ORIGINAL RESEARCH ARTICLE
`
`Clin Pharmacokinet 2004; 43 (5): 329-340
`0312-5963/04/0005-0329/$31.00/0
`
`© 2004 Adis Data Information BV. All rights reserved.
`
`Pharmacokinetics and Subjective
`Effects of Sublingual Buprenorphine,
`Alone or in Combination
`with Naloxone
`Lack of Dose Proportionality
`
`Debra S. Harris,1 John E. Mendelson,1 Emil T. Lin,2 Robert A. Upton2 and
`Reese T. Jones1
`1 Drug Dependence Research Center, Langley Porter Psychiatric Institute, University of
`California, San Francisco, San Francisco, California, USA
`2 Department of Biopharmaceutical Sciences, University of California, San Francisco, San
`Francisco, California, USA
`
`Abstract
`
`Objective: Buprenorphine and buprenorphine/naloxone combinations are effec-
`tive pharmacotherapies for opioid dependence, but doses are considerably greater
`than analgesic doses. Because dose-related buprenorphine opioid agonist effects
`may plateau at higher doses, we evaluated the pharmacokinetics and pharmaco-
`dynamics of expected therapeutic doses.
`Design: The first experiment examined a range of sublingual buprenorphine
`solution doses with an ascending dose design (n = 12). The second experiment
`examined a range of doses of sublingual buprenorphine/naloxone tablets along
`with one dose of buprenorphine alone tablets with a balanced crossover
`design (n = 8).
`Participants: Twenty nondependent, opioid-experienced volunteers.
`Methods: Subjects in the solution experiment received sublingual buprenorphine
`solution in single ascending doses of 4, 8, 16 and 32mg. Subjects in the tablet
`experiment received sublingual tablets combining buprenorphine 4, 8 and 16mg
`with naloxone at a 4 : 1 ratio or buprenorphine 16mg alone, given as single doses.
`Plasma buprenorphine, norbuprenorphine and naloxone concentrations and phar-
`macodynamic effects were measured for 48–72 hours after administration.
`Results: Buprenorphine concentrations increased with dose, but not proportional-
`ly. Dose-adjusted areas under the concentration-time curve for buprenorphine
`32mg solution, buprenorphine 16mg tablet and buprenorphine/naloxone 16/4mg
`tablet were only 54 β 16%, 70 β 25% and 72 β 17%, respectively, of that of the
`4mg dose of sublingual solution or tablet. No differences were found between
`dose strengths for most subjective and physiological effects. Pupil constriction at
`48 hours after administration of solution did, however, increase with dose.
`Subjects reported greater intoxication with the 32mg solution dose, even though
`acceptability of the 4mg dose was greatest. Naloxone did not change the bioavail-
`ability or effects of the buprenorphine 16mg tablet.
`
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`330
`
`Harris et al.
`
`Conclusion: Less than dose-proportional increases in plasma buprenorphine
`concentrations may contribute to the observed plateau for most pharmacodynamic
`effects as the dose is increased.
`
`Buprenorphine administered sublingually is use-
`ful for the treatment of opioid addiction. Doses of 8
`mg/day or more are frequently used for maintenance
`treatment.[1-4] Buprenorphine is administered sub-
`lingually because of its extensive first-pass metabol-
`ism[5] by liver microsomal cytochrome P450 (CYP)
`3A4.[6] Relatively
`little
`is known about
`the
`pharmacokinetics and pharmacodynamics of bupre-
`norphine given in higher doses, although it is known
`that the subjective and physiological effects of
`buprenorphine do not increase in proportion to dose
`at doses above 4mg up to 16mg.[7,8] Although
`dose-proportional increases in buprenorphine plas-
`ma concentrations have been reported with doses up
`to 32mg,[7] the immunoassay used in that study did
`not clearly distinguish buprenorphine from its meta-
`bolites.
`A combination dose product (Suboxone± 1) con-
`tains naloxone and buprenorphine to decrease diver-
`sion to intravenous use. Naloxone (alone) in much
`larger doses is sufficiently well absorbed sub-
`lingually to precipitate withdrawal in opioid-depen-
`dent persons, but doses of sublingual naloxone of up
`to 1–2mg can be administered without precipitating
`withdrawal.[9] Naloxone in a ratio of buprenorphine
`to naloxone of 4 : 1 when administered intra-
`venously precipitates opioid withdrawal severe
`enough in dependent users to deter diversion to
`intravenous use,[10] but has no opioid antagonist
`effects when administered sublingually at doses
`used for treatment of opioid dependence.[11-13] The
`bioavailability of sublingual naloxone in tablet form
`has yet to be rigorously established, but is probably
`less than the reported 10–30% from naloxone
`solutions.[11,14] In contrast, the bioavailability of
`sublingual buprenorphine
`from
`solutions
`is
`30–55%.[11,14-17] The large difference in sublingual
`bioavailability between buprenorphine and nalox-
`one accounts for the difference in sublingual and
`intravenous pharmacodynamic effects.
`
`Here we report the results of two experiments
`examining relationships between buprenorphine and
`naloxone doses and plasma concentrations and sub-
`jective and physiological effects. Buprenorphine
`and the buprenorphine/naloxone combination doses
`were in the range of those used for treating opioid
`dependence. We also attempted to determine the
`bioavailability of sublingual naloxone. Information
`on relationships between dose, plasma concentra-
`tions and medication effects may aid in optimising
`dosage.
`
`Methods
`
`Study Design
`
`In the first experiment, buprenorphine was ad-
`ministered by solution given sublingually. In the
`second, buprenorphine and naloxone combination
`sublingual tablets were used. Buprenorphine and
`norbuprenorphine plasma concentrations (and urine
`concentrations in the tablet study) and subjective
`and physiological effects were compared between
`doses.
`Subjects were admitted to the General Clinical
`Research Center ward no later than the evening
`before each dose and remained until 48 hours fol-
`lowing drug administration. They returned at 72
`hours for additional measures in the solution study.
`
`Solution Experiment
`Twelve subjects received a single dose each of
`four ascending doses (4, 8, 16 and 32mg) of sublin-
`gual buprenorphine in 1mL of a 30% ethanol solu-
`tion. Washout periods were at least 8 days between
`the 4 and 8mg doses and at least 10 days between the
`higher doses.
`
`Tablet Experiment
`Eight other subjects received the following four
`single doses in tablet form approximately 1 week
`apart in a randomised balanced crossover study with
`
`1 The use of trade names is for product identification purposes only and does not imply endorsement.
`
`© 2004 Adis Data Information BV. All rights reserved.
`
`Clin Pharmacokinet 2004; 43 (5)
`
`Page 2
`
`

`
`Sublingual Buprenorphine
`
`331
`
`the first subject randomised to an order block and
`each subsequent subject randomised to one of the
`remaining order blocks: buprenorphine 4mg/nalox-
`one 1mg (B4/N1), buprenorphine 8mg/naloxone
`2mg (B8/N2), buprenorphine 16mg/naloxone 4mg
`(B16/N4), buprenorphine 16mg alone (B16/N0).
`Buprenorphine 8mg/naloxone 2mg was adminis-
`tered as a single tablet. The other three doses were
`given as tablets as follows: B4/N1, two tablets of
`buprenorphine 2mg/naloxone 0.5mg; B16/N4, two
`tablets of buprenorphine 8mg/naloxone 2mg; B16/
`N0, two tablets of buprenorphine 8mg. Therefore,
`the doses were only partially blinded.
`
`Study Population
`
`Healthy volunteers, between the ages of 21 and
`45 years and within 15% of ideal bodyweight for
`height, were screened by laboratory tests and physi-
`cal examination to eliminate those with medical
`illness. All were occasional users of illicit opioids,
`but not dependent. The women were not pregnant.
`Subjects were excluded if they had excessive caries,
`gingivitis or oral infectious or inflammatory disease.
`Other exclusions were drug dependence (other than
`on nicotine and caffeine), hypersensitivity to opioids
`or naloxone, and medication use. Written informed
`consent was obtained prior to participation. The
`studies were approved by the Committee on Human
`Research (IRB), University of California, San Fran-
`cisco, and carried out in accordance with appropri-
`ate ethical guidelines. Subjects were paid for partici-
`pating.
`
`Buprenorphine and Naloxone
`Dose Preparation
`
`from the study. Subjects abstained from smoking
`and eating for 1 hour before drug administration and
`did not eat, drink or smoke for 1 hour after. The
`buprenorphine dose in a 1mL solution or the combi-
`nation tablet(s) were placed under the tongue. Sub-
`jects were asked not to swallow for 5 minutes after
`administration for the solution experiment. For the
`tablet experiment, they were instructed not to swal-
`low until the tablet had disintegrated. The sublingual
`area was examined for tablet fragments at 5 minutes
`after administration. If fragments remained, the sub-
`ject was asked not to swallow until the tablet(s) were
`completely dissolved (i.e. the subject could no long-
`er detect the fragments) or until 10 minutes follow-
`ing administration, whichever occurred first. The
`time of any premature swallows was recorded.
`
`Biological Fluid Sampling
`
`Blood samples (7mL per sample) were obtained
`through an intravenous catheter immediately before
`administration and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4,
`6, 8, 10, 12, 18, 24, 30, 36, 48 and 72 hours after for
`the solution experiment and at 0.25, 0.5, 1, 1.5, 2, 3,
`4, 6, 8, 10, 12, 24, 30, 36 and 48 hours after drug
`administration for the tablet study. Samples were
`immediately cooled and plasma was separated by
`centrifugation within 30 minutes of blood collec-
`tion. Samples were stored at –20τC until assayed.
`In the tablet experiment only, urine was collected
`for 48 hours after administration. Urine was stored
`at –20τC until assayed.
`
`Measurement of Plasma and
`Urine Buprenorphine
`
`Plasma and urine concentrations of bupre-
`Buprenorphine solutions were manufactured by
`norphine, norbuprenorphine and naloxone were
`the University of Kentucky, Pharmaceutical Tech-
`determined by a liquid chromatography/mass
`nology Unit, Lexington, KY, USA, and the combi-
`spectrometry/mass
`spectrometry
`(LC/MS/MS)
`nation tablets by Reckitt and Colman, Hull, UK. method.[18] Samples were analysed with a PE Sciex-
`Medications were supplied by the National Institute API III system monitored with LC/MS/MS in multi-
`on Drug Abuse. The strength of the tablet was based
`ple reaction monitoring mode. In plasma, the lower
`on the free base content.
`limit of quantification was 0.050 • g/L for bupre-
`norphine, norbuprenorphine and naloxone. Interday
`precision analysis used 12 samples for each of four
`concentrations in six separate runs. Intraday preci-
`sion analysis used six samples for each of four
`concentrations. For the solution experiment, calibra-
`
`Subjects provided a sample for urine drug screen
`on admission. A positive screen for illicit drugs
`caused postponement of the session or exclusion
`
`Buprenorphine Administration
`
`© 2004 Adis Data Information BV. All rights reserved.
`
`Clin Pharmacokinet 2004; 43 (5)
`
`Page 3
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`

`
`332
`
`Harris et al.
`
`Physiological Measures
`
`tion curves were linear from 0.05 to 0.2 • g/L. Co-
`efficient of variation (CV) ranged from 3.48 to
`Heart rate, blood pressure, and pulse oximetry
`12.0% for plasma buprenorphine. The relative error
`were measured with a cardiovascular monitor (VSM
`(RE) ranged from –0.0175 to +4.37%. Accuracy and
`2; Physio Control, Redmond, WA, USA) prior to
`precision of spiked control samples at 0.2, 0.4, 1, 6
`and 15 • g/L, assayed concurrently with study sam-
`administration and at approximately the same times
`as blood collections. Rate pressure product was cal-
`ples, showed a CV ranging from 5.14 to 10.1% and
`culated as the product of heart rate and systolic
`an RE ranging from –1.13 to +3.82%. Interday
`blood pressure. Respiratory rate was measured by
`precision and accuracy CV ranged from 5.85 to
`counting inhalations per minute. Pupil diameter was
`9.94% for norbuprenorphine and from 6.62 to
`measured on the horizontal axis from photographs
`8.36% for naloxone. The RE ranged from 0 to
`taken under consistent light and eye fixation condi-
`7.25% for norbuprenorphine and from –2.67 to
`tions with a Polaroid CU-5 Land Camera with lens
`+7.87% for naloxone. Intraday CVs ranged from
`adjusted for close-up photography. A reference pho-
`3.29 to 7.27% for norbuprenorphine and from 3.50
`to of the eye and ruler was used to convert measured
`to 7.70% for naloxone, and REs from –8.67 to
`values to actual mm units. Measurements were tak-
`+7.87% for norbuprenorphine and from –3.33 to
`en predose and at 1, 3, 6 and 48 hours after adminis-
`+11.0% for naloxone.
`tration for the solution study and at 1, 3 and 6 hours
`For the tablet experiment, coefficients of varia-
`for the tablet study. Saliva pH was measured (Ac-
`tion for the interday precision analysis of 12 samples
`cumet 1001 hand-held pH meter; Fisher Scientific,
`for each of four concentrations in six separate runs
`Pittsburgh, PA, USA) just before drug administra-
`ranged from 5.19 to 6.45% for buprenorphine, from tion in both experiments and again immediately
`5.85 to 9.94% for norbuprenorphine, and from 6.62
`after swallowing following sublingual dissolution of
`to 8.36% for naloxone. RE ranged from –2.67 to
`the tablet.
`+9.13% for buprenorphine, from 0 to 7.25% for
`norbuprenorphine, and from –2.67 to +7.87% for
`naloxone. In intraday precision analysis of six sam-
`ples for each of four concentrations, CVs ranged
`from 1.42 to 3.22% and REs ranged from –2.67 to
`+12.0% for buprenorphine. CVs ranged from 3.29 to
`7.27% and REs ranged from –8.67 to +7.87% for
`norbuprenorphine. CVs ranged from 3.50 to 7.70%,
`and REs ranged from –3.33 to +11.0% for naloxone.
`In urine (tablet experiment only), the lower limit
`of quantification was 0.2 • g/L for buprenorphine
`and naloxone and 0.5 • g/L for norbuprenorphine. In
`interday precision analysis, CVs ranged from 2.25 to
`6.59% for buprenorphine, from 4.01 to 7.32% for
`norbuprenorphine, and from 4.54 to 5.68% for
`naloxone. REs ranged from +2.57 to +9.56% for
`buprenorphine, from +0.59 to +12.2% for norbupre-
`norphine, and from +3.61 to +9.74% for naloxone.
`In intraday precision analysis, CVs ranged from
`1.92 to 7.45% for buprenorphine, from 3.69 to
`9.23% for norbuprenorphine, and from 3.01 to
`5.27% for naloxone. REs ranged from –5.81 to
`+3.11% for buprenorphine, from –3.45 to +8.14%
`for norbuprenorphine, and from –1.57 to +4.12% for
`naloxone.
`
`Subjective Measures
`
`Subjective symptom reports were obtained from
`subjects before administration, at frequent intervals
`for the first 6 hours, and at 24 and 48 hours after
`administration. Subjects were asked to estimate in-
`tensity of global intoxication and opioid withdrawal
`by verbally reporting a number between 0 and 100,
`where 0 was no effect and 100 the maximum effect.
`Good drug effect, bad drug effect, drug liking and
`sickness were rated with a visual analogue scale by
`marking along a 10cm line from 0 (not at all) to 100
`(extreme).
`The ‘Opiate Agonist Scale’ contains 16 opioid
`agonist effect items.[19] Intensity of each item was
`rated from 0 to 4, with 0 as no effect and 4 as
`maximum effect for a maximum total score of 64.
`The ‘Opiate Withdrawal Scale’ (tablet experi-
`ment only) consisted of 21 typical opioid antagonist
`symptoms.[19] Intensity of each item was rated from
`0 to 4 with 0 as no effect and 4 as maximum effect
`for a maximum total score of 84.
`Subjects were asked to report any other effects or
`symptoms and whether the drug they received
`
`© 2004 Adis Data Information BV. All rights reserved.
`
`Clin Pharmacokinet 2004; 43 (5)
`
`Page 4
`
`

`
`Sublingual Buprenorphine
`
`333
`
`would be acceptable to them as a medication. Re- means analysis. Effects were considered significant
`at p ≤ 0.05. Data were adjusted for sphericity
`searchers recorded vomiting episodes and amounts
`and other objective ill effects during the 6-hour
`using the Huynh-Feldt adjustment factor. Huynh-
`observation period, asked about problems or ‘bad
`Feldt corrected significance values are reported
`effects’ from the drug the morning following admin-
`(SuperANOVA, Macintosh, Berkeley, CA, USA).
`istration, and reviewed chart nursing notes for ad-
`verse effects.
`Subjective reports were collected using paper and
`pencil for the solution experiment and with a com-
`puter for the combination tablet experiment.
`
`Results
`
`Study Population
`
`Statistical Analysis
`
`Ten men and two women (aged 23–34 years)
`took part in the solution experiment. Most typically
`used 0.125–0.5g of heroin per occasion. Seven men
`Pharmacokinetic Measures
`and one woman in the combination tablet experi-
`The following pharmacokinetic parameters were ment (aged 22–42 years) reported similar use. Mean
`estimated for buprenorphine from plasma concen-
`bodyweight was not statistically significantly differ-
`tration-time profiles using standard noncompart-
`ent between experiments.
`mental methods: area under the plasma concentra-
`tion time curve (AUC) to 72 hours for the solution
`experiment and 48 hours for the tablet experiment
`(AUC72 and AUC48), peak plasma concentrations
`(Cmax) and peak times (tmax). AUC was determined
`using the trapezoidal method for periods of increas-
`ing or stationary concentration and the logarithmic-
`trapezoidal method for periods of decreasing con-
`centration to the last measured plasma concentration
`for unextrapolated AUCs.
` All pharmacokinetic parameters were statisti-
`cally analysed as their logarithmic (natural) trans-
`forms, except peak time, which was analysed un-
`transformed. All parameters, except peak time, were
`analysed per drug dose with dose correction made
`before the logarithmic transformation. Pharmaco-
`kinetic parameters were compared between treat-
`ments using linear regression and analysis of vari-
`ance (ANOVA). If a significant test was found, then
`further comparison between treatments used a
`Tukey multiple comparison procedure.
`
`Salivary pH and Tablet Dissolution Time
`
`No significant difference was found in salivary
`pH between conditions (table I). Mean β SD dissolu-
`tion times for the tablet study were 4 β 1, 7 β 2, 8 β 1
`and 7 β 1 minutes for the 4mg, 8mg and 16mg
`buprenorphine combination tablets, and the 16mg
`buprenorphine alone tablets, respectively. Tablet
`dissolution time was significantly shorter with the
`
`Table I. Salivary pH
`
`Condition
`
`Solution experiment (predose only)
`Buprenorphine 4mg
`Buprenorphine 8mg
`Buprenorphine 16mg
`Buprenorphine 32mg
`
`Tablet experiment
`Buprenorphine 4mg/naloxone 1mg
`predose
`postdose
`Buprenorphine 8mg/naloxone 2mg
`predose
`postdose
`Buprenorphine 16mg/naloxone 4mg
`predose
`postdose
`Buprenorphine 16mg alone
`predose
`postdose
`
`Salivary pH
`(mean β SD)
`
`6.9 β 0.4
`6.7 β 0.4
`6.7 β 0.4
`6.9 β 0.4
`
`6.9 β 0.6
`6.4 β 0.4
`
`6.8 β 0.6
`6.5 β 0.5
`
`6.7 β 0.4
`6.3 β 0.5
`
`6.9 β 0.7
`6.4 β 0.3
`
`Physiological and Subjective Measures
`Physiological and subjective effects were
`analysed by repeated-measures ANOVA with treat-
`ment as the within-subject factor. Postdose values in
`each condition were compared with baseline values
`and with one another. Values were converted into
`change scores by subtracting baseline values from
`postdrug values. Change scores were analysed by
`ANOVA. Following a significant test, pairwise
`comparisons were performed using the least squares
`
`© 2004 Adis Data Information BV. All rights reserved.
`
`Clin Pharmacokinet 2004; 43 (5)
`
`Page 5
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`

`
`334
`
`Harris et al.
`
`Pharmacokinetic Measures
`
`Figure 1 illustrates the time course of bupre-
`norphine and norbuprenorphine plasma concentra-
`tions. Derived pharmacokinetic values are in table
`II, including dose-corrected mean AUC and Cmax
`values. Extrapolated AUC values (AUC®) were not
`compared because we could not characterise the
`terminal slope for several of the concentration-time
`curves due to fluctuating terminal values. This diffi-
`culty also precluded calculation of valid half-lives.
`
`4mg buprenorphine/naloxone tablet than with the with the dose of buprenorphine in the tablet study.
`other tablets (p < 0.05). Dissolution times were not
`The highest buprenorphine dose (16mg), whether
`significantly different between the other dose condi-
`alone or in combination with naloxone 4mg, gener-
`tions. Tablet dissolution time was not significantly
`ated a lower AUC48 for each of buprenorphine and
`correlated with post-treatment saliva pH. Of the
`norbuprenorphine per mg of dose than did the low-
`eight subjects given tablets, two frequently swal-
`est buprenorphine dose (buprenorphine 4mg/nalox-
`lowed prematurely. One had typical buprenorphine
`one 1mg). Per mg of dose, buprenorphine AUC48
`concentrations. For the other, plasma concentrations
`from buprenorphine 16mg alone and in combination
`were lower than the group mean but did not meet the
`with naloxone was only 70 β 25% and 72 β 17%,
`outlier criterion of two standard deviations from the
`respectively, of that from the buprenorphine 4mg
`mean and were no lower than the values of some of
`combination dose. Comparing the 16mg tablet of
`the other subjects, so data were included in the
`buprenorphine alone to the 16mg solution, the tablet
`analysis. One subject in the solution study swal-
`yielded 72% of the AUC48 and 65% of the Cmax of
`lowed prematurely at 1 minute 40 seconds after the
`that of the solution. However, the 24-hour bupre-
`4mg dose. His data were similar to those of the other
`norphine concentrations were not significantly dif-
`subjects at this dose and were included in the ana-
`ferent. Norbuprenorphine plasma concentrations at
`lysis.
`later collection times were relatively higher than
`those of buprenorphine, yielding a larger AUC48.
`Compared with the same buprenorphine dose condi-
`tions in the solution study, the ratios of norbupre-
`norphine to buprenorphine AUC48 were larger for
`the 4, 8 and both 16mg doses (with and without
`naloxone) in the tablet study (p < 0.05, 0.01, 0.01
`and 0.01, respectively).
`So many naloxone concentrations were below the
`level of detection that comparisons between dose
`conditions could not be made. Only five of the eight
`subjects had more than two plasma concentrations
`Solution Experiment
`of naloxone above the detection threshold at the
`The tmax for the solution did not differ with dose
`highest dose. The highest AUC was only 0.55
`(not dose-adjusted). However, a consistent trend for
`• g h/L.
`lower relative values with each increase in dose was
`Naloxone did not alter the bioavailability of
`noted for dose-adjusted AUC72 and Cmax, con-
`buprenorphine from the 16mg buprenorphine tablet
`firmed by statistically significant contrasts for linear
`as assessed by comparisons of the buprenorphine
`trend output by the ANOVA (p = 0.0001, and p =
`AUC48 (i.e. buprenorphine 16mg/naloxone 4mg
`0.0001, respectively). AUC72 per mg of dose admin-
`tablet versus buprenorphine 16mg alone tablet).
`istered after the 4mg and 8mg doses did not differ,
`However, naloxone did increase (p < 0.05) the
`but the dose-corrected AUC72 for the 16mg dose
`was only 72 β 14%, and for the 32mg dose only 54 β
`buprenorphine concentration at 24 hours after ad-
`16%, of that of the 4mg dose. Per mg dose adminis- ministration with the buprenorphine 16mg tablet by
`tered, the 8, 16 and 32mg doses yielded only 84 β
`34% (from 0.387 β 0.19 to 0.519 β 0.16 • g/L).
`23%, 63 β 19% and 52 β 16%, respectively, of the
`Only a small percentage of the buprenorphine
`Cmax of the 4mg dose.
`dose was excreted unchanged in the 48-hour urine
`collection. The total of buprenorphine and norbupre-
`norphine and their hydrolysable conjugates was
`only 4.1 β 1.6–5.7 β 2.2%.
`
`Tablet Experiment
`Similarly, mean buprenorphine AUC48 and mean
`Cmax also increased, but less than proportionally,
`
`© 2004 Adis Data Information BV. All rights reserved.
`
`Clin Pharmacokinet 2004; 43 (5)
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`Page 6
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`

`
`335
`
`B4/N1
`B8/N2
`B16/N4
`B32/N0
`
`Sublingual Buprenorphine
`
`Solution
`
`Buprenorphine
`
`B4
`B8
`B16
`B32
`
`Tablet
`
`Buprenorphine
`
`
`
`
`
`Norbuprenorphine
`
`Norbuprenorphine
`
`14
`
`12
`
`10
`
`8
`
`6
`
`4
`
`2
`
`0
`
`3.5
`
`3.0
`
`2.5
`
`2.0
`
`1.5
`
`1.0
`
`0.5
`
`0
`
`Concentration (μg/L)
`
`Concentration (μg/L)
`
`0
`
`3
`
`6
`
`9
`9
`Time (h)
`Time (h)
`Fig. 1. Plasma concentration-time curves for buprenorphine and norbuprenorphine after sublingual doses of buprenorphine and/or nalox-
`one. Values are means β standard error. Bx = buprenorphine xmg; Bx/Ny = buprenorphine xmg/naloxone ymg.
`
`12 24 48 72
`
`0
`
`3
`
`6
`
`12 24
`
`48
`
`Physiological Effects
`
`Heart rate, blood pressure, rate-pressure product,
`respiratory rate and pulse oximetry were not signifi-
`cantly different between doses in either experiment.
`However, at 48 hours after solution doses, pupils
`were still constricted, with larger doses producing
`
`greater constriction. A dose-response effect was
`found at this time (p < 0.01). The pupil constriction
`after the 32mg dose was greater than with the 4mg
`dose (t = 2.87, p < 0.01) [figure 2]. Pupil diameter in
`the tablet study was not significantly different be-
`tween conditions but was not measured at 48 hours.
`
`© 2004 Adis Data Information BV. All rights reserved.
`
`Clin Pharmacokinet 2004; 43 (5)
`
`Page 7
`
`

`
`336
`
`Harris et al.
`
`Table II. Plasma pharmacokinetics of buprenorphine and norbuprenorphine after sublingual doses of buprenorphine and/or naloxone.
`Values are means β SD (n = 12 for solution doses and n = 8 for tablet doses)
`Doses (mg)
`Dose-adjusted AUC
`Unadjusted AUC
`Dose-adjusted Cmax Unadjusted Cmax
`(• g h/L per mg)a
`(• g h/L)a
`(• g/L per mg)
`(• g/L)
`
`Unadjusted tmax
`(h)
`
`Buprenorphine
`Sublingual solution
`B4
`B8
`B16
`B32
`p-Value
`
`Sublingual tablet
`B4/N1
`B8/N2
`B16/N4
`B16/N0
`p-Value
`
`4.34 β 1.36
`3.84 β 1.23
`3.02 β 0.86
`2.20 β 0.50
`p = 0.0001 (B32 <
`B16 < B4 and B8)
`
`3.13 β 1.09
`2.53 β 1.09
`2.18 β 0.73
`2.04 β 0.51
`p = 0.0029
`(B16/N4 < B4/N1;
`B16/N0 < B4/N1)
`
`Norbuprenorphine
`Sublingual solution
`B4
`B8
`B16
`B32
`p-Value
`
`1.86 β 0.98
`2.06 β 0.93
`1.79 β 0.96
`1.55 β 0.95
`p = NS
`
`17.36 β 5.44
`30.70 β 9.86
`48.26 β 13.72
`70.30 β 15.86
`
`12.52 β 4.37
`20.22 β 8.70
`34.89 β 11.63
`32.63 β 8.23
`
`7.44 β 3.92
`16.49 β 7.40
`28.62 β 15.38
`49.59 β 30.33
`
`0.890 β 0.378
`0.729 β 0.346
`0.523 β 0.179
`0.428 β 0.137
`p = 0.0001 (B32
`and B16 < B8 < B4)
`
`3.56 β 1.51
`5.83 β 2.77
`8.37 β 2.86
`13.70 β 4.38
`
`0.460 β 0.180
`0.375 β 0.191
`0.372 β 0.143
`0.342 β 0.079
`p = NS
`
`1.84 β 0.72
`3.00 β 1.53
`5.95 β 2.28
`5.47 β 1.27
`
`0.083 β 0.042
`0.111 β 0.042
`0.077 β 0.055
`0.077 β 0.054
`p = 0.01 (B4, B16
`and B32 < B8)
`
`0.33 β 0.17
`0.88 β 0.34
`1.24 β 0.87
`2.48 β 1.74
`
`1.09 β 0.40
`1.16 β 0.54
`1.17 β 0.40
`1.00 β 0.34
`p = NS
`
`1.06 β 0.42
`1.01 β 0.36
`0.79 β 0.27
`1.04 β 0.65
`p = NS
`
`3.92 β 8.27
`2.96 β 3.06
`2.75 β 2.65
`3.23 β 4.93
`p = NS
`
`Sublingual tablet
`B4/N1
`B8/N2
`B16/N4
`B16/N0
`p-Value
`
`15.24 β 6.13
`23.16 β 7.78
`40.62 β 18.49
`32.64 β 7.63
`
`3.81 β 1.53
`2.90 β 0.97
`2.54 β 1.16
`2.04 β 0.48
`p = 0.0026
`(B16/N4 < B4N1;
`B16N0 < B4N1)
`a Unextrapolated; AUC72 for solution and AUC48 for tablets.
`AUC = area under the plasma concentration-time curve; AUCx = AUC to x hours; Bx = buprenorphine xmg; Bx/Ny = buprenorphine xmg/
`naloxone ymg; Cmax = peak plasma concentration; h = hours; n = number of subjects; NS = not significant; tmax = time to achieve Cmax.
`
`0.208 β 0.068
`0.185 β 0.070
`0.219 β 0.087
`0.159 β 0.081
`p = NS
`
`0.83 β 0.27
`1.48 β 0.56
`3.50 β 1.39
`2.54 β 1.29
`
`4.81 β 8.00
`1.07 β 0.48
`0.98 β 0.42
`1.44 β 0.86
`p = NS
`
`Subjective Measures
`
`Larger doses of solution, but not larger doses of
`tablet, produced
`increased global
`intoxication.
`Global intoxication in the solution experiment was
`rated significantly higher following administration
`of the 32mg sublingual solution than after the 4 and
`8mg doses (t = –2.85, p < 0.01), but not compared
`with the 16mg dose. Intoxication appeared within 30
`minutes after administration, peaked at approxi-
`mately 120 minutes and remained moderately high
`
`to the end of the 6-hour testing session, and was
`back to baseline by 24 hours.
`Compared with baseline, ratings of drug liking
`and good drug effect increased in all conditions.
`However, compared across conditions in the solu-
`tion experiment, drug liking was significantly higher
`across time in the 4mg condition than after the 8, 16
`and 32mg doses (t = 2.15, p < 0.04; t = 2.15, p <
`0.04; and t = 3.01, p < 0.01, respectively) and
`remained high to the end of the 6-hour session. Drug
`
`© 2004 Adis Data Information BV. All rights reserved.
`
`Clin Pharmacokinet 2004; 43 (5)
`
`Page 8
`
`

`
`Sublingual Buprenorphine
`
`337
`
`Differences in dose-corrected AUC could reflect
`liking for the tablet increased with increasing dose,
`but this was not statistically significant. Good drug
`a difference either in bioavailability or in clearance.
`effect and opioid agonist ratings were not different
`The randomised dose order in the tablet experiment
`between the solution or tablet conditions. Peak rat- makes induction of enzymes producing faster clear-
`ings for global intoxication and drug liking are
`ance a less likely explanation. The proportionately
`shown in figure 3.
`decreasing AUC of a major metabolite, norbupre-
`For both experiments, unpleasant effects were
`norphine, with increasing buprenorphine dose is al-
`small and statistically nonsignificant. Global with-
`so more consistent with decreased sublingual ab-
`drawal effects peak means were ≤ 8 (out of a poss-
`sorption, rather than a change in elimination. Tablet
`ible maximum of 100), opioid withdrawal symp-
`dissolution for the 4mg buprenorphine/naloxone
`toms peak means ≤ 5 (out of 84), and ratings of
`dose was shorter than for the others, allowing less
`sickness and bad drug effect peak means ≤ 18 (out of
`time for swallowing which, in turn, could result in
`100) with any dose of the solution or tablets.
`poorer absorption from the stomach and intestines
`for the larger doses compared with the smaller. The
`higher norbuprenorphine to buprenorphine ratios in
`the tablet study compared with the solution study
`suggests that more of the tablet may be swallowed,
`as proportionately increased norbuprenorphine con-
`centrations are found with oral administration.[21]
`Although larger doses may simply be more difficult
`to mechanically hold under the tongue, resulting in
`more drug swallowed before absorption, it is also
`possible that larger doses may saturate the tissue
`transporter mechanisms, increasing sequestration of
`buprenorphine in sublingual tissues.[22] Drug that is
`not moving through sublingual tissues may be swal-
`lowed and cleared by CYP3A4 in the liver or by the
`
`B4
`B8
`B16
`B32
`
`5.0
`
`4.5
`
`4.0
`
`3.5
`
`3.0
`
`2.5
`
`2.0
`
`Pupil size (mm)
`
`0
`
`2
`
`4
`Time (h)
`Fig. 2. Mean pupil size versus time in the solution experiment.
`Values are means β standard error. Bx = buprenorphine xmg.
`
`6
`
`24
`
`48
`
`© 2004 Adis Data Information BV. All rights reserved.
`
`Clin Pharmacokinet 2004; 43 (5)
`
`Subject Comments
`
`Acceptability of the buprenorphine solution as an
`opioid-like medication was 68% for the 4mg dose,
`25% for the 8mg dose, and 33% for the 16 and 32mg
`doses. Similarly, acceptability was highest (88%)
`for the buprenorphine 4mg/naloxone 1mg tablet and
`lowest (50%) for the buprenorphine 16mg tablet.
`
`Adverse Effects
`
`In the solution experiment, nausea or vomiting
`was reported by 9 of the 12 subjects. Vomiting was
`more frequent after increased dose. Difficulty uri-
`nating (hesitancy or brief, spontaneously resolving
`retention over the course of the evening following
`administration) was reported by half of the subjects.
`In the tablet study, 3 of the 12 subjects vomited.
`Vomiting was unrelated to dose.
`
`Discussion
`
`Pharmacokinetic Measures
`
`AUC for buprenorphine in both experiments in-
`creased with dose but less than proportionally. Sev-
`eral subjects vomited in both experiments. This
`raises the question of whether vomiting contributed
`to the lack of dose proportionality. It is possible that
`if a large proportion of the buprenorphine dose were
`swallowed, vomiting might explain this finding.
`However, vomiting was related to increasing dose
`only in the solution experiment and very little bupre-
`norphine is available after oral doses.[5,20] Therefore,
`loss of buprenorphine from vomiting would be un-
`likely to significantly alter plasma concentrations.
`
`Page 9
`
`

`
`338
`
`Harris et al.
`
`Solution
`
`Tablet
`
`Intoxication
`
`Intoxication
`
`Drug liking
`
`Drug liking
`
`80
`
`60
`
`40
`
`20
`
`0
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Score (0100)
`
`Score (0100)
`
`B32
`B16
`B8
`B4
`B16/N0
`B16/N4
`B8/N2
`B4/N1
`Fig. 3. Mean peak rating for global intoxication and drug liking for buprenorphine solutions (n = 12) and tablets (n = 8). Values are means β
`standard error. Bx = buprenorphine xmg; Bx/Ny = buprenorphine xmg/naloxone ymg.
`
`hepatobiliary system. Faecal excretion accounts for with buprenorphine and its metabolites, yielding
`more than 74% of the elimination of buprenorphine
`higher concentrations of ‘buprenorphine equivalents’
`and norbuprenorphine, based on animal and autopsy
`in the higher dose conditions, may account for the
`studies.[23,24] The low, approximately 5%, recovery
`different findings. Unless the metabolites are bio-
`of buprenorphine, norbuprenorphine a