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Pharmacokinetics of high-dose buprenorphine following single administration of sublingual tablet formulations in opioid naı̈ve healthy male volunteers under a naltrexone block
Drug and Alcohol Dependence 72 (2003) 75 /83 www.elsevier.com/locate/drugalcdep
Pharmacokinetics of high-dose buprenorphine following single administration of sublingual tablet formulations in opioid naı¨ve healthy male volunteers under a naltrexone block Sarah D. McAleer *, Richard J. Mills, Torsten Polack, Tanweer Hussain, Paul E. Rolan, Alan D. Gibbs, Frank G.P. Mullins, Ziad Hussein Medeval Limited, Skelton House, Manchester Science Park, Lloyd Street North, Manchester M15 6SH, UK Received 12 December 2002; accepted 29 May 2003
Abstract Sublingual buprenorphine formulations have been developed as treatments for opioid dependence. In three studies, opioid naı¨ve healthy male subjects received Subutex† tablets (buprenorphine 2 and 8 mg [N /27] or 12 and 16 mg [N /27]) or Suboxone† (two formulations) tablets (buprenorphine 8 mg/naloxone 2 mg [N /36]) sublingually, under a naltrexone block for assessment of buprenorphine pharmacokinetics and tablet disintegration times. Plasma buprenorphine was quantified up to 72 h post-dose using a sensitive LC /MS/MS assay. Mean Cmax values ranged from 1.6 to 6.4 ng/ml and tmax from 0.5 to 3 h. Concentrations declined biexponentially and fluctuations after a meal suggested enterohepatic recirculation of buprenorphine. The terminal half-life was approximately 26 h (range 9 /69). Cmax and AUC appeared to increase in proportion to Subutex† dose over 8 /16 mg. The Suboxone† formulations were bioequivalent. The least squares mean (90% CI) treatment ratio for Cmax was 1.00 (0.92 /1.10) and AUC was 1.00 (0.95 /1.06). Median times of disintegration were similar for all doses and formulations (range 6 /12 min). Sublingual buprenorphine, up to 40 times the 400 mg analgesic dose, was well tolerated in these opioid naı¨ve subjects, as administration of naltrexone 50 /150 mg was sufficient to attenuate anticipated adverse effects in this population of subjects. # 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Buprenorphine; Sublingual; Pharmacokinetics; Volunteers; Naltrexone
1. Introduction Buprenorphine is a partial agonist at the m opioid receptor and an antagonist at the k opioid receptor. It has a relatively long duration of action and a substantially lower dependence liability than pure agonist analgesics such as morphine and diamorphine, although limited euphoric effects have been observed in some individuals. This has led to its therapeutic use as a maintenance/treatment agent for opiate dependence. As the bioavailability of buprenorphine via the oral route is low (ca. 14%) due to extensive first-pass metabolism (McQuay and Moore, 1995), sublingual administration has been targeted as a route for outpatient dosing in the
* Corresponding author. Tel.: /44-161-226-6525; fax: /44-161226-8936. E-mail address: [email protected] (S.D. McAleer).
treatment of opioid dependence. Two sublingual tablet formulations, one containing buprenorphine (Subutex† 2 and 8 mg tablets) and one containing buprenorphine and naloxone (Suboxone† 2 mg/0.5 mg and 8 mg/2 mg tablets) have recently been approved by the US Food and Drug Administration for the treatment of opioid dependence. Intravenous abuse of sublingual buprenorphine provides some reinforcement of drug addiction behaviour and ‘reward’ that limits its use in the community. However, Suboxone† , containing the combination of buprenorphine and naloxone, has been shown to produce withdrawal symptoms if misused intravenously by opioid-dependent individuals (Mendelson et al., 1999) and thus is preferable for outpatient use in order to minimise potential misuse. We report here pharmacokinetic data from three studies that were performed during the development of Subutex† and Suboxone† . The objectives were to assess
03765-8716/03/$ - see front matter # 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/S0376-8716(03)00188-1
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the pharmacokinetics of buprenorphine following single sublingual doses of Subutex† and to assess whether two formulations of Suboxone† were bioequivalent. These data represent one of the most extensive published description of the pharmacokinetics of sublingual buprenorphine at high doses based on plasma buprenorphine concentrations measured using a new sensitive LC /MS/MS assay. The three studies were conducted in healthy male volunteers who were non-opioid-dependent. One of the problems of administration of buprenorphine to opiate naı¨ve subjects is, however, the potential for adverse effects, including nausea, vomiting, drowsiness and euphoria. At higher doses, respiratory depression can occur. All of these effects would be expected to be attenuated in the presence of naltrexone, a nonspecific opioid antagonist of the centrally mediated effects of opioid analgesics, which will antagonise the effects of m opioid and k opioid agonists. Therefore, these studies were conducted under a naltrexone block in order to improve the tolerability of buprenorphine. Naltrexone is a well-established treatment for opioid overdose or abuse and it has been used to block the adverse effects of morphine in Phase I studies in healthy volunteers without compromising the pharmacokinetic results (Bashaw et al., 1995; Kaiko et al., 1995; Wright et al., 1993). As centrally mediated effects of buprenorphine should have been blocked, volunteers should neither have become more tolerant nor exhibit a withdrawal phenomenon after repeated administrations in short succession.
2. Methods 2.1. Participants The participants were all healthy male subjects, with no history of opiate abuse, who gave their consent to take part in one of these studies. Thirty-six subjects (19 / 42 years), 33 subjects (19 /40 years) and 36 subjects (19 / 43 years) participated in Studies 1 /3, respectively. All subjects were healthy as assessed by physical examination, 12-lead electrocardiogram, hematology and biochemistry testing and urinalysis. They all met the entry criteria, including a negative urine drugs of abuse screen and an alcohol breath test. The protocols and consent forms for each study were reviewed and approved prior to study commencement by an Independent Ethics Committee in Manchester. Each study was performed in compliance with the guidelines of the Declaration of Helsinki, the Data Protection Act, 1998 and in accordance with the International Conference on Harmonisation guidelines for Good Clinical Practice (ICH GCP): CPMP/ICH/ 135/95, January 1997. A payment was made to each subject for giving up their time to participate in a study.
2.2. Drugs Subutex† tablets (containing buprenorphine hydrochloride 2 or 8 mg) and Suboxone† A and Suboxone† B tablets (containing buprenorphine hydrochloride 8 mg and naloxone 2 mg) were supplied by Reckitt Benckiser Healthcare (UK) Ltd. The two formulations of Suboxone† tablets differed only in non-active excipients, which were not anticipated to affect bioavailability. The doses of buprenorphine used in these studies were selected as they are relevant doses used in the treatment of opioid dependence. Naltrexone 50 mg tablets for oral administration were also administered prior to and after dosing with buprenorphine at doses of 50/150 mg to attenuate the anticipated adverse effects related to buprenorphine. 2.3. Procedures 2.3.1. Study design Studies 1 and 2 were open studies where Subutex† tablets were administered as single doses of 2 and 8 mg (Study 1) and 12 and 16 mg (Study 2), in ascending dose order. Each subject was to receive only two doses of Subutex† . Study 3 was a single dose, randomised, open, two-way crossover study, where Suboxone† A and Suboxone† B 8 mg tablets were administered. These studies were performed sequentially in number order. For Study 1, subjects were admitted to the Clinical Unit at approximately 07:00 h in the morning of Day 0, the day before each study drug administration. Urine drugs of abuse and alcohol breath tests were performed. A first dose of 100 mg naltrexone was administered orally and subjects were then resident in the Clinical Unit until discharge after the 72 h post-dose assessments. On Day 1 of each period, a second dose of naltrexone 100 mg was administered orally at approximately 07:00 h prior to subjects being served with a light, low-fat breakfast. Subjects were administered Subutex† 2 mg at approximately 08:00 h and advised to place the tablet under the tongue and try to avoid swallowing until the tablet had disintegrated. The subjects were recumbent for the first 4 h post-dose and were served a standard lunch and dinner at approximately 4 and 10 h after dosing, respectively. Fluids were allowed ad libitum following the first 10 min after dose administration or from when tablet disintegration was confirmed, if after 10 min post-dose. Blood and urine samples were collected for routine clinical laboratory tests, vital signs were performed and adverse events were monitored. A further dose of naltrexone 100 or 150 mg may also have been given at 20:00 h on Day 1 if thought clinically necessary. Standard meals were served on Days 2 and 3 and fluids were allowed ad libitum. A dose of naltrexone 100 or 150 mg was administered in the morning of Day 2. Following the 72 h assessments in
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the morning of Day 3, subjects were allowed home. The procedures for the second treatment period, where subjects received a single Subutex† 8 mg tablet, were identical to the first. Dosing periods were separated by a washout interval of at least 10 days. Within 10 days after the last study drug administration, subjects attended the Clinical Unit for a post-study medical to make sure that they were in satisfactory health. One subject could not be included in the pharmacokinetic population as they swallowed one of the Subutex† treatments instead of allowing it to disintegrate sublingually. Twenty-seven subjects successfully completed both Subutex† treatment periods. Study 2 was identical in design to Study 1, except that the Subutex† doses were 12 mg (2 /Subutex† 2 mg tablets and 1 /Subutex† 8 mg tablet) and 16 mg (2 / Subutex† 8 mg tablets). Twenty-seven subjects successfully completed both Subutex† treatment periods. Study 3 procedures for each dosing period were the same as in Studies 1 and 2, except that the dose of naltrexone administered was 50 mg, the first dose in the morning of Day 0, a second dose in the morning of Day 1 and a third dose in the morning of Day 2. Thirty-six subjects successfully completed both Suboxone† treatment periods. As Study 1 was performed first, the dose of naltrexone was set conservatively at 100 mg, with an increase allowed to 150 mg if clinically necessary. For Study 3, the naltrexone dose was reduced to 50 mg, based on the tolerability of the 8 mg buprenorphine dose in Study 1. In all three studies assessments of tablet disintegration were made at 2-min intervals until tablet disintegration, the actual time of which was noted by the investigator. Nineteen 5 ml blood samples (20 /7 ml samples in Study 3) were withdrawn through an indwelling catheter, or by separate venepuncture, pre-dose and at frequent intervals up to 72 h post-dose into polypropylene lithium heparin tubes. The samples were centrifuged within 30 min of collection at 1500 /g for 10 min at 4 8C and the separated plasma stored at /70 8C until analysis. 2.3.2. Bioanalytical method A liquid chromatographic tandem mass spectrometric (LC /MS/MS) assay was developed and validated for the measurement of buprenorphine in human plasma. The method involves initial diethyl ether extraction using deuterated buprenorphine as an internal standard (concentration /6.25 ng/ml), followed by separation on a Hypersil BDS C18 (100 /2.1 mm; 3 mm) column with 0.01 M ammonium acetate (pH 4): acetonitrile (60:40 v/ v) as mobile phase at a flow rate of 0.3 ml/min. The MS/ MS conditions included a capillary voltage of 3.15 V, a cone voltage of 50 V for both buprenorphine and internal standard and a collision energy of 60 eV for both buprenorphine and internal standard. The parent
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to daughter ion transitions were 468.3 /55.0 a.m.u. for buprenorphine and 472.3 /59.0 a.m.u. for the internal standard. The lower limit of quantification (LLOQ) for buprenorphine was established at 0.05 ng/ml and the assay was linear up to 10.07 ng/ml. Quality control sample concentrations were 0.05, 1.71, 5.04 and 9.82 ng/ ml in Study 1, 0.06, 1.71, 5.10 and 10.01 ng/ml in Study 2 and 0.12, 1.70, 4.82 and 8.77 ng/ml in Study 3. Over all three studies, inter-assay precision ranged from 3.7 to 26.4% and inter-assay bias from /6.0 to 6.9%. For precision, the upper value of 26.4% given is from Study 1, where outlier exclusion criteria were not used to calculate the final assay statistics, a procedure which was applied to these data in Studies 2 and 3. At the LLOQ, the precision of the quality control samples ranged from 15.3 to 26.4% and the bias from /3.8 to 5.5%. There were no significant interfering peaks at the retention times of buprenorphine or internal standard in blank human plasma, or when norbuprenorphine, the major metabolite of buprenorphine, or naltrexone were added. Representative chromatograms are shown in Fig. 1. 2.4. Pharmacokinetic and statistical analysis Pharmacokinetic analysis by standard model-independent methods was performed using WinNonlinTM Professional Version 3.2. The following buprenorphine pharmacokinetic parameters were determined using the actual blood sampling times following drug administration: maximum observed plasma concentration (Cmax) and the corresponding time of the observed Cmax (tmax) were obtained from the actual observations. AUCt was calculated using linear trapezoids from time zero to Cmax and log-linear trapezoids (assuming an exponential decay) from Cmax to the last quantifiable plasma concentration (Ct). The apparent plasma elimination rate constant, lz, was determined by linear regression of the logarithm of plasma concentration on time over the terminal phase using at least three timepoints. AUC was calculated as AUCt/Ct/lz and the terminal half-life (t1/2z) was derived from ln(2)/lz. Descriptive statistics were used to summarise the individual pharmacokinetic parameters for each dose level and formulation. The bioequivalence of Suboxone† B to Suboxone† A was determined by analyses of variance (ANOVA) of the log transformed Cmax and AUC. The statistical model included factors accounting for variation due to treatment sequence, subject nested within sequence, period and treatment. The sequence effect was tested against the subject within sequence mean square; all other effects were tested against the residual error (error mean square). Statistical significance was taken at the 5% level. The difference between the mean log-transformed endpoints was estimated, together with the 90% confidence intervals (CI) for
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Fig. 1. Representative chromatogram of extracted blank plasma with internal standard (A) and extracted subject sample with internal standard (B). Y -axis (cycles per second) normalised to 100% of highest peak.
these differences. The results were back transformed to give point estimates of the least square mean ratios (Suboxone† B/Suboxone† A) and associated 90% CI
for each pharmacokinetic parameter. tmax was analysed using the non-parametric Wilcoxon’s matched pairs test. In Study 3, the Investigator’s assessment of the extent of
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tablet disintegration at each 2-min timepoint and the time of disintegration were compared between formulations using the Wilcoxon Rank Sum Test. All statistical analyses were performed in SAS† System version 8. Mean and 95% CI for the parameters normalised to the 2 mg dose were plotted against dose in Studies 1 and 2 for an assessment of dose-proportionality.
3. Results 3.1. Pharmacokinetics (Mean9/S.D.) plasma linear concentration-time profiles are given in Figs. 2 /4 for Studies 1 /3, respectively. The pharmacokinetic parameters are summarised in Table 1. In each of the studies there were instances where the extrapolated area of the AUC was greater than 30% and in these cases the AUC and t1/2z values were excluded from the summary statistics. In addition, although some half-life values were not estimated over a time interval of at least twice the resultant half-life, they were none the less included in the summary statistics. In the majority of subjects, plasma buprenorphine concentrations were quantifiable at 0.25 h post-dose and increased reasonably rapidly, with Cmax values occurring from approximately 0.5 to 3 h post-dose, at all dose levels and formulations studied. Concentrations declined bi-exponentially and the terminal decline in plasma buprenorphine concentrations in many individuals was not smooth, with fluctuations clearly visible, especially a secondary peak around 10 h post-dose, an example of which is shown in Fig. 5 for a typical subject.
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Following administration of Subutex† 2 mg, plasma buprenorphine concentrations fell below the LLOQ of the assay at timepoints as early as 12 h post-dose, with considerable inter-subject variability between 12 and 48 h post-dose. It is likely that the analytical sensitivity was insufficient to truly estimate the AUCt at the 2 mg dose level. In addition, reliable estimation of lz and hence AUC and t1/2z was possible in only a few subjects at the 2 mg dose level. At 8, 12 and 16 mg, the majority of subjects had quantifiable buprenorphine concentrations up to 72 h post-dose and determination of lz was possible in the majority of subjects at the 8 mg dose level and in all subjects at the 12 and 16 mg dose levels. The estimated apparent terminal half-life was approximately 26 h (range 9 /69 h). Mean dose-normalised Cmax and AUC values appeared not to change with dose (Fig. 6), indicating approximate dose-proportional increases of these parameters across the 8/16 mg doses in Studies 1 and 2. Data from Study 3 were excluded from these comparisons due to the different buprenorphine formulations used. As the AUC values were not adequately estimated at 2 mg, these data were also excluded from the comparison plots. For the Suboxone† study (Study 3), the least squares mean ratios (90% CI) were 1.00 (0.92 /1.10) for Cmax, 0.99 (0.95 /1.04) for AUCt and 1.00 (0.95 /1.06) for AUC. The 90% CIs were well within the 0.8 and 1.25 limits required by the regulatory authorities for acceptance of bioequivalence. No statistically significant difference (P /0.49) in tmax was identified between the two treatments, nor were there any statistically significant treatment, period or sequence effects.
Fig. 2. Mean9/S.D. plasma buprenorphine concentrations following single administration of 2 mg Subutex† (1 /2 mg sublingual tablet; m) and 8 mg Subutex† (1 /8 mg sublingual tablet; j) (N /27).
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Fig. 3. Mean9/S.D. plasma buprenorphine concentrations following single administration of 12 mg Subutex† (2 /2 and 1 /8 mg sublingual tablets; m) and 16 mg Subutex† (2 /8 mg sublingual tablets; j) (N /27).
3.2. Tablet disintegration
3.3. Safety
Median (range) in vivo times of sublingual disintegration were 6 (2 /17) and 12 (6 /32) min for Subutex† at 2 and 8 mg, respectively, and 9 (3 /20) and 8 (3 /24) min for Subutex† at 12 and 16 mg, respectively. Similar values were obtained for Suboxone† A and B formulations, with median times of disintegration of 11.5 (5 /28) and 8 (3 /26) min, respectively. In each study these times were not statistically significantly different.
In Study 1, eight subjects were withdrawn from the study, four of which were due to adverse events, and four due to personal reasons. Of the adverse event related withdrawals, only one was considered possibly related to buprenorphine administration and one to naltrexone administration (nausea, vomiting and abdominal pain). In Study 2, six subjects were withdrawn from the study, one due to an adverse event (headache)
Fig. 4. Mean9/S.D. plasma buprenorphine concentrations following single administration of two formulations of Suboxone† (formulation A /m; formulation B /j) sublingual tablets (N /36).
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Table 1 Summary (mean9/S.D.) buprenorphine pharmacokinetic parameters following single dose administration of Subutex† and Suboxone† sublingual tablets Parameter
Study 1 (N /27) †
Cmax (ng/ml) tmax (h)a AUCt (ng h/ml) AUC (ng h/ml) t1/2z (h)
Study 2 (N /27) †
†
Study 3 (N /36) †
Subutex , 2 mg
Subutex , 8 mg
Subutex , 12 mg
Subutex , 16 mg
Suboxone† A, 8 mg
Suboxone† B, 8 mg
1.69/0.5 1.50 (1.00 /3.00) 9.059/2.67 ND ND
4.09/1.2 1.02 (0.75 /2.00) 26.899/7.16 31.819/8.20b 30.029/11.99b
5.49/1.8 1.00 (0.50 /2.00) 36.529/9.40 41.619/11.98c 25.639/7.05c
6.49/2.6 0.75 (0.50 /2.00) 46.199/14.51 52.009/17.06 23.899/6.55
3.29/1.3 1.00 (0.50 /2.00) 21.729/8.14 24.559/9.29d 25.519/8.40d
3.29/1.2 1.00 (0.50 /2.02) 21.309/6.88 24.609/7.99 26.799/8.17
ND, not determined. a Median (range). b N /23. c N /26. d N /35.
that started approximately 24 h after a single naltrexone 100 mg dose, two due to protocol deviations and three due to personal reasons. In Study 3, no subjects were withdrawn from the study. Anticipated adverse events of headache, fatigue, nausea, dizziness and vomiting did occur in all three studies, but were of mild or moderate intensity and did not require additional medication, except for some incidences of headache. Administration of prophylactic naltrexone can be considered to have markedly attenuated these adverse events, with three doses of 50 mg administered on three occasions sufficient to attenuate the effects of a single 8 mg buprenorphine dose. At the 16 mg dose level, 100 mg naltrexone was sufficient in the majority of subjects, but on some occasions the dose had to be increased to 150 mg. Naltrexone administration itself did result in some adverse events of fatigue, nausea and headache, but
these were generally of mild or moderate severity. There were no apparent differences in the tolerability of naltrexone at 50, 100 or 150 mg.
4. Discussion The aim of these studies was to provide comprehensive pharmacokinetic data of sublingual buprenorphine at doses of 2 /16 mg in a large number of healthy volunteers, together with assessments of tablet disintegration times. The administration of concomitant naltrexone was extremely effective in allowing buprenorphine up to 16 mg, a dose that is 40-fold higher than the highest analgesic sublingual dose, to be administered to healthy subjects without them suffering from more than moderate buprenorphine-related ad-
Fig. 5. Plasma buprenorphine concentrations following single administration of Subutex† 16 mg in a typical subject.
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Fig. 6. Mean9/95% CI plots of dose-normalised Cmax and AUC values against dose for Study 1 (8 mg) and Study 2 (12 and 16 mg).
verse effects. This indicates the utility of the naltrexone block in performing pharmacokinetic studies with opioids in healthy volunteers. Time to peak plasma buprenorphine concentrations ranged from approximately 0.5 to 3 h, which is in good agreement with the range 1 /3 h observed in earlier studies in volunteers where buprenorphine was administered in the form of a solution or as sublingual tablets (Bullingham et al., 1982; Mendelson et al., 1997; Schuh and Johanson, 1999). Absolute bioavailability via the sublingual route ranges from 30 to 55% (Bullingham et al., 1982; Kuhlman et al., 1996; Mendelson et al., 1997), depending on the formulation (oral solution or tablet). The percentage absorbed from a solution was not significantly different whether the solution was in contact with the buccal mucosa for either 2.5 or 10 min (Weinberg et al., 1988), or for either 3 or 5 min (Mendelson et al., 1997), although direct comparisons may not be applicable as buffered aqueous solutions were used by Weinberg et al. (1988) and 30% ethanolic solutions by Mendelson et al. (1997). Therefore, when in solution, contact of buprenorphine with the buccal
mucosa is only required for a few minutes to allow maximum absorption. This would indicate that with tablet formulations, once dissolution is complete, the fraction absorbed into the buccal mucosa would be complete soon after. We have shown apparent doseproportional increases in both Cmax and AUC over the dose range 8/16 mg within Studies 1 and 2, which indicates no limits on sublingual absorption in this dose range. This has also been observed in an earlier study, where plasma concentrations were linearly related to dose in four subjects who received single doses of sublingual buprenorphine from 1 to 32 mg (Walsh et al., 1994). Early studies of buprenorphine pharmacokinetics may have had limitations due to insufficient assay sensitivity due to the type of detection employed or selectivity when using radioimmunoassay (Everhart et al., 1997). The bioanalytical method employed in the studies reported here was sufficiently sensitive to quantify plasma buprenorphine concentrations after a single 2 mg sublingual dose and allow adequate characterisation of the terminal phase at the 8, 12 and 16 mg doses. The fluctuations observed in the plasma profiles of many individuals are likely to be the result of enterohepatic recirculation, although these fluctuations were not observed in the mean profiles. Buprenorphine and/ or its glucuronide conjugate present in bile are released into the small intestine on contraction of the gall bladder in response to the meal given to each volunteer at 10 h post-dose and buprenorphine is subsequently reabsorbed. This is in agreement with Cone et al. (1984), who showed that the greatest percentage of a sublingual dose is recovered in faeces, indicating biliary excretion and possible enterohepatic recirculation. Buprenorphine is metabolised by 14-N -dealkylation to norbuprenorphine by cytochrome P450 3A4 (Iribarne et al., 1997; Kobayashi et al., 1998), with both parent and metabolite conjugated to glucuronide (Cone et al., 1984; Hand et al., 1986). The molecular weight of buprenorphine free base (467.6) is increased by 176 when conjugated to glucuronide, which is above the threshold for active biliary secretion in man (Dobrinska, 1989). In addition to this, the glucuronide conjugate is more polar than the free base, another property for likely biliary excretion. In some cases the discontinuities in the log-linear decline of plasma buprenorphine concentration profiles did complicate estimation of the terminal half-life, but in general the half-life of buprenorphine was well estimated, with mean values ranging from approximately 23 to 30 h. This compares well with the mean 28 h value reported by Kuhlman et al. (1996) following sublingual administration of 4 mg buprenorphine (as a 30% alcoholic solution held under the tongue for 10 min). This is much longer than the approximate 3 h half-life value (range 2 /8 h) following intravenous administration of 1.2 mg buprenorphine (Kuhlman et al., 1996).
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These authors proposed that the longer half-life following the sublingual route was due to slow distribution from the buccal mucosa, acting as a depot of the drug, into the systemic circulation. However, it is possible that the half-life reported after intravenous administration may have been estimated during buprenorphine distribution and the true value was not estimable due to limitations of assay sensitivity. In the series of studies reported here, the bi-exponential elimination of buprenorphine has been clearly demonstrated by combination of high doses and a more sensitive assay. There was moderate inter-individual variation in the pharmacokinetic parameters following administration of Subutex† tablets. Coefficient of variation values for Cmax and AUC ranged from 26 to 30% at 2 and 8 mg and from 26 to 41% at 12 and 16 mg. There was no apparent correlation between the time of tablet disintegration and tmax or Cmax. This implies that the processes of tablet disintegration and absorption of buprenorphine into the buccal mucosa were rapid in comparison to distribution out of the buccal mucosa into the systemic circulation.
Acknowledgements The studies included in this manuscript were conducted on behalf of Reckitt Benckiser Healthcare (UK) Limited, Dansom Lane, Hull HU8 7DS, UK. The authors wish to thank all the clinical staff at Medeval Limited involved in the conduct of these three studies and numerous personnel at Reckitt Benckiser Healthcare Limited for their comments on the manuscript.
References Bashaw, E.D., Kaiko, R.F., Grandy, R.P., Reder, R.F., Goldenheim, P.D., 1995. Relative bioavailability of controlled-release oral morphine during naltrexone blockade. Int. J. Clin. Pharmacol. Ther. 33, 524 /529. Bullingham, R.E., McQuay, H.J., Porter, E.J., Allen, M.C., Moore, R.A., 1982. Sublingual buprenorphine used postoperatively: ten hour plasma drug concentration analysis. Br. J. Clin. Pharmacol. 13, 665 /673.
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Cone, E.J., Gorodetzky, C.W., Yousefnejad, D., Buchwald, W.F., Johnson, R.E., 1984. The metabolism and excretion of buprenorphine in humans. Drug Metab. Dispos. 12, 577 /581. Dobrinska, M.R., 1989. Enterohepatic circulation of drugs. J. Clin. Pharmacol. 29, 577 /580. Everhart, E.T., Cheung, P., Shwonek, P., Zabel, K., Tisdale, E.C., Jacob, P., 3rd, Mendelson, J., Jones, R.T., 1997. Subnanogramconcentration measurement of buprenorphine in human plasma by electron-capture capillary gas chromatography: application to pharmacokinetics of sublingual buprenorphine. Clin. Chem. 43, 2292 /2302. Hand, C.W., Baldwin, D., Moore, R.A., Allen, M.C., McQuay, H.J., 1986. Radioimmunoassay of buprenorphine with iodine label: analysis of buprenorphine and metabolites in human plasma. Ann. Clin. Biochem. 23, 47 /53. Iribarne, C., Picart, D., Dreano, Y., Bail, J.P., Berthou, F., 1997. Involvement of cytochrome P450 3A4 in N -dealkylation of buprenorphine in human liver microsomes. Life Sci. 60, 1953 / 1964. Kaiko, R.F., Grandy, R.P., Reder, R.F., Goldenheim, P.D., Sackler, R.S., 1995. A bioequivalence study of oral controlled-release morphine using naltrexone blockade. J. Clin. Pharmacol. 35, 499 /504. Kobayashi, K., Yamamoto, T., Chiba, K., Tani, M., Shimada, N., Ishizaki, T., Kuroiwa, Y., 1998. Human buprenorphine N -dealkylation is catalyzed by cytochrome P450 3A4. Drug Metab. Dispos. 26, 818 /821. Kuhlman, J.J., Jr, Lalani, S., Magluilo, J., Jr, Levine, B., Darwin, W.D., 1996. Human pharmacokinetics of intravenous, sublingual, and buccal buprenorphine. J. Anal. Toxicol. 20, 369 /378. McQuay, H.J., Moore, R.A., 1995. Buprenorphine kinetics in humans. In: Cowan, A., Lewis, J.W. (Eds.), Buprenorphine: Combatting Drug Abuse with a Unique Opioid. Wiley, New York, pp. 137 / 147. Mendelson, J., Jones, R.T., Welm, S., Baggott, M., Fernandez, I., Melby, A.K., Nath, R.P., 1997. Buprenorphine and naloxone combinations: the effects of three dose ratios in morphinestabilized, opiate-dependent volunteers. Psychopharmacology 141, 37 /46. Mendelson, J., Upton, R.A., Everhart, E.T., Jacob, P., 3rd, Jones, R.T., 1997. Bioavailability of sublingual buprenorphine. J. Clin. Pharmacol. 37, 31 /37. Schuh, K.J., Johanson, C.E., 1999. Pharmacokinetic comparison of the buprenorphine sublingual liquid and tablet. Drug Alcohol Depend. 56, 55 /60. Walsh, S.L., Preston, K.L., Stitzer, M.L., Cone, E.J., Bigelow, G.E., 1994. Clinical pharmacology of buprenorphine: ceiling effects at high doses. Clin. Pharmacol. Ther. 55, 569 /580. Weinberg, D.S., Inturrisi, C.E., Reidenberg, B., Moulin, D.E., Nip, T.J., Wallenstein, S., Houde, R.W., Foley, K.M., 1988. Sublingual absorption of selected opioid analgesics. Clin. Pharmacol. Ther. 44, 335 /342. Wright, C., Kaiko, R., Bashaw, D., 1993. Use of naltrexone in opioid PK studies. Clin. Pharmacol. Ther. 53, 185.
Pharmacokinetics of high-dose buprenorphine following single administration of sublingual tablet formulations in opioid naı¨ve healthy male volunteers under a naltrexone block Sarah D. McAleer *, Richard J. Mills, Torsten Polack, Tanweer Hussain, Paul E. Rolan, Alan D. Gibbs, Frank G.P. Mullins, Ziad Hussein Medeval Limited, Skelton House, Manchester Science Park, Lloyd Street North, Manchester M15 6SH, UK Received 12 December 2002; accepted 29 May 2003
Abstract Sublingual buprenorphine formulations have been developed as treatments for opioid dependence. In three studies, opioid naı¨ve healthy male subjects received Subutex† tablets (buprenorphine 2 and 8 mg [N /27] or 12 and 16 mg [N /27]) or Suboxone† (two formulations) tablets (buprenorphine 8 mg/naloxone 2 mg [N /36]) sublingually, under a naltrexone block for assessment of buprenorphine pharmacokinetics and tablet disintegration times. Plasma buprenorphine was quantified up to 72 h post-dose using a sensitive LC /MS/MS assay. Mean Cmax values ranged from 1.6 to 6.4 ng/ml and tmax from 0.5 to 3 h. Concentrations declined biexponentially and fluctuations after a meal suggested enterohepatic recirculation of buprenorphine. The terminal half-life was approximately 26 h (range 9 /69). Cmax and AUC appeared to increase in proportion to Subutex† dose over 8 /16 mg. The Suboxone† formulations were bioequivalent. The least squares mean (90% CI) treatment ratio for Cmax was 1.00 (0.92 /1.10) and AUC was 1.00 (0.95 /1.06). Median times of disintegration were similar for all doses and formulations (range 6 /12 min). Sublingual buprenorphine, up to 40 times the 400 mg analgesic dose, was well tolerated in these opioid naı¨ve subjects, as administration of naltrexone 50 /150 mg was sufficient to attenuate anticipated adverse effects in this population of subjects. # 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Buprenorphine; Sublingual; Pharmacokinetics; Volunteers; Naltrexone
1. Introduction Buprenorphine is a partial agonist at the m opioid receptor and an antagonist at the k opioid receptor. It has a relatively long duration of action and a substantially lower dependence liability than pure agonist analgesics such as morphine and diamorphine, although limited euphoric effects have been observed in some individuals. This has led to its therapeutic use as a maintenance/treatment agent for opiate dependence. As the bioavailability of buprenorphine via the oral route is low (ca. 14%) due to extensive first-pass metabolism (McQuay and Moore, 1995), sublingual administration has been targeted as a route for outpatient dosing in the
* Corresponding author. Tel.: /44-161-226-6525; fax: /44-161226-8936. E-mail address: [email protected] (S.D. McAleer).
treatment of opioid dependence. Two sublingual tablet formulations, one containing buprenorphine (Subutex† 2 and 8 mg tablets) and one containing buprenorphine and naloxone (Suboxone† 2 mg/0.5 mg and 8 mg/2 mg tablets) have recently been approved by the US Food and Drug Administration for the treatment of opioid dependence. Intravenous abuse of sublingual buprenorphine provides some reinforcement of drug addiction behaviour and ‘reward’ that limits its use in the community. However, Suboxone† , containing the combination of buprenorphine and naloxone, has been shown to produce withdrawal symptoms if misused intravenously by opioid-dependent individuals (Mendelson et al., 1999) and thus is preferable for outpatient use in order to minimise potential misuse. We report here pharmacokinetic data from three studies that were performed during the development of Subutex† and Suboxone† . The objectives were to assess
03765-8716/03/$ - see front matter # 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/S0376-8716(03)00188-1
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the pharmacokinetics of buprenorphine following single sublingual doses of Subutex† and to assess whether two formulations of Suboxone† were bioequivalent. These data represent one of the most extensive published description of the pharmacokinetics of sublingual buprenorphine at high doses based on plasma buprenorphine concentrations measured using a new sensitive LC /MS/MS assay. The three studies were conducted in healthy male volunteers who were non-opioid-dependent. One of the problems of administration of buprenorphine to opiate naı¨ve subjects is, however, the potential for adverse effects, including nausea, vomiting, drowsiness and euphoria. At higher doses, respiratory depression can occur. All of these effects would be expected to be attenuated in the presence of naltrexone, a nonspecific opioid antagonist of the centrally mediated effects of opioid analgesics, which will antagonise the effects of m opioid and k opioid agonists. Therefore, these studies were conducted under a naltrexone block in order to improve the tolerability of buprenorphine. Naltrexone is a well-established treatment for opioid overdose or abuse and it has been used to block the adverse effects of morphine in Phase I studies in healthy volunteers without compromising the pharmacokinetic results (Bashaw et al., 1995; Kaiko et al., 1995; Wright et al., 1993). As centrally mediated effects of buprenorphine should have been blocked, volunteers should neither have become more tolerant nor exhibit a withdrawal phenomenon after repeated administrations in short succession.
2. Methods 2.1. Participants The participants were all healthy male subjects, with no history of opiate abuse, who gave their consent to take part in one of these studies. Thirty-six subjects (19 / 42 years), 33 subjects (19 /40 years) and 36 subjects (19 / 43 years) participated in Studies 1 /3, respectively. All subjects were healthy as assessed by physical examination, 12-lead electrocardiogram, hematology and biochemistry testing and urinalysis. They all met the entry criteria, including a negative urine drugs of abuse screen and an alcohol breath test. The protocols and consent forms for each study were reviewed and approved prior to study commencement by an Independent Ethics Committee in Manchester. Each study was performed in compliance with the guidelines of the Declaration of Helsinki, the Data Protection Act, 1998 and in accordance with the International Conference on Harmonisation guidelines for Good Clinical Practice (ICH GCP): CPMP/ICH/ 135/95, January 1997. A payment was made to each subject for giving up their time to participate in a study.
2.2. Drugs Subutex† tablets (containing buprenorphine hydrochloride 2 or 8 mg) and Suboxone† A and Suboxone† B tablets (containing buprenorphine hydrochloride 8 mg and naloxone 2 mg) were supplied by Reckitt Benckiser Healthcare (UK) Ltd. The two formulations of Suboxone† tablets differed only in non-active excipients, which were not anticipated to affect bioavailability. The doses of buprenorphine used in these studies were selected as they are relevant doses used in the treatment of opioid dependence. Naltrexone 50 mg tablets for oral administration were also administered prior to and after dosing with buprenorphine at doses of 50/150 mg to attenuate the anticipated adverse effects related to buprenorphine. 2.3. Procedures 2.3.1. Study design Studies 1 and 2 were open studies where Subutex† tablets were administered as single doses of 2 and 8 mg (Study 1) and 12 and 16 mg (Study 2), in ascending dose order. Each subject was to receive only two doses of Subutex† . Study 3 was a single dose, randomised, open, two-way crossover study, where Suboxone† A and Suboxone† B 8 mg tablets were administered. These studies were performed sequentially in number order. For Study 1, subjects were admitted to the Clinical Unit at approximately 07:00 h in the morning of Day 0, the day before each study drug administration. Urine drugs of abuse and alcohol breath tests were performed. A first dose of 100 mg naltrexone was administered orally and subjects were then resident in the Clinical Unit until discharge after the 72 h post-dose assessments. On Day 1 of each period, a second dose of naltrexone 100 mg was administered orally at approximately 07:00 h prior to subjects being served with a light, low-fat breakfast. Subjects were administered Subutex† 2 mg at approximately 08:00 h and advised to place the tablet under the tongue and try to avoid swallowing until the tablet had disintegrated. The subjects were recumbent for the first 4 h post-dose and were served a standard lunch and dinner at approximately 4 and 10 h after dosing, respectively. Fluids were allowed ad libitum following the first 10 min after dose administration or from when tablet disintegration was confirmed, if after 10 min post-dose. Blood and urine samples were collected for routine clinical laboratory tests, vital signs were performed and adverse events were monitored. A further dose of naltrexone 100 or 150 mg may also have been given at 20:00 h on Day 1 if thought clinically necessary. Standard meals were served on Days 2 and 3 and fluids were allowed ad libitum. A dose of naltrexone 100 or 150 mg was administered in the morning of Day 2. Following the 72 h assessments in
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the morning of Day 3, subjects were allowed home. The procedures for the second treatment period, where subjects received a single Subutex† 8 mg tablet, were identical to the first. Dosing periods were separated by a washout interval of at least 10 days. Within 10 days after the last study drug administration, subjects attended the Clinical Unit for a post-study medical to make sure that they were in satisfactory health. One subject could not be included in the pharmacokinetic population as they swallowed one of the Subutex† treatments instead of allowing it to disintegrate sublingually. Twenty-seven subjects successfully completed both Subutex† treatment periods. Study 2 was identical in design to Study 1, except that the Subutex† doses were 12 mg (2 /Subutex† 2 mg tablets and 1 /Subutex† 8 mg tablet) and 16 mg (2 / Subutex† 8 mg tablets). Twenty-seven subjects successfully completed both Subutex† treatment periods. Study 3 procedures for each dosing period were the same as in Studies 1 and 2, except that the dose of naltrexone administered was 50 mg, the first dose in the morning of Day 0, a second dose in the morning of Day 1 and a third dose in the morning of Day 2. Thirty-six subjects successfully completed both Suboxone† treatment periods. As Study 1 was performed first, the dose of naltrexone was set conservatively at 100 mg, with an increase allowed to 150 mg if clinically necessary. For Study 3, the naltrexone dose was reduced to 50 mg, based on the tolerability of the 8 mg buprenorphine dose in Study 1. In all three studies assessments of tablet disintegration were made at 2-min intervals until tablet disintegration, the actual time of which was noted by the investigator. Nineteen 5 ml blood samples (20 /7 ml samples in Study 3) were withdrawn through an indwelling catheter, or by separate venepuncture, pre-dose and at frequent intervals up to 72 h post-dose into polypropylene lithium heparin tubes. The samples were centrifuged within 30 min of collection at 1500 /g for 10 min at 4 8C and the separated plasma stored at /70 8C until analysis. 2.3.2. Bioanalytical method A liquid chromatographic tandem mass spectrometric (LC /MS/MS) assay was developed and validated for the measurement of buprenorphine in human plasma. The method involves initial diethyl ether extraction using deuterated buprenorphine as an internal standard (concentration /6.25 ng/ml), followed by separation on a Hypersil BDS C18 (100 /2.1 mm; 3 mm) column with 0.01 M ammonium acetate (pH 4): acetonitrile (60:40 v/ v) as mobile phase at a flow rate of 0.3 ml/min. The MS/ MS conditions included a capillary voltage of 3.15 V, a cone voltage of 50 V for both buprenorphine and internal standard and a collision energy of 60 eV for both buprenorphine and internal standard. The parent
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to daughter ion transitions were 468.3 /55.0 a.m.u. for buprenorphine and 472.3 /59.0 a.m.u. for the internal standard. The lower limit of quantification (LLOQ) for buprenorphine was established at 0.05 ng/ml and the assay was linear up to 10.07 ng/ml. Quality control sample concentrations were 0.05, 1.71, 5.04 and 9.82 ng/ ml in Study 1, 0.06, 1.71, 5.10 and 10.01 ng/ml in Study 2 and 0.12, 1.70, 4.82 and 8.77 ng/ml in Study 3. Over all three studies, inter-assay precision ranged from 3.7 to 26.4% and inter-assay bias from /6.0 to 6.9%. For precision, the upper value of 26.4% given is from Study 1, where outlier exclusion criteria were not used to calculate the final assay statistics, a procedure which was applied to these data in Studies 2 and 3. At the LLOQ, the precision of the quality control samples ranged from 15.3 to 26.4% and the bias from /3.8 to 5.5%. There were no significant interfering peaks at the retention times of buprenorphine or internal standard in blank human plasma, or when norbuprenorphine, the major metabolite of buprenorphine, or naltrexone were added. Representative chromatograms are shown in Fig. 1. 2.4. Pharmacokinetic and statistical analysis Pharmacokinetic analysis by standard model-independent methods was performed using WinNonlinTM Professional Version 3.2. The following buprenorphine pharmacokinetic parameters were determined using the actual blood sampling times following drug administration: maximum observed plasma concentration (Cmax) and the corresponding time of the observed Cmax (tmax) were obtained from the actual observations. AUCt was calculated using linear trapezoids from time zero to Cmax and log-linear trapezoids (assuming an exponential decay) from Cmax to the last quantifiable plasma concentration (Ct). The apparent plasma elimination rate constant, lz, was determined by linear regression of the logarithm of plasma concentration on time over the terminal phase using at least three timepoints. AUC was calculated as AUCt/Ct/lz and the terminal half-life (t1/2z) was derived from ln(2)/lz. Descriptive statistics were used to summarise the individual pharmacokinetic parameters for each dose level and formulation. The bioequivalence of Suboxone† B to Suboxone† A was determined by analyses of variance (ANOVA) of the log transformed Cmax and AUC. The statistical model included factors accounting for variation due to treatment sequence, subject nested within sequence, period and treatment. The sequence effect was tested against the subject within sequence mean square; all other effects were tested against the residual error (error mean square). Statistical significance was taken at the 5% level. The difference between the mean log-transformed endpoints was estimated, together with the 90% confidence intervals (CI) for
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Fig. 1. Representative chromatogram of extracted blank plasma with internal standard (A) and extracted subject sample with internal standard (B). Y -axis (cycles per second) normalised to 100% of highest peak.
these differences. The results were back transformed to give point estimates of the least square mean ratios (Suboxone† B/Suboxone† A) and associated 90% CI
for each pharmacokinetic parameter. tmax was analysed using the non-parametric Wilcoxon’s matched pairs test. In Study 3, the Investigator’s assessment of the extent of
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tablet disintegration at each 2-min timepoint and the time of disintegration were compared between formulations using the Wilcoxon Rank Sum Test. All statistical analyses were performed in SAS† System version 8. Mean and 95% CI for the parameters normalised to the 2 mg dose were plotted against dose in Studies 1 and 2 for an assessment of dose-proportionality.
3. Results 3.1. Pharmacokinetics (Mean9/S.D.) plasma linear concentration-time profiles are given in Figs. 2 /4 for Studies 1 /3, respectively. The pharmacokinetic parameters are summarised in Table 1. In each of the studies there were instances where the extrapolated area of the AUC was greater than 30% and in these cases the AUC and t1/2z values were excluded from the summary statistics. In addition, although some half-life values were not estimated over a time interval of at least twice the resultant half-life, they were none the less included in the summary statistics. In the majority of subjects, plasma buprenorphine concentrations were quantifiable at 0.25 h post-dose and increased reasonably rapidly, with Cmax values occurring from approximately 0.5 to 3 h post-dose, at all dose levels and formulations studied. Concentrations declined bi-exponentially and the terminal decline in plasma buprenorphine concentrations in many individuals was not smooth, with fluctuations clearly visible, especially a secondary peak around 10 h post-dose, an example of which is shown in Fig. 5 for a typical subject.
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Following administration of Subutex† 2 mg, plasma buprenorphine concentrations fell below the LLOQ of the assay at timepoints as early as 12 h post-dose, with considerable inter-subject variability between 12 and 48 h post-dose. It is likely that the analytical sensitivity was insufficient to truly estimate the AUCt at the 2 mg dose level. In addition, reliable estimation of lz and hence AUC and t1/2z was possible in only a few subjects at the 2 mg dose level. At 8, 12 and 16 mg, the majority of subjects had quantifiable buprenorphine concentrations up to 72 h post-dose and determination of lz was possible in the majority of subjects at the 8 mg dose level and in all subjects at the 12 and 16 mg dose levels. The estimated apparent terminal half-life was approximately 26 h (range 9 /69 h). Mean dose-normalised Cmax and AUC values appeared not to change with dose (Fig. 6), indicating approximate dose-proportional increases of these parameters across the 8/16 mg doses in Studies 1 and 2. Data from Study 3 were excluded from these comparisons due to the different buprenorphine formulations used. As the AUC values were not adequately estimated at 2 mg, these data were also excluded from the comparison plots. For the Suboxone† study (Study 3), the least squares mean ratios (90% CI) were 1.00 (0.92 /1.10) for Cmax, 0.99 (0.95 /1.04) for AUCt and 1.00 (0.95 /1.06) for AUC. The 90% CIs were well within the 0.8 and 1.25 limits required by the regulatory authorities for acceptance of bioequivalence. No statistically significant difference (P /0.49) in tmax was identified between the two treatments, nor were there any statistically significant treatment, period or sequence effects.
Fig. 2. Mean9/S.D. plasma buprenorphine concentrations following single administration of 2 mg Subutex† (1 /2 mg sublingual tablet; m) and 8 mg Subutex† (1 /8 mg sublingual tablet; j) (N /27).
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Fig. 3. Mean9/S.D. plasma buprenorphine concentrations following single administration of 12 mg Subutex† (2 /2 and 1 /8 mg sublingual tablets; m) and 16 mg Subutex† (2 /8 mg sublingual tablets; j) (N /27).
3.2. Tablet disintegration
3.3. Safety
Median (range) in vivo times of sublingual disintegration were 6 (2 /17) and 12 (6 /32) min for Subutex† at 2 and 8 mg, respectively, and 9 (3 /20) and 8 (3 /24) min for Subutex† at 12 and 16 mg, respectively. Similar values were obtained for Suboxone† A and B formulations, with median times of disintegration of 11.5 (5 /28) and 8 (3 /26) min, respectively. In each study these times were not statistically significantly different.
In Study 1, eight subjects were withdrawn from the study, four of which were due to adverse events, and four due to personal reasons. Of the adverse event related withdrawals, only one was considered possibly related to buprenorphine administration and one to naltrexone administration (nausea, vomiting and abdominal pain). In Study 2, six subjects were withdrawn from the study, one due to an adverse event (headache)
Fig. 4. Mean9/S.D. plasma buprenorphine concentrations following single administration of two formulations of Suboxone† (formulation A /m; formulation B /j) sublingual tablets (N /36).
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Table 1 Summary (mean9/S.D.) buprenorphine pharmacokinetic parameters following single dose administration of Subutex† and Suboxone† sublingual tablets Parameter
Study 1 (N /27) †
Cmax (ng/ml) tmax (h)a AUCt (ng h/ml) AUC (ng h/ml) t1/2z (h)
Study 2 (N /27) †
†
Study 3 (N /36) †
Subutex , 2 mg
Subutex , 8 mg
Subutex , 12 mg
Subutex , 16 mg
Suboxone† A, 8 mg
Suboxone† B, 8 mg
1.69/0.5 1.50 (1.00 /3.00) 9.059/2.67 ND ND
4.09/1.2 1.02 (0.75 /2.00) 26.899/7.16 31.819/8.20b 30.029/11.99b
5.49/1.8 1.00 (0.50 /2.00) 36.529/9.40 41.619/11.98c 25.639/7.05c
6.49/2.6 0.75 (0.50 /2.00) 46.199/14.51 52.009/17.06 23.899/6.55
3.29/1.3 1.00 (0.50 /2.00) 21.729/8.14 24.559/9.29d 25.519/8.40d
3.29/1.2 1.00 (0.50 /2.02) 21.309/6.88 24.609/7.99 26.799/8.17
ND, not determined. a Median (range). b N /23. c N /26. d N /35.
that started approximately 24 h after a single naltrexone 100 mg dose, two due to protocol deviations and three due to personal reasons. In Study 3, no subjects were withdrawn from the study. Anticipated adverse events of headache, fatigue, nausea, dizziness and vomiting did occur in all three studies, but were of mild or moderate intensity and did not require additional medication, except for some incidences of headache. Administration of prophylactic naltrexone can be considered to have markedly attenuated these adverse events, with three doses of 50 mg administered on three occasions sufficient to attenuate the effects of a single 8 mg buprenorphine dose. At the 16 mg dose level, 100 mg naltrexone was sufficient in the majority of subjects, but on some occasions the dose had to be increased to 150 mg. Naltrexone administration itself did result in some adverse events of fatigue, nausea and headache, but
these were generally of mild or moderate severity. There were no apparent differences in the tolerability of naltrexone at 50, 100 or 150 mg.
4. Discussion The aim of these studies was to provide comprehensive pharmacokinetic data of sublingual buprenorphine at doses of 2 /16 mg in a large number of healthy volunteers, together with assessments of tablet disintegration times. The administration of concomitant naltrexone was extremely effective in allowing buprenorphine up to 16 mg, a dose that is 40-fold higher than the highest analgesic sublingual dose, to be administered to healthy subjects without them suffering from more than moderate buprenorphine-related ad-
Fig. 5. Plasma buprenorphine concentrations following single administration of Subutex† 16 mg in a typical subject.
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Fig. 6. Mean9/95% CI plots of dose-normalised Cmax and AUC values against dose for Study 1 (8 mg) and Study 2 (12 and 16 mg).
verse effects. This indicates the utility of the naltrexone block in performing pharmacokinetic studies with opioids in healthy volunteers. Time to peak plasma buprenorphine concentrations ranged from approximately 0.5 to 3 h, which is in good agreement with the range 1 /3 h observed in earlier studies in volunteers where buprenorphine was administered in the form of a solution or as sublingual tablets (Bullingham et al., 1982; Mendelson et al., 1997; Schuh and Johanson, 1999). Absolute bioavailability via the sublingual route ranges from 30 to 55% (Bullingham et al., 1982; Kuhlman et al., 1996; Mendelson et al., 1997), depending on the formulation (oral solution or tablet). The percentage absorbed from a solution was not significantly different whether the solution was in contact with the buccal mucosa for either 2.5 or 10 min (Weinberg et al., 1988), or for either 3 or 5 min (Mendelson et al., 1997), although direct comparisons may not be applicable as buffered aqueous solutions were used by Weinberg et al. (1988) and 30% ethanolic solutions by Mendelson et al. (1997). Therefore, when in solution, contact of buprenorphine with the buccal
mucosa is only required for a few minutes to allow maximum absorption. This would indicate that with tablet formulations, once dissolution is complete, the fraction absorbed into the buccal mucosa would be complete soon after. We have shown apparent doseproportional increases in both Cmax and AUC over the dose range 8/16 mg within Studies 1 and 2, which indicates no limits on sublingual absorption in this dose range. This has also been observed in an earlier study, where plasma concentrations were linearly related to dose in four subjects who received single doses of sublingual buprenorphine from 1 to 32 mg (Walsh et al., 1994). Early studies of buprenorphine pharmacokinetics may have had limitations due to insufficient assay sensitivity due to the type of detection employed or selectivity when using radioimmunoassay (Everhart et al., 1997). The bioanalytical method employed in the studies reported here was sufficiently sensitive to quantify plasma buprenorphine concentrations after a single 2 mg sublingual dose and allow adequate characterisation of the terminal phase at the 8, 12 and 16 mg doses. The fluctuations observed in the plasma profiles of many individuals are likely to be the result of enterohepatic recirculation, although these fluctuations were not observed in the mean profiles. Buprenorphine and/ or its glucuronide conjugate present in bile are released into the small intestine on contraction of the gall bladder in response to the meal given to each volunteer at 10 h post-dose and buprenorphine is subsequently reabsorbed. This is in agreement with Cone et al. (1984), who showed that the greatest percentage of a sublingual dose is recovered in faeces, indicating biliary excretion and possible enterohepatic recirculation. Buprenorphine is metabolised by 14-N -dealkylation to norbuprenorphine by cytochrome P450 3A4 (Iribarne et al., 1997; Kobayashi et al., 1998), with both parent and metabolite conjugated to glucuronide (Cone et al., 1984; Hand et al., 1986). The molecular weight of buprenorphine free base (467.6) is increased by 176 when conjugated to glucuronide, which is above the threshold for active biliary secretion in man (Dobrinska, 1989). In addition to this, the glucuronide conjugate is more polar than the free base, another property for likely biliary excretion. In some cases the discontinuities in the log-linear decline of plasma buprenorphine concentration profiles did complicate estimation of the terminal half-life, but in general the half-life of buprenorphine was well estimated, with mean values ranging from approximately 23 to 30 h. This compares well with the mean 28 h value reported by Kuhlman et al. (1996) following sublingual administration of 4 mg buprenorphine (as a 30% alcoholic solution held under the tongue for 10 min). This is much longer than the approximate 3 h half-life value (range 2 /8 h) following intravenous administration of 1.2 mg buprenorphine (Kuhlman et al., 1996).
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These authors proposed that the longer half-life following the sublingual route was due to slow distribution from the buccal mucosa, acting as a depot of the drug, into the systemic circulation. However, it is possible that the half-life reported after intravenous administration may have been estimated during buprenorphine distribution and the true value was not estimable due to limitations of assay sensitivity. In the series of studies reported here, the bi-exponential elimination of buprenorphine has been clearly demonstrated by combination of high doses and a more sensitive assay. There was moderate inter-individual variation in the pharmacokinetic parameters following administration of Subutex† tablets. Coefficient of variation values for Cmax and AUC ranged from 26 to 30% at 2 and 8 mg and from 26 to 41% at 12 and 16 mg. There was no apparent correlation between the time of tablet disintegration and tmax or Cmax. This implies that the processes of tablet disintegration and absorption of buprenorphine into the buccal mucosa were rapid in comparison to distribution out of the buccal mucosa into the systemic circulation.
Acknowledgements The studies included in this manuscript were conducted on behalf of Reckitt Benckiser Healthcare (UK) Limited, Dansom Lane, Hull HU8 7DS, UK. The authors wish to thank all the clinical staff at Medeval Limited involved in the conduct of these three studies and numerous personnel at Reckitt Benckiser Healthcare Limited for their comments on the manuscript.
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