`The zmtisera used in these assays typically cross-reacted
`with one of buprenorphine‘s primary metabolites, either
`norbuprenorphine or
`the glucuronide conjugate of
`buprenorphine.
`the extent of which depended on the
`hapten used to generate the antisera. However. most of
`the PK studies conducted at
`the doses relevant for
`
`treating opiate addiction were performed in the 1990s.
`By this time. more specific assay methods had been
`developed using electron-capture gas chromatography.
`gas chromatography—mass spectrometry. high pressure-
`liquid chromatography with electron capture,
`liquid
`chromatography—mass spectrometry. or liquid chroma-
`tography-tandem mass
`spectrometry. The limit of
`quantitation (LOQ) for these methods was generally in
`the range of 0.05-0.2 ng/ml (Kuhlman et al.. 1996:
`Moody et al.. 1997: Everhart et al.. 1997: Harris et al..
`2000).
`
`3. Buprenorphine
`
`3.1. Absorption and clistrihulion
`
`Buprenorphine is a very lipophilie compound. which
`readily permeates the gastrointestinal and oral mucosal
`membrane. However. the oral bioavailability of bupre-
`norphine is very poor
`(Walter and lnturrisi.
`l995)
`because of a significant
`first-pass effect. Sublingual
`administration provides a way to avoid lirst pass
`metabolism. but low availability may still occur if part
`of the dose is swallowed rather than kept under the
`tongue. The sublingual uptake of buprenorphine is
`rapidegenerally complete in 2-4 min when adminis-
`tered in solution (Weinberg et al.. 1988: Abreu and
`Bigelow. 1996: Mendelson et al.. 1997). Increasing the
`sublingual holding time for the solution to 10 min does
`not appear to significantly increase the amount ab-
`sorbed (Weinberg et al.. 1988: Mendelson et al.. 1997).
`When given in tablet fonn. the sublingual uptake is also
`affected by the dissolution rate of the tablet in saliva.
`The bioavailability data for buprenorphine in both
`solution and tablet forms will be presented in detail
`later.
`
`3.2. Metabolism and excretion
`
`Buprenorphine is extensively metabolized by glucur-
`onidation and N -dealkylation to form its conjugate and
`norbuprenorphine. respectively (Fig. 1). Norbuprenor-
`phine further conjugates with glucuronic acid. Cyto-
`chrome P450 (CYP) 3A4 is the primary metabolizing
`enzyme for N-dealkylation (lribarne et al.. 1997: K0-
`bayashi et al.. 1998). Extensive metabolism in the
`gastrointestinal tract and liver. results in low bioavail-
`ability of buprenorphine after oral administration. The
`tnajority (50-~70‘/o) of the dose is excreted in the feces
`and only lO—30% is excreted in the urine following
`parenteral or oral administration (Walter and lnturrisi.
`1995: Jones and Mendelson, 1997). Only 1.0 and 2.7% of
`the dose in the urine was excreted as unchanged
`buprenorphine and norbuprenorphine. respectively. In
`contrast. more than half of the dose was excreted in the
`
`feces in the unconjugated forms of buprenorphine (5%
`conjugated vs. 33% ttnconjugated) and norbuprenor-
`phine (2% conjugated vs. 21% unconjugated) (Jones and
`Mendelson. I997). A similar metabolite excretion profile
`was also observed for the subcutaneous. sublingual and
`oral dosing (Cone et al.. l984)—the conjugated fonns of
`buprenorphine and norbuprenorphine were the major
`species in the urine while the un-conjugated forms were
`the major ones in feces. The unconjugated buprenor-
`phine and norbuprenorphine observed in the feces are
`likely coming from the conjugated metabolites. which
`are excreted into the bile and subsequently hydrolyzed in
`the gastrointestinal tract.
`
`
`
`Buprenorphine
`
`Norbuprenorphine
`
`R Gluc
`
`uronlde
`Conjugates
`
`/
`
`Fig. l. Metabolic pathways for buprenorphine.
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`S41
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`is likely that enterohepatic recycling of buprenor-
`It
`phine occurs in humans and may contribute to the long
`terminal half-life and the long duration of action for
`buprenorphine.
`
`3.3. Metabolite—norhuprenorpIiine
`
`Norbuprenorphine is a major metabolite of bupre-
`norphine. Following multiple sublingual doses. the peak
`norbuprenorphine plasma level
`is lower than that for
`buprenorphine although trough levels for norbuprenor~
`phinc are about 40% higher than those for the parent
`(Kuhlman et al.. 1996; Harris et al.. 2000: Jones and
`
`Upton, 1997). The overall systemic exposure for norbu-
`prenorphine. estimated from the area under the plasma
`concentration —time curve (AUC).
`is approximately
`equal to that for buprenorphine. However.
`the brain
`exposure to norbuprenorphine is expected to be much
`lower than that for buprenorphine because norbupre-
`norphine is very polar and does not cross the blood
`brain barrier as readily as buprenorphine. As evidenced
`in a study in rats. the brain exposure to norbuprenor-
`phine is less than one-tenth of that for buprenorphine
`(Ohtani et al.. 1997). Since norbuprenorphine is a weak
`opiate agonist and its intrinsic activity is about one-
`fourth that of buprenorphine (Ohtani et al.. 1995). itcan
`be assumed that norbuprenorphine does not contribute
`significantly to the ellicacy ol‘ buprenorphine. A recent
`study in rats suggests that norbuprenorphine is a more
`potent respiratory depressant than buprenorphine and
`that its action may be mediated by the opioid receptors
`in the lung rather than in the brain (Ohtani et al.. 1997).
`If this holds in humans, norbuprenorphine may con-
`tribute to the respiratory depressant effect of buprenor-
`phinc.
`
`4. Naloxone
`
`Naloxone is more hydrophilie than buprenorphine.
`The sublingual absorption of naloxone was significantly
`lower than that of buprenorphine when determined by
`either measurement of the unabsorbed drug in the oral
`rinse (Weinberg et al.. 1988) or by classic bioavailability
`studies (Harris et al.. 2000). Naloxone is also rapidly
`distributed to the brain and has a high brain to plasma
`ratio (Berkowitz. 1976).
`Naloxone is rapidly metabolized by glucuronidation.
`N-dealkylation and reduction of the 6-oxo group to
`form the conjugated. N-dealkylated and the 6-OH
`metabolites. respectively (Fig. 2). The latter two meta-
`bolites are further conjugated with glueuronie acid
`(Weinstein et al..
`1973). The urinary excretion of
`naloxone is
`rapid. with 24—37% of a labeled dose
`appearing in the lirst 6 h and very little radioactivity
`measurable after 48 h (Fishman et al.. 1973).
`
`H0
`
`0 N/\f
`
`Namxune
`
`6-OH Metabolite
`
`
`
`N-dealkyl Metabolite
`
`Glucuronide
`Conjugates
`
`Fig. 2. Metabolic pathways for naloxone.
`
`5. Pharmacokinctics for the intravenous route of
`administration
`
`In early studies in surgical patients. plasma bupre-
`norphine levels, measured by an immunoassay method,
`followed a multi-exponential decline after the intrave-
`nous administration of 0.3 and 0.6 mg doses of
`buprenorphine. The half-life was variously reported to
`be 2-5 h and appeared to depend on when the last
`plasma sample was taken (Btillingham et al.. 1980, 1982;
`Watson et al.. 1982).
`A summary of the PK parameters for buprenorphine
`from recent studies. using more specilic assay methods
`than the earlier studies. is presented in Table 1. In the
`study by Jones and Upton (I997). an intravenous
`combined dose of 4 mg buprenorphine and 4 mg
`naloxone was given to subjects who had been main-
`tained on 8 mg buprenorphine for at least 10 days (the
`first
`7 days with buprenorphine alone followed by
`buprenorphine 8 mg alone or in combination with 4
`mg or 8 mg doses of naloxone). The plasma levels of
`buprenorphine and naloxone for this study are shown in
`Fig. 3. The terminal half-life for naloxone was 1.0 h
`indicating a much more rapid decline than that for
`buprenorphine. which was characterized by a multi-
`exponential decline with a mean terminal half-life of
`approximately 32 h.
`When lower doses (l -~2 mg) of buprenorphine were
`used. a shorter mean half-life (3- 18 h) was reported
`although the mean clearances were very close for all the
`studies. rangittg from 59 to 77 Ill: (Jones and Upton.
`1997: Mendelson et al.. 1997; Kuhlman et al.. 1996). The
`large apparent dilTerence in these half-lives may be due
`to the fact that the plasma levels in these low dose
`studies declined to the LOQ rapidly and as a result. a
`terminal hall‘-life could not be reliably estimated. The
`volume of distribution. a function of hall‘-life. is conse-
`
`quently highly variable—ranging from 335 to 2800 I.
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`Table 1
`PK of buprenorphine and naloxone following intravenous administration (mean ;I_ SD.)
`
`Drug
`
`Dose (mg)
`
`Clearance (l/ht
`
`Hall‘-life (h)
`
`Vd_. (l)
`
`Reference
`
`Buprenorphine
`
`Naloxone
`
`4
`l
`l.2
`4
`0.4
`
`58.9i 1 L5
`62.5 j;2I.8
`76.8 126.2
`26l 183
`-
`
`32.l1|Z.0
`16120
`3.21125
`l.0 10.43
`l.l 10.2
`
`2828: I480
`IO741; I028
`335i232
`370 L 176
`—
`
`Jones and Upton. I997
`Mendelson el al.. I997
`Kuhlrnan et al.. I996
`Jones and Upton. l997
`Nagi et al.. 1976
`
`Vd,.,. volume of distribution at stead}-—stttte.
`
`
`
`
`
`Plasmaconcentrationtnglrnl.)
`
`-0- Buprenorphlne
`- fl - Natoxone
`
`
`
`0
`
`12
`
`24
`
`36
`
`48
`Time (Hour)
`
`60
`
`72
`
`B4
`
`96
`
`Fig. 3. A semilogarithmic plot of the time course of mean plasma
`levels of buprenorphine and naloxone following an intravenous
`administration of a combination of 4 mg buprenorphine and 4 mg
`naloxone in nine subjects (data from Jones and Upton. I997).
`
`As presented in Table l. the half-life for naloxone is l
`h for all the doses (Jones and Upton. 1997: Nagi et al..
`I976). The clearance for naloxone is about 260 l/h and
`the volume ofdistribution about 3701.
`
`6. Pharmacokinetics for the sublingual route of
`administration
`
`6. 1. Bi01waiIubili!_t.'— ~ solution
`
`When administered sublingually in a 30% alcohol
`solution. the muoosal absorption for buprenorphine was
`rapid. Absolute bioavailability of approximately 30%
`was reported for the 2 mg solution dose held under the
`tongue for either 3 or 5 min (Mendelson et al.. 1997).
`Bioavailability of 51% was reported in a separate study
`when a 4 mg solution dose was compared with a [.2 mg
`intravenous dose (Kuhlman et al.. 1996). There was
`wide variation between subjects in the amount of
`buprenorphine absorbed in both studies. The maximal
`plasma concentration for both studies occurred approxi-
`mately l h after dosing and. when corrected for dose.
`
`was very close. The difference in bioavailability may be
`due to the fact that the LOQ ofthe assay methods used
`in these two studies were dilTerent—0.l ng/ml for the
`Mendelson et al. study and 0.2 ng/ml for the Kuhlman et
`al. study. In the latter study. the plasma levels for most
`of the subjects declined to LOQ in 13 h after the
`intravenous dose and resulted in a much shorter
`
`apparent terminal half-life of 3 h compared with the
`terminal half-life of 16 h reported by Mendelson et al.
`(1997). Consequently,
`the estimated AUC,
`for
`the
`intravenous dose in the Kuhlman et al. study would be
`lotver and contribute to a higher estimated bioavai|-
`ability.
`The bioavailability of naloxone in sublingual dosing is
`much lower than that for buprenorphine. In a steady-
`state study when buprenorphine was given daily for at
`least 7 days.
`the absolute bioavailability of sublingual
`buprenorphine doses of 8 mg, given alone or
`in
`combination with 4 and 8 mg of naloxone. was
`approximately 40% (Harris ct al.. 2000). The absolute
`bioavailability of sublingual naloxone. given in combi-
`nation with 8 mg of buprenorphine. was 9 and 7% for
`the 4 and 8 mg naloxone doses. respectively (Jones and
`Upton, 1997 Harris et al., 2000). No significant changes
`in buprenorphine PK were found with the concurrent
`administration of naloxone. Table 2 presents a summary
`of absolute bioavailability data for buprenorphine and
`naloxone.
`
`6.2. Bim1I=tIiInbiliry— table!
`
`The sublingual absorption for the tablet is governed
`by the saliva dissolution and the partition of the drug
`through the mucosa! membrane into the systematic
`circulation. The time required for the complete dissolu-
`tion of the tablets in the saliva is quite variable. In a
`study by Jones et al. (1997). it took approximately 4 min
`for
`the 4:] mg (two tablets) combination tablet
`to
`completely dissolve when held under the tongue and 7
`and 8 min. respectively. for the 8:2 mg dose (one tablet)
`and the 1624 mg dose (two tablets). There were two
`incidences with the 8:2 and the 16:4 mg doses. respec-
`tively. in which complete dissolution did not occur in l0
`min. In general, more tilne is required for the complete
`dissolution of higher tablet doses. However. the differ-
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`Tm‘.timetoreachmaximalplasmaeoiiceiitratioiiafterdosing;C,,._.(.maximalplasmaconceiitration.
`
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`
`
`ence in dissolution times did not appear to have any
`significant effect on the absorption rate of buprenor-
`phine. Buprenorphine is rapidly absorbed and peak
`concentration occurred at 1 h for all the three doses (421.
`8:2 and 16:4 mg) when administered sublingually. A
`typical plasma coneentration—time.curve following sub-
`lingual administration of the combination tablet for the
`16:4 mg dose (the dose used for the elficacy trial) is
`presented in Fig. 4. The maximal concentration for
`norbuprenorphine, a major metabolite of buprenor-
`phine. occurred at about 1 h and the level was lower
`than that
`for buprenorphine. Naloxone levels were
`much lower
`than buprcnorphinc and fell below the
`detection limit (0.05 ng/ml) in approximately 3 h.
`
`6.3. Relatire hioavailahililv of table! to so/ulion
`'
`.
`.
`.
`.
`There is no apparent difference in the time (Tum of l
`h) to reach the peak concentration between the solution
`formulation and the tablet formulation (Nath et al..
`1999). However.
`the bioavailability for
`the tablet
`formulation is lower than that for the solution formula-
`tion. There is a very large iritersubject variability for the
`relative bioavailability of the tablet
`to the solution
`formulation. The relative bioavailability was reported
`to be 50% (range of 11-82%) in a single dose study
`comparing the 8 mg buprenorphine solution to the 8 mg
`tablet in six subjects (Nath ct al.. 1999). In a multiple-
`dose study, 24 subjects received the 8 mg buprenorphine
`solution for I0 days and the 16 mg buprenorphine tablet
`dose for 10 days in a randomized crossover design. The
`relative bioavailability for tablet to solution determined
`by the steady-state plasma concentration was 71%
`(range 40-1 um) (Ajir ct al.. 2000).
`In another multiple dose study. 14 opiate dependent
`patients were maintained on daily buprcnorphine doses
`using an ascending order of 2. 4. and 8 mg solution
`doses followed by an 8 mg tablet dose. Patients were on
`each dose for at least 7 days. The relative bioavailability
`ofthe 8 mg tablet compared with the 8 mg solution was
`64% (Sehiih and Johanson. 1999). The higher bioavail-
`ability observed for the multiple dose study as compared
`with the single dose study may be due to the fact that the
`plasma levels used in the estimation of the AUC for the
`multiple dose study (24 h steady-state plasma levels)
`were all above the LOQ. In the single dose study. the
`plasma levels quickly declined to the LOQ making it
`difficult to reliably estimate the terminal half-life and the
`extrapolated area under the curve used in the calculation
`of bioavailability. As a result. the single dose study may
`underestimate the bioavailability. A difference might
`also result from the subjects having learned to hold the
`tablet under the tongue better during the multiple
`dosing schedule which would in turn result in improved
`absorption of buprcnorphine. The steady-state data
`probably provides a better estimate of the relative
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`DrugDosageformDose(mg)DosageregimenNumberofsubjectsCu...‘(ng/ml)Tm...(blBiouvailnbility("/..)Reference
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Sublingualabsolutebioavailabilityforbuprenorphineandnaloxone(mean15.0.)
`
`
`
`
`
`
`
`
`
`Table2
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`' ‘ I ' ‘ Norbuprenorphine
`*‘—Naloxone
`
`(nglml) “‘”Buprenorphine
`
`Plasmaconcentration
`
`I1
`Time (hours)
`
`I6
`
`20
`
`24
`
`Fig. 4. The time course of plasma levels of buprcnorphine. norbuprenorphine and naloxone for a subject receiving a sublingual dose of the
`combination tablet of buprcnorphine (I6 mg) and naloxone (4 mg) (data from Jones et al.. 1997).
`
`bioavailability ( ~ 70% tablet to solution) in the actual
`clinical situation.
`
`6.4. Dose [)r()])0I'll0n(llll_l' of the buprenorp/tine nuloxone
`table!
`
`6.4.]. Single dose sm(l_t'
`The PK of the sublingual combination tablet of
`buprcnorphine and naloxonc (at 4:1
`ratio)
`in the
`buprcnorphine dose range of 4 mg (2 x 2 mg tablets).
`8 mg. 16 mg (2 x 8 mg tablets) and 24 mg (3 x 8 mg
`tablets) was investigated in an open-label. dose—ascend-
`ing.
`foul-—way crossover study in 12 non—dependent
`opiate-experienced subjects (Hitzemann et al.. 1998).
`The mean plasma concentrations of buprcnorphine and
`naloxone increased with dose. The naloxone plasma
`levels were much lower and declined much more quickly
`than those of buprcnorphine. Mean AUC values and
`maximal concentration (Cmnx) of buprcnorphine in-
`creased with an increasing sublingual dose of the
`combination tablet. There was a wide inter-patient
`variability in the plasma |evels~particularly with the
`24 mg dose. Although an increase in dose resulted in an
`increase in plasma level. the increases in CW.‘ and AUC
`were not always proportional to the dose especially for
`higher doses.
`This result is similar to another single dose PK study
`comparing 4. 8 and 16 mg of the combination tablet
`with the 16 mg buprcnorphine tablet containing buprc-
`norphine (Jones et al.. 1997). Similar data were also
`obtained for buprcnorphine alone when given in the
`tablet fortn at doses from 4 to 24 mg (unpublished data).
`
`the plasma buprcnorphine
`In the solution dose form.
`levels were higher than in the tablet form. Nevertheless.
`the data also showed an increase in buprcnorphine peak
`concentrations and AUC values with the dose (Walsh ct
`al.. 1994; Welm ct al.. 2000') but the increase was not
`
`always proportional
`formulation.
`
`to the dose for
`
`the solution
`
`6. 4.2. Chronic dosing
`(ri¢II.s'
`
`(rough plusnm levels from clinical
`
`The plasma levels of buprcnorphine and naloxonc
`were determined in a multiple-center clinical trial. This
`trial consisted of two phases. The first phase was a 4-
`week efficacy trial conducted at eight centers. Subjects
`were randomized into three groups that received daily
`sublingual doses of either: (I) the combination tablet
`(l6:4 mg). (2) buprcnorphine alone tablet (16 mg) or (3)
`placebo tablet. The second phase was an open label
`safety trial. in which the subjects received the combina-
`tion tablets in a flexible dosing regimen up to a
`buprcnorphine level of 24 mg for up to 48 additional
`weeks. Four additional sites participated in this open-
`label 52-week phase.
`After the first week of dosing. three plasma samples
`were obtained from each subject at a predose, 2 and 6 h
`time point. The three samples could be taken on any
`single day or one could be taken on an alternate day for
`convenience. A total of 472 subjects participated in the
`study and trough plasma samples for 283 subjects could
`be obtained. Out of 283.
`there were 31 subjects on
`placebo and 252 subjects on active drug. Since the
`majority ofthe subjects participated in the efficacy trial.
`
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`
`545
`
`most ( 135 subjects) were on the 16 mg dose either as the
`buprenorphine alone (41 subjects) or the combination
`tablet (94 subjects) when the plasma samples were taken.
`All
`the other subjects were on the combination tablet
`with I2 on the 24:6 mg, 47 on the 20:5 mg. 53 on the
`l2:3mg dose. and 7 on the 8:2 mg dose. In the safety
`phase of the trial. when Ilexible dosing was allowed. a
`majority of the subjects were on doses of 12:3, 16:4 and
`20:5 mg for the combination tablets. Naloxone was not
`detected in the pre-dose samples. As shown in Fig. 5.
`there was
`large intersubject variability in pre-dose
`(trough) buprenorphine plasma levels. An increase in
`dose always resulted in an increase in plasma level.
`although it
`is difficult
`to detenninc if it
`is dose-
`proportional because of the large inter-subject varia-
`bility. The mean trough plasma buprenorphine level of
`L2 ng/ml for the 16 mg dose of buprenorphine for the
`multicenter trial is similar to the mean of l.6 ng/ml for a
`well-controlled PK study involving 24 subjects (Ajir et
`al.. 2000). As expected. the intersubjeet variability for
`the multicenter trial (CV of 60%. plasma levels ranging
`0.lA5.3 ng/ml) is much larger than that for the well-
`controlled PK study (CV of 40%. plasma levels ranging
`0.6-3.3 ng/ml).
`
`7. Factors that affect the pharmacokiuetics of
`buprenorphine
`
`A population PK analysis was conducted for the data
`collected in the above multicenter clinical
`trial using
`NONlinear Mixed Effects Modeling lNONMEN)
`(Boeckmann et al.. I992). The data suggest a decrease
`in buprenorphine clearance with increase in age. aspar-
`tate transaminase (AST) or alanine aminotransferase
`(ALT) (Holford. 2000). Buprenorphine clearance may
`decrease in older patients or patients with hepatic
`impairment and dosage reduction may be needed with
`these patients.
`
`3.5
`
`3.0
`
`2.5
`
`2.0
`
`1 .5
`
`1 .0
`
`0.5
`
`
`
`Buprenorphlneconcentratlon
`
`(nglml)
`
`(I990) on the effect of
`A study by Hand et al.
`impaired renal function on the disposition of buprenor-
`phine in patients receiving buprenorphine for analgesia
`indicated no difference in buprenorphine clearance
`between the normal patients and those with impaired
`renal function. However, the plasma levels for metabo-
`lites, buprenorphine conjugates and norbuprenorphine.
`were considerably higher in renal
`impaired patients.
`This is consistent with the fact that buprenorphine is
`eliminated primarily by hepatic metabolism. The accu~
`xnulation of norbuprenorphine may not produce sig~
`niftcant CNS effect because norbuprenorphine is both a
`weak agonist and has limited permeability through the
`blood brain barrier. Nevertheless. caution should be
`exercised as norbuprenorphine may produce respiratory
`depression, which may be mediated thorough peripheral
`receptors at the lung (Ohtani et al.. I997).
`
`8. Summary
`
`The sublingual buprenorphine---naloxone combina-
`tion tahlet provides an effective treatment for opiate
`addiction. The naloxone component does not appear to
`diminish the efficacy of buprenorphine. Naloxone
`absorption is minimal by this route. The sublingual
`absorption of buprenorphine is rapid. with peak plasma
`concentration occurring at
`I h after dosing. Increasing
`buprenorphine dose results in increasing plasma levels
`although this may not be dose-proportional. especially
`at higher doses. The tenninal half-life is very long (32 h).
`The long terminal half-life and the ceiling elI'ect are
`consistent with the clinical observation that multiples of
`the daily dose can be given every other day or twice a
`week to provide adequate therapeutic effect (Bickel et
`al.. 1999: Amass et al.. I994. 2000, 2001: Schottenfeld et
`al.. 2000). There is considerable inter-subject Variability
`in buprenorphine plasma levels. Since individual opiate
`dependence levels also show great variability, doses
`must be carefully titrated to the patients clinical
`response. The partial agonist characteristics of bupre-
`norphine allow more flexibility in achieving the optimal
`clinical dose with reduced concerns about
`toxicity
`compared with full agonists. The addition of naloxone
`does not reduce the efficacy of sublingually administered
`buprenorphine. but creates adverse responses in opiate-
`dependent subjects when used intravenously. signifi-
`cantly limiting potential abuse and adding further
`support to the use of buprenorphine for office-based
`treatment of opiate addiction.
`
`0
`
`4
`
`8
`
`12
`
`16
`
`20
`
`24
`
`Dose (mg)
`
`References
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