`
`www.elsevier.com/locate/drugalcdep
`
`Review
`
`Pharmacokinetics of the combination tablet of buprenorphine and
`naloxone
`
`C. Nora Chiang *, Richard L. Hawks
`
`Division of Treatment Research and Development, National Institute on Drug Abuse, 6001 Executive Blvd, Room 4123 Bethesda, MD 20892, USA
`
`Received 19 December 2002; accepted 4 February 2003
`
`Abstract
`
`The sublingual combination tablet formulation of buprenorphine and naloxone at a fixed dose ratio of 4:1 has been shown to be
`as effective 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: (1) naloxone is poorly absorbed sublingually relative to buprenorphine and (2)
`the half-life for buprenorphine is much longer than for naloxone (32 vs. 1 h for naloxone). The sublingual absorption of
`buprenorphine 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 buprenorphine. 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
`buprenorphine, the effective 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; Naloxone; Pharmacokinetics; Metabolism; Opiate
`
`1. 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 buprenorphine: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 4:1 to 24:6 mg depending on the individual
`patient’s dependence level (Johnson et al., this volume).
`Buprenorphine, a long acting mu-opiate partial agonist
`(Jasinski et al., 1978) has been shown to be effective for
`treating opiate-dependence (Johnson et al., 1992; Fudala
`and Johnson, 1995; Bickel and Amass, 1995; Ling et al.,
`1998). Naloxone is a short-acting opiate antagonist and
`can precipitate a moderate to severe withdrawal syn-
`drome in opiate-dependent individuals (Jasinski et al.,
`
`* Corresponding author. Tel.: /1-301-443-5280; fax: /1-301-443-
`2599.
`E-mail address: nchiang@nih.gov (C.N. Chiang).
`
`1978; O’Brien et al., 1978). The addition of naloxone to
`the buprenorphine 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 et al., 2000)
`because of the differential in both sublingual absorption
`(40% for buprenorphine vs. 10% for naloxone for the
`solution formulation) (Harris et al., 2000) and duration
`of action (1 day for buprenorphine vs. 1 h for naloxone)
`(Jasinski et al., 1978; Berkowitz, 1976). Because of its
`anticipated limited abuse potential, this combination
`formulation is expected to be useful in a broad treat-
`ment setting that includes office-based practice (Bridge
`et al., 2003).
`This report summarizes the pharmacokinetics (PK)
`and metabolism data for buprenorphine and naloxone
`focusing specifically on the combination tablet. Data for
`
`03765-8716/03/$ - see front matter. Published by Elsevier Science Ireland Ltd.
`doi:10.1016/S0376-8716(03)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 a- and b-globulin fractions
`(Walter and Inturrisi, 1995).
`
`2. Analytical methods
`
`Immunoassay was the method used in most PK
`studies for buprenorphine in the 1980s (Moore, 1995).
`The antisera 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 distribution
`
`Buprenorphine is a very lipophilic compound, which
`readily permeates the gastrointestinal and oral mucosal
`membrane. However, the oral bioavailability of bupre-
`norphine is very poor (Walter and Inturrisi, 1995)
`because of a significant first-pass effect. Sublingual
`administration provides a way to avoid first 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
`rapid*/generally 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 form, 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 (Iribarne et al., 1997; Ko-
`bayashi et al., 1998). Extensive metabolism in the
`gastrointestinal tract and liver, results in low bioavail-
`ability of buprenorphine after oral administration. The
`majority (50 /70%) of the dose is excreted in the feces
`and only 10 /30% is excreted in the urine following
`parenteral or oral administration (Walter and Inturrisi,
`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% unconjugated) and norbuprenor-
`phine (2% conjugated vs. 21% unconjugated) (Jones and
`Mendelson, 1997). A similar metabolite excretion profile
`was also observed for the subcutaneous, sublingual and
`oral dosing (Cone et al., 1984)*/the conjugated forms 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.
`
`Fig. 1. Metabolic pathways for buprenorphine.
`
`Page 2
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`
`S41
`
`It is likely that enterohepatic recycling of buprenor-
`phine occurs in humans and may contribute to the long
`terminal half-life and the long duration of action for
`buprenorphine.
`
`3.3. Metabolite*/norbuprenorphine
`
`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-
`phine 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), it can
`be assumed that norbuprenorphine does not contribute
`significantly to the efficacy of 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-
`phine.
`
`4. Naloxone
`
`Naloxone is more hydrophilic 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 glucuronic acid
`(Weinstein et al., 1973). The urinary excretion of
`naloxone is rapid, with 24 /37% of a labeled dose
`appearing in the first 6 h and very little radioactivity
`measurable after 48 h (Fishman et al., 1973).
`
`Fig. 2. Metabolic pathways for naloxone.
`
`5. Pharmacokinetics 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 (Bullingham et al., 1980, 1982;
`Watson et al., 1982).
`A summary of the PK parameters for buprenorphine
`from recent studies, using more specific assay methods
`than the earlier studies, is presented in Table 1. In the
`study by Jones and Upton (1997), 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 (1 /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, ranging from 59 to 77 l/h (Jones and Upton,
`1997; Mendelson et al., 1997; Kuhlman et al., 1996). The
`large apparent difference 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 half-life could not be reliably estimated. The
`volume of distribution, a function of half-life, is conse-
`quently highly variable*/ranging from 335 to 2800 l.
`
`Page 3
`
`
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`C.N. Chiang, R.L. Hawks / Drug and Alcohol Dependence 70 (2003) S39 /S47
`
`Table 1
`PK of buprenorphine and naloxone following intravenous administration (mean9/S.D.)
`
`Drug
`
`Dose (mg)
`
`Clearance (l/h)
`
`Half-life (h)
`
`Vdss (l)
`
`Reference
`
`Buprenorphine
`
`Naloxone
`
`4
`1
`1.2
`4
`0.4
`
`58.99/11.5
`62.59/21.8
`76.89/26.2
`2619/83
` /
`
`32.19/12.0
`169/20
`3.219/2.5
`1.09/0.43
`1.19/0.2
`
`28289/1480
`10749/1028
`3359/232
`3709/176
` /
`
`Jones and Upton, 1997
`Mendelson et al., 1997
`Kuhlman et al., 1996
`Jones and Upton, 1997
`Nagi et al., 1976
`
`Vdss, volume of distribution at steady-state.
`
`was very close. The difference in bioavailability may be
`due to the fact that the LOQ of the assay methods used
`in these two studies were different*/0.1 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
`lower and contribute to a higher estimated bioavail-
`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 et 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.
`
`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, 1997).
`
`As presented in Table 1, the half-life for naloxone is 1
`h for all the doses (Jones and Upton, 1997; Nagi et al.,
`1976). The clearance for naloxone is about 260 l/h and
`the volume of distribution about 370 l.
`
`6. Pharmacokinetics for the sublingual route of
`administration
`
`6.2. Bioavailability*/tablet
`
`6.1. Bioavailability*/solution
`
`When administered sublingually in a 30% alcohol
`solution, the mucosal 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 1.2 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 1 h after dosing and, when corrected for dose,
`
`The sublingual absorption for the tablet is governed
`by the saliva dissolution and the partition of the drug
`through the mucosal 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 4:1 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 16:4 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 10
`min. In general, more time is required for the complete
`dissolution of higher tablet doses. However, the differ-
`
`Page 4
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`C.N. Chiang, R.L. Hawks / Drug and Alcohol Dependence 70 (2003) S39 /S47
`
`S43
`
`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 (4:1,
`8:2 and 16:4 mg) when administered sublingually. A
`typical plasma concentration /time curve following sub-
`lingual administration of the combination tablet for the
`16:4 mg dose (the dose used for the efficacy 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 buprenorphine and fell below the
`detection limit (0.05 ng/ml) in approximately 3 h.
`
`6.3. Relative bioavailability of tablet to solution
`
`There is no apparent difference in the time (Tmax of 1
`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 intersubject 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 et al., 1999). In a multiple-
`dose study, 24 subjects received the 8 mg buprenorphine
`solution for 10 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 /110%) (Ajir et al., 2000).
`In another multiple dose study, 14 opiate dependent
`patients were maintained on daily buprenorphine 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
`of the 8 mg tablet compared with the 8 mg solution was
`64% (Schuh 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 buprenorphine. The steady-state data
`probably provides a better estimate of the relative
`
`JonesandUpton,1997
`JonesandUpton,1997
`JonesandUpton,1997
`Kuhlmanetal.,1996
`Mendelsonetal.,1997
`
`79/4
`99/6
`429/9
`519/29
`309/10
`
`1.019/0.31
`0.939/0.25
`1.09/0.31
`0.719/0.18
`1.629/0.55
`
`0.939/0.71
`0.669/0.53
`9.409/4.13
`3.319/1.81
`1.729/0.87
`
`6
`
`6
`
`9
`
`9
`
`9
`
`Dailyfor7days
`Dailyfor7days
`Dailyfor7days
`Singledose
`Singledose
`
`2
`
`4
`
`8
`
`4
`
`8
`
`Solution
`Solution
`Solution
`Solution
`Solution
`
`Reference
`
`Bioavailability(%)
`
`Tmax(h)
`
`Cmax(ng/ml)
`
`Numberofsubjects
`
`DosageformDose(mg)Dosageregimen
`
`Naloxone(with8mgBuprenorphine)
`
`Buprenorphine
`
`Drug
`
`Tmax,timetoreachmaximalplasmaconcentrationafterdosing;Cmax,maximalplasmaconcentration.
`
`Sublingualabsolutebioavailabilityforbuprenorphineandnaloxone(mean9/S.D.)
`Table2
`
`Page 5
`
`
`
`S44
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`
`Fig. 4. The time course of plasma levels of buprenorphine, norbuprenorphine and naloxone for a subject receiving a sublingual dose of the
`combination tablet of buprenorphine (16 mg) and naloxone (4 mg) (data from Jones et al., 1997).
`
`bioavailability (/70% tablet to solution) in the actual
`clinical situation.
`
`6.4. Dose proportionality of the buprenorphine /naloxone
`tablet
`
`6.4.1. Single dose study
`The PK of the sublingual combination tablet of
`buprenorphine and naloxone (at 4:1 ratio)
`in the
`buprenorphine dose range of 4 mg (2/2 mg tablets),
`8 mg, 16 mg (2/8 mg tablets) and 24 mg (3/8 mg
`tablets) was investigated in an open-label, dose-ascend-
`ing, four-way crossover study in 12 non-dependent
`opiate-experienced subjects (Hitzemann et al., 1998).
`The mean plasma concentrations of buprenorphine and
`naloxone increased with dose. The naloxone plasma
`levels were much lower and declined much more quickly
`than those of buprenorphine. Mean AUC values and
`maximal concentration (Cmax) of buprenorphine in-
`creased with an increasing sublingual dose of
`the
`combination tablet. There was a wide inter-patient
`variability in the plasma levels*/particularly with the
`24 mg dose. Although an increase in dose resulted in an
`increase in plasma level, the increases in Cmax 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 buprenorphine tablet containing bupre-
`norphine (Jones et al., 1997). Similar data were also
`obtained for buprenorphine alone when given in the
`tablet form at doses from 4 to 24 mg (unpublished data).
`
`In the solution dose form, the plasma buprenorphine
`levels were higher than in the tablet form. Nevertheless,
`the data also showed an increase in buprenorphine peak
`concentrations and AUC values with the dose (Walsh et
`al., 1994; Welm et al., 2000) but the increase was not
`always proportional
`to the dose for
`the solution
`formulation.
`
`6.4.2. Chronic dosing*/trough plasma levels from clinical
`trials
`The plasma levels of buprenorphine and naloxone
`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; (1) the combination tablet
`(16:4 mg), (2) buprenorphine 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
`buprenorphine 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 of the subjects participated in the efficacy trial,
`
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`
`S45
`
`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 12 on the 24:6 mg, 47 on the 20:5 mg, 53 on the
`12:3mg dose, and 7 on the 8:2 mg dose. In the safety
`phase of the trial, when flexible 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 determine if
`it
`is dose-
`proportional because of the large inter-subject varia-
`bility. The mean trough plasma buprenorphine level of
`1.2 ng/ml for the 16 mg dose of buprenorphine for the
`multicenter trial is similar to the mean of 1.6 ng/ml for a
`well-controlled PK study involving 24 subjects (Ajir et
`al., 2000). As expected, the intersubject variability for
`the multicenter trial (CV of 60%, plasma levels ranging
`0.1 /5.3 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 pharmacokinetics of
`buprenorphine
`
`A population PK analysis was conducted for the data
`collected in the above multicenter clinical trial using
`NONlinear Mixed Effects Modeling (NONMEN)
`(Boeckmann et al., 1992). 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.
`
`A study by Hand et al. (1990) on the effect of
`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-
`mulation of norbuprenorphine may not produce sig-
`nificant 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., 1997).
`
`8. Summary
`
`The sublingual buprenorphine /naloxone combina-
`tion tablet 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 1 h after dosing. Increasing
`buprenorphine dose results in increasing plasma levels
`although this may not be dose-proportional, especially
`at higher doses. The terminal half-life is very long (32 h).
`The long terminal half-life and the ceiling effect 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., 1994, 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 patient’s 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.
`
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