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Pharmacokinetic comparison of the buprenorphine sublingual liquid and tablet
Drug and Alcohol Dependence 56 (1999) 55 – 60
Pharmacokinetic comparison of the buprenorphine sublingual liquid and tablet Kory J. Schuh *, Chris-Ellyn Johanson Wayne State Uni6ersity School of Medicine, Department of Psychiatry and Beha6ioral Neurosciences, Research Di6ision on Substance Abuse, 2761 E. Jefferson, Detroit, MI 48207, USA Received 2 November 1998; received in revised form 22 January 1999; accepted 24 January 1999
Abstract Buprenorphine is a m opioid partial agonist being developed as a treatment for opioid dependence. Buprenorphine, usually administered as a sublingual liquid, is now being developed as a sublingual tablet for clinical use. The present study compared participants’ plasma concentrations after daily maintenance on three buprenorphine liquid doses (2, 4 and 8 mg) and one tablet dose (8 mg). Fourteen opioid-dependent individuals (11 males, three females) participated. Plasma samples were collected over a 24-h period after at least 7 days of maintenance on each dose. Results showed that the liquid doses produced dose-related increases in plasma concentrations. The 8-mg tablet produced mean plasma concentrations significantly lower than those of the 8-mg liquid, although there was substantial individual variability. Thus, the buprenorphine tablet dose might have to be adjusted to produce plasma concentrations equivalent to those of the liquid. © 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Buprenorphine; Tablet; Plasma; Pharmacokinetics; Pharmacotherapy
1. Introduction Buprenorphine is a partial m opioid agonist marketed as an analgesic and under development as a treatment for opioid dependence. Both as an analgesic and as an opioid maintenance treatment, buprenorphine appears to be safe and effective. Due to its partial agonist profile, buprenorphine produces limited respiratory depression even after administration of high doses (Lewis, 1985; Walsh et al., 1994, 1995). A relatively mild withdrawal syndrome has been reported following discontinuation of chronic administration (Jasinski et al., 1978; Mello and Mendelson, 1980; Kosten et al., 1991), most likely due to its high affinity (Hambrook and Rance, 1976; Dum and Herz, 1981). Chronically administered buprenorphine attenuates the effects of subsequently administered opioid challenges (Jasinski et al., 1978; Bickel et al., 1988; Rosen et al., 1994; Schuh et al., 1995) and reduces heroin self-administration (Mello and Mendelson, 1980; Mello et al., 1982). In * Corresponding author. Tel.: +1-313-993-1378; fax: + 1-313-9931372. E-mail address: [email protected] (K.J. Schuh)
clinical trials, buprenorphine maintenance can be as effective as methadone in reducing illicit opioid use (Johnson et al., 1992; Strain et al., 1994). Because buprenorphine has a long duration of action (Hambrook and Rance, 1976), it has been shown to retain its efficacy using alternate-day dosing schedules when the daily dose or double the daily dose is alternated with placebo administrations (Fudala et al., 1990; Amass et al., 1994; Johnson et al., 1995). Buprenorphine has generally been administered as a sublingual liquid which the patient holds under his/her tongue for 5 min. Mendelson et al. (1997) showed bioavailability for the buprenorphine liquid at approximately 30%, and equivalent results from sublingual exposure times of 3 or 5 min. Kuhlman et al. (1996) showed bioavailability of a 4-mg liquid by the sublingual and buccal routes to be 51.4 and 27.8%, respectively. Walsh et al. (1994) measured plasma concentrations up to 96 h after sublingual administration of 2, 4, 8, 16 and 32 mg buprenorphine. Results showed proportionate increases in plasma concentration as a function of dose indicating no apparent limit on the sublingual absorption. Plasma concentrations peaked 60 min after administration of 2 and 4 mg, and 30 min after 8, 16 and 32 mg.
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When used clinically, it is expected that buprenorphine will be available as a sublingual tablet instead of a liquid. A tablet will be used because of the difficulties in packaging an alcoholic solution for commercial production, in addition to stability problems with the solution. Recent studies have compared the plasma concentrations produced by these two formulations. Mendelson et al. (1996) compared an 8-mg sublingual tablet with an 8-mg solution. Results indicate that area-under-the-curve (AUC) and peak concentration were less after the tablet than after the solution. The tablet yielded about 50 – 60% of the buprenorphine compared with the 8-mg solution. The present study was done to compare the plasma concentrations produced by three doses of the liquid buprenorphine (2, 4 and 8 mg) with the 8-mg tablet when stable plasma concentrations had been achieved after a minimum of seven daily administrations.
2. Method
2.1. Participants Fourteen volunteers (11 males and three females) participated in the study. Ages ranged from 20–50 (mean =40). Years of opioid abuse ranged from 3 to 30 (mean = 16). Participants were recruited by word-ofmouth, newspaper advertisements, and circulation of flyers. Participants were opioid dependent confirmed by self-report, opioid-positive urine samples, and the Structured Clinical Interview for DSM (SCID) IV. Participants underwent routine medical screening, which included physical examination, EKG, hematology, and urinalysis testing, and were free of significant medical problems and major mental illness other than their drug abuse. The study was approved by the Wayne State University Institutional Review Board, and participants gave their written informed consent before beginning the study. It was explained to the subjects that this study involved comparing the plasma concentrations produced by three buprenorphine liquid doses and one tablet dose. Participants were offered free HIV testing and education, weekly counseling sessions, and a referral for further treatment when their participation in this study ended. Participants were paid for their time.
2.2. Drugs Buprenorphine HCl (NIH/NIDA/MDD, Chemistry and Pharmaceutics Branch, Rockville, MD) was provided packaged into 1-ml plastic containers in concentrations of 2, 4 and 8 mg/ml, and as an 8-mg sublingual tablet. Uncoated tablets for sublingual administration (Batch 06001/069) contained 8 mg of buprenorphine
base per tablet (as the HCl salt). Each tablet also contained lactose, mannitol, corn starch, povidone K30, citric acid, sodium citrate, and magnesium stearate. For detoxification, 0 and 1 mg/ml solutions were prepared from buprenorphine HCl powder using a 30% ETOH vehicle. These doses were placed in 1.0-ml syringes. Each dose was placed under the tongue and held in place for at least 5 min. Tablet doses were generally kept under the tongue until they had completely dissolved which could sometimes take longer than 5 min. Buprenorphine administrations were observed and timed by a staff member.
2.3. Procedures All participants were maintained on daily buprenorphine doses using ascending doses of 2, 4, 8 mg liquid, and 8 mg tablet before being detoxified. They participated in four test sessions, one at the end of each of these dosing phases. Participants were maintained on each dose for at least 7 days before each of the test sessions. In the event of a missed dose, dosing was extended to ensure that the participant received at least five consecutive daily doses before each test session. After the last 8-mg tablet dose, participants were detoxified by receiving 4, 2, 1 and 0 mg buprenorphine for at least 1 week at each dose. Urine samples were collected three times per week and analyzed using an Abbott ADx system (model c 1689-96) to determine the participants’ use of opiates, methadone, cocaine, benzodiazepines, and barbiturates. During weeks when the participants had no test sessions, urine samples were collected and analyzed on Monday, Wednesday and Friday. During weeks when the participants had a test session, urine samples were analyzed during the first 2 days of the session, and 1 other day that week. If a participant’s urine indicated use of any drug (including methadone) other than opiates, that session was rescheduled. Test sessions took place over a 3-day period. On the first day, a urine and a plasma sample were collected 15 min before administering the participant’s daily buprenorphine dose (24 h before the next day’s dose). During the second day, a urine sample was first collected. The participant then blew into an alcohol breathalyzer to determine recent alcohol consumption. If the participant was sober (breath alcohol level5 0.003%) and the urine drug test indicated no recent drug use other than opiates, the session was continued. A plasma sample was collected 15 min before the buprenorphine dose was administered as well as 30, 60, 120, 180, 240 and 360 min after the dose. On the third day, a plasma sample was collected 15 min before the buprenorphine dose (approximately 24 h after the previous day’s dose).
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Blood samples were collected into 10-ml Vacutainers containing the anticoagulant heparin (green top tubes) using ‘butterfly’ or straight needles. The tubes were inverted several times and then centrifuged for 15 min. The plasma was siphoned using plastic, disposable pipettes, placed into plastic tubes, and kept frozen at − 20°C. Plasma concentrations were determined by the Center for Human Toxicology at the University of Utah using liquid chromatography/tandem mass spectrometry. Sensitivity of this method is demonstrated by a 0.1-ng/ml lower limit of quantitation. Results of acceptable quality control samples were accurate within 14% of their target concentrations, and precise percent coefficients of variance did not exceed 14%.
2.4. Data analysis Buprenorphine plasma concentration raw data were analyzed using a two-way repeated-measures analysis of variance (ANOVA) with buprenorphine dosing phase and time as factors. Post-hoc tests were conducted to compare dosing phase within each time point using two-tailed matched-pairs t-tests. Raw data were also used to obtain AUCs for each buprenorphine dosing phase. The AUCs were calculated based upon the plasma concentrations produced by one buprenorphine dose. Therefore, the plasma concentrations from the − 24-h and −15-min timepoints were not included. The pre-existing trough levels were not subtracted. The last timepoint was not extrapolated to infinity. The concentrations from + 30 min to +24 h were weighted based upon the time intervals between data points. The weight of each timepoint was one-half the distance between it and the previous point plus one-half the distance between it and the next point. The first and last timepoints were weighted only with one-half the distance between them and the contiguous points. The plasma samples collected during the first and third day and the first sample of the second day were averaged to obtain the trough concentrations at each dosing phase. Peak concentrations, AUCs, and trough concentrations were analyzed using one-way repeated-measures ANOVAs. To determine if participants who had high (or low) plasma concentrations during a particular dosing phase also had high (or low) concentrations during the other dosing phases, concentrations produced by the three ascending liquid doses and the tablet dose were rank ordered from 1 (participant with the highest concentration at each dosing phase) to 14 (participant with the lowest concentration at each dosing phase). The rank orders were analyzed using a two-tailed Spearman correlation coefficient. Lastly, to determine if plasma concentrations produced by the dosing phases could predict the number of opioid-positive urine samples (e.g. did participants with the highest buprenorphine plasma concentrations have the fewest
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opioid-positive urine samples), plasma concentrations averaged over the four dosing phases were rank ordered from 1 (participant with the highest average concentration) to 14 (participant with the lowest average concentration) and were correlated with rank ordered % opioid positive urine samples. Again, a two-tailed Spearman Correlation Coefficient was used.
3. Results The two-way ANOVA indicated significant dosing phase effects [F(3,39)= 32.02; PB 0.001)], time effects [F(8,104)= 56.44; P B 0.001)], and a dosing phase× time interaction [F(24,312)= 8.19; P B 0.001)]. Visual inspection of the data indicates that the 8-mg liquid produced the highest plasma concentrations (Fig. 1). For all doses, average concentrations peaked 120 min after buprenorphine administration at which time the average plasma concentrations were 1.99, 2.37, 5.22 and 2.87 ng/ml for the 2-, 4-, 8-mg liquid, and the 8-mg tablet doses, respectively. Therefore, at the 120 min time point the plasma concentrations produced by the 8-mg tablet were 55% of those produced by the 8-mg liquid. Post-hoc tests comparing the plasma concentrations produced by each dosing phase within each time point indicate that the 8-mg liquid dosing phase produced plasma concentrations significantly higher than the other dosing phases at nearly all of the time points. Specifically comparing the 8-mg liquid and tablet, the liquid produced plasma concentrations significantly greater than the tablet at all time points except 24 h and 15 min before the dose, and 24 h after the dose. The 8-mg tablet produced concentrations greater than the 2-mg dose at all time points and greater than the 4-mg dose at 24 h and 15 min before the dose, and at 360 min and 24 h after the dose. The 4-mg dose produced
Fig. 1. Mean buprenorphine plasma concentrations ( 9standard errors) at each of the nine time points for each of the four dosing phases.
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Fig. 2. Mean peak plasma concentrations, mean AUC, and mean trough concentrations for each of the four dosing phases.
concentrations greater than the 2-mg dose at 24 h before the dose and 120, 240 and 360 min, and 24 h after the dose. Average peak concentrations were 2.04, 2.74, 5.83 and 3.02 ng/ml for the 2-, 4-, 8-mg liquid, and the 8-mg tablet doses, respectively (Fig. 2). A significant dosing phase effect was detected with a one-way ANOVA [F(3,39)= 30.71; PB 0.001]. Matched-pairs t-tests of peak concentrations indicated that all doses were significantly different from the others excepting the 4-mg liquid and 8-mg tablet doses. Average peak concentrations of the 8-mg tablet were 52% of the 8-mg liquid. For the areas-under-the-curve, the one-way ANOVA indicated a significant dosing phase effect [F(3,39)= 24.08; PB 0.001]. Matched-pairs t-tests showed that each dosing phase produced plasma concentrations significantly different from all others (Fig. 2). Mean AUC were 0.70, 0.87, 1.93 and 1.24 ng/ml for the 2-, 4-, 8-mg liquid, and 8-mg tablet dosing phases, respectively. Thus, the mean AUC for the tablet was approximately 64% of the mean liquid AUC.
Trough concentrations were calculated by averaging the concentrations from plasma samples collected approximately 24 h before, 15 min before, and 24 h after the test dose (i.e. plasma samples were collected just prior to the daily dose for 3 consecutive days). These three samples were each collected approximately 24 h after each previous dose. Mean trough concentrations were 0.25, 0.36, 0.77 and 0.64 ng/ml for the 2-, 4-, 8-mg liquid, and 8-mg tablet dosing phases, respectively (Fig. 2). Repeated measures ANOVA indicated a significant dosing phase effect [F(3,39)= 14.53; PB0.001]. Matched-pairs t-tests revealed that each dosing phase produced trough concentrations significantly different from the others, excepting the 8-mg liquid and tablet doses which did not significantly differ. The 8-mg tablet produced trough plasma concentrations that were 83% of those produced by the 8-mg liquid. The mean data obscures the substantial individual variability in the plasma concentrations obtained. As shown in Fig. 3, peak plasma concentrations after the 8-mg liquid dose ranged from 3.28 to 13.39 ng/ml. Peak plasma concentrations after the 8-mg tablet ranged from 1.86 to 5.00 ng/ml. When concentrations were rank ordered, significant correlations were found. The 2-mg dose versus the 4- and 8-mg liquid doses had Spearman r values of 0.81 and 0.85, respectively, with P valuesB 0.001. The 4-mg dose versus the 8-mg liquid dose had an r value of 0.80, with P= 0.001. These results indicate that subjects tended to have the same rank ordering of plasma concentrations (e.g. lower, intermediate, or higher concentrations) with each of the three liquid doses. In contrast, none of the correlations were significant when the three liquid doses were each compared with the 8-mg tablet dose indicating that the plasma concentrations produced by the liquid are not predictive of those produced by the tablet. Urine samples were generally collected three times per week and tested to determine illicit drug use. Opioids were present in 70.4% of all urine samples. For individual subjects, percent of urine samples containing opioids ranged from 8 to 100%. To determine if illicit opioid use could be predicted based upon the plasma buprenorphine concentrations, concentrations were rank ordered and were correlated with rank ordered % opioid positive urine samples. The Spearman r value was 0.29 (P= 0.31) indicating no significant correlation between the two variables.
4. Discussion This study was conducted to compare the plasma concentrations produced by three buprenorphine sublingual liquid doses with those of a buprenorphine sublingual tablet dose. Results indicate that the 8-mg buprenorphine liquid produced plasma concentrations
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significantly higher than any of the other dosages, both lower liquid doses and the 8-mg tablet. Mean concentration at the 120-min time point, mean peak concentration, and AUC of the 8-mg tablet were 55, 52 and 63%, respectively, of the 8-mg liquid concentrations. These data suggest that the buprenorphine tablet dose might have to be adjusted to produce plasma concentrations equivalent to those of the liquid. Similar results have been found in other studies. Mendelson et al. (1996) found that the buprenorphine tablet yielded about 50–60% of the 8-mg solution yield. However, in the present study the trough concentrations of the 8-mg tablet and 8-mg liquid doses were not significantly different. Trough concentrations of the 8-mg tablet were 83% of the 8-mg liquid dose. There were large individual differences in the plasma concentrations produced by the buprenorphine doses.
Fig. 3. Individual data from each of the 14 participants showing the buprenorphine plasma concentrations produced by each of the four dosing phases. In order to prevent flattening of the time point curves, the Y-axis values are not equivalent.
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These differences do not appear to be related to body weight or gender. The highest buprenorphine concentrations were produced by the 8-mg liquid in subjects 235 and 534. These subjects were males of nearly average weight. In comparison, subject 642 was a very heavy male and subject 981 was a light female; however, these subjects had comparable plasma concentrations that were below the group average. Of the three females, two had plasma concentrations below the group average, while one had concentrations above the average. It is possible these individual differences could be due to the pH in the participants’ mouths, producing more absorption in some participants. However, this cannot be verified because pH was not measured. It is interesting to note that large individual differences in buprenorphine plasma concentrations have also been observed in other studies (Kuhlman et al., 1996). It is also noteworthy that there were two subjects (188 and 772) for whom the 8-mg liquid and the 8-mg tablet produced nearly equivalent plasma concentrations. Furthermore, there were significant correlations between the plasma concentrations produced by the three liquid doses. For example, participants who tended to have the highest (or lowest) concentrations after one dose of the liquid also tended to have the highest (or lowest) concentrations after the other two liquid doses. However, the concentrations produced by the liquid doses were not predictive of those produced by the 8-mg tablet dose. These data suggest stable individual differences with the liquid doses but an influence of environmental factors with the tablet dose. The data from the present study are relevant for determining the optimal clinical dose of buprenorphine. Although there have been numerous attempts to determine optimal dose from clinical trials using the liquid dose, these data might not be helpful if there is now a switch from liquid doses to tablet doses. Given the lack of within-subject correlation between the liquid and tablet plasma concentrations, it will be difficult to ascertain the optimal tablet dose from the available data with the liquid form. However, it is interesting to note that the 8-mg liquid and tablet doses did not produce significantly different trough concentrations. Six hours after administration, the plasma concentrations produced by the 8-mg liquid were significantly higher than those produced by the tablet. However, by 24 h post-administration the concentrations did not differ. The present study did not ascertain the time at which the concentrations were no longer different, but if the trough concentrations are more important than peak concentrations for clinical efficacy, the 8-mg tablet might be as efficacious as the 8-mg liquid dose. It is interesting to note that in France, where the buprenorphine tablet is used clinically, the mean dose is reported to be 11 mg/day. The most commonly prescribed dosage is 6–8 mg. Nearly 80% of patients receive 4–16
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mg/day which was mostly taken once daily (56%), although this dose was split into two or more parts in 43% of cases (Bouchez and Vignau, 1998). In conclusion, this study indicates that the 8-mg buprenorphine tablet does not produce plasma concentrations equal to the 8-mg and is nearly 50% lower. If the 8-mg tablet is not altered, the different plasma concentrations produced by these two dosing forms must be considered when using the buprenorphine tablet in clinical settings.
Acknowledgements The authors thank Pamela Gary, L.P.N, Ja’Near Mathis, Jill Kuennen, M.A., Loraine DiCerbo, B.A., Debra Kish, B.A., and Kirsten Hines, B.S. for technical services, Mark Greenwald, Ph.D. for assistance with preparing the manuscript, John Hopper, M.D. and Rickie Hardaway, M.D. for medical supervision, Nora Chiang, Ph.D. for assistance with the study design, Reckitt & Colman for supplying buprenorphine, David Moody, Ph.D. and The University of Utah Center for Human Toxicology where the plasma samples were analyzed, and James Woods, Ph.D., the principal investigator of NIH grant, DA00254 from the National Institute on Drug Abuse, that supported the study. This study was supported by a research grant (Joe Young, Sr.) from the state of Michigan.
References Amass, L., Bickel, W.K., Higgins, S.T., Badger, G., 1994. Alternateday dosing during buprenorphine treatment of opioid dependence. Life Sci. 17, 1215–1228. Bickel, W.K., Stitzer, M.L., Bigelow, G.E., Liebson, I.A., Jasinski, D.R., Johnson, R.E., 1988. Buprenorphine: dose-related blockade of opioid challenge effects in opioid dependent humans. J. Pharmacol. Exp. Ther. 247, 47–53. Bouchez, J., Vignau, J., 1998. The French experience—the pharmacist, general practitioner and patient perspective. Eur. Addict. Res. 4 (Suppl. 1), 19 –23. Dum, J.E., Herz, A., 1981. In vivo receptor binding of the opiate partial agonist, buprenorphine, correlated with its agonistic and antagonistic actions. Br. J. Pharmacol. 74, 627–633. Fudala, P.J., Jaffe, J.H., Dax, E.M., Johnson, R.E., 1990. Use of buprenorphine in the treatment of opioid addiction. II. Physiologic and behavioral effects of daily and alternate-day administration and abrupt withdrawal. Clin. Pharmacol. Ther. 47, 525 – 534.
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Hambrook, J.M., Rance, M.J., 1976. The interaction of buprenorphine with the opiate receptor: lipophilicity as a determining factor in drug-receptor kinetics. In: Kosterlitz, H.W. (Ed.), Opiates and Endogenous Opioid Peptides. Elsevier/North Holland, Amsterdam, pp. 295 – 301. Jasinski, D.R., Pevnick, J.S., Griffith, J.D., 1978. Human pharmacology and abuse potential of the analgesic buprenorphine. Arch. Gen. Psychiatry 35, 501 – 506. Johnson, R.E., Jaffe, J.H., Fudala, P.J., 1992. A controlled trial of buprenorphine treatment for opioid dependence. J. Am. Med. Assoc. 267, 2750 – 2755. Johnson, R.E., Eissenberg, T., Stitzer, M.L., Strain, E.C., Liebson, I.A., Bigelow, G.E., 1995. Buprenorphine treatment of opioid dependence: clinical trial of daily versus alternate-day dosing. Drug Alcohol Depend. 40, 27 – 35. Kosten, T.R., Morgan, C., Kleber, H.D., 1991. Treatment of heroin addicts using buprenorphine. Am. J. Drug Alcohol Abuse 17, 119 – 128. Kuhlman, J.J., Lalani, S., Magluilo, J., Levine, B., Darwin, W.D., 1996. Human pharmacokinetics of intravenous, sublingual, and buccal buprenorphine. J. Anal. Toxicol. 20, 369 – 378. Lewis, J.W., 1985. Buprenorphine. Drug Alcohol Depend. 14, 363– 372. Mello, N.K., Mendelson, J.H., 1980. Buprenorphine suppresses heroin use by heroin addicts. Science 207, 657 – 659. Mello, N.K., Mendelson, J.H., Kuehnle, J.C., 1982. Buprenorphine effects on human heroin self-administration: an operant analysis. J. Pharmacol. Exp. Ther. 223, 30 – 39. Mendelson, J., Upton, R., Jones, R.T., 1996. Buprenorphine pharmacokinetics: bioavailability of an 8 mg sublingual tablet formulation. In: Harris, L.S. III (Ed.), Problems of Drug Dependence 1995: Proceedings of the 57th Annual Scientific Meeting, NIDA Research Monograph Series c 162. US Government Printing Office, Washington, DC, p. 112. Mendelson, J., Upton, R.A., Everhart, E.T., Jacob, P. III, Jones, R.T., 1997. Bioavailability of sublingual buprenorphine. J Clin. Pharm. 37, 31 – 37. Rosen, M.I., Wallace, E.A., McMahon, T.J., Pearsall, H.R., Woods, S.W., Price, L.H., Kosten, T.R., 1994. Buprenorphine: duration of blockade of effects of intramuscular hydromorphone. Drug Alcohol Depend. 35, 141 – 149. Schuh, K.J., Walsh, S.L., Stitzer, M.L., 1995. A comparison of buprenorphine’s and naltrexone’s opioid blockade abilities. In: Harris, L.S. (Ed.), Problems of Drug Dependence 1994: Proceedings of the 56th Annual Scientific Meeting, NIDA Research Monograph Series c153. US Government Printing Office, Washington, DC, p. 254. Strain, E.C., Stitzer, M.L., Liebson, I.A., Bigelow, G.E., 1994. Comparison of buprenorphine and methadone in the treatment of opioid dependence. Am. J. Psychiatry 151, 1025 – 1030. 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. Walsh, S.L., Preston, K.L., Bigelow, G.E., Stitzer, M.L., 1995. Acute administration of buprenorphine in humans: partial agonist and blockade effects. J. Pharmacol. Exp. Ther. 274, 361 – 372.
Pharmacokinetic comparison of the buprenorphine sublingual liquid and tablet Kory J. Schuh *, Chris-Ellyn Johanson Wayne State Uni6ersity School of Medicine, Department of Psychiatry and Beha6ioral Neurosciences, Research Di6ision on Substance Abuse, 2761 E. Jefferson, Detroit, MI 48207, USA Received 2 November 1998; received in revised form 22 January 1999; accepted 24 January 1999
Abstract Buprenorphine is a m opioid partial agonist being developed as a treatment for opioid dependence. Buprenorphine, usually administered as a sublingual liquid, is now being developed as a sublingual tablet for clinical use. The present study compared participants’ plasma concentrations after daily maintenance on three buprenorphine liquid doses (2, 4 and 8 mg) and one tablet dose (8 mg). Fourteen opioid-dependent individuals (11 males, three females) participated. Plasma samples were collected over a 24-h period after at least 7 days of maintenance on each dose. Results showed that the liquid doses produced dose-related increases in plasma concentrations. The 8-mg tablet produced mean plasma concentrations significantly lower than those of the 8-mg liquid, although there was substantial individual variability. Thus, the buprenorphine tablet dose might have to be adjusted to produce plasma concentrations equivalent to those of the liquid. © 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Buprenorphine; Tablet; Plasma; Pharmacokinetics; Pharmacotherapy
1. Introduction Buprenorphine is a partial m opioid agonist marketed as an analgesic and under development as a treatment for opioid dependence. Both as an analgesic and as an opioid maintenance treatment, buprenorphine appears to be safe and effective. Due to its partial agonist profile, buprenorphine produces limited respiratory depression even after administration of high doses (Lewis, 1985; Walsh et al., 1994, 1995). A relatively mild withdrawal syndrome has been reported following discontinuation of chronic administration (Jasinski et al., 1978; Mello and Mendelson, 1980; Kosten et al., 1991), most likely due to its high affinity (Hambrook and Rance, 1976; Dum and Herz, 1981). Chronically administered buprenorphine attenuates the effects of subsequently administered opioid challenges (Jasinski et al., 1978; Bickel et al., 1988; Rosen et al., 1994; Schuh et al., 1995) and reduces heroin self-administration (Mello and Mendelson, 1980; Mello et al., 1982). In * Corresponding author. Tel.: +1-313-993-1378; fax: + 1-313-9931372. E-mail address: [email protected] (K.J. Schuh)
clinical trials, buprenorphine maintenance can be as effective as methadone in reducing illicit opioid use (Johnson et al., 1992; Strain et al., 1994). Because buprenorphine has a long duration of action (Hambrook and Rance, 1976), it has been shown to retain its efficacy using alternate-day dosing schedules when the daily dose or double the daily dose is alternated with placebo administrations (Fudala et al., 1990; Amass et al., 1994; Johnson et al., 1995). Buprenorphine has generally been administered as a sublingual liquid which the patient holds under his/her tongue for 5 min. Mendelson et al. (1997) showed bioavailability for the buprenorphine liquid at approximately 30%, and equivalent results from sublingual exposure times of 3 or 5 min. Kuhlman et al. (1996) showed bioavailability of a 4-mg liquid by the sublingual and buccal routes to be 51.4 and 27.8%, respectively. Walsh et al. (1994) measured plasma concentrations up to 96 h after sublingual administration of 2, 4, 8, 16 and 32 mg buprenorphine. Results showed proportionate increases in plasma concentration as a function of dose indicating no apparent limit on the sublingual absorption. Plasma concentrations peaked 60 min after administration of 2 and 4 mg, and 30 min after 8, 16 and 32 mg.
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When used clinically, it is expected that buprenorphine will be available as a sublingual tablet instead of a liquid. A tablet will be used because of the difficulties in packaging an alcoholic solution for commercial production, in addition to stability problems with the solution. Recent studies have compared the plasma concentrations produced by these two formulations. Mendelson et al. (1996) compared an 8-mg sublingual tablet with an 8-mg solution. Results indicate that area-under-the-curve (AUC) and peak concentration were less after the tablet than after the solution. The tablet yielded about 50 – 60% of the buprenorphine compared with the 8-mg solution. The present study was done to compare the plasma concentrations produced by three doses of the liquid buprenorphine (2, 4 and 8 mg) with the 8-mg tablet when stable plasma concentrations had been achieved after a minimum of seven daily administrations.
2. Method
2.1. Participants Fourteen volunteers (11 males and three females) participated in the study. Ages ranged from 20–50 (mean =40). Years of opioid abuse ranged from 3 to 30 (mean = 16). Participants were recruited by word-ofmouth, newspaper advertisements, and circulation of flyers. Participants were opioid dependent confirmed by self-report, opioid-positive urine samples, and the Structured Clinical Interview for DSM (SCID) IV. Participants underwent routine medical screening, which included physical examination, EKG, hematology, and urinalysis testing, and were free of significant medical problems and major mental illness other than their drug abuse. The study was approved by the Wayne State University Institutional Review Board, and participants gave their written informed consent before beginning the study. It was explained to the subjects that this study involved comparing the plasma concentrations produced by three buprenorphine liquid doses and one tablet dose. Participants were offered free HIV testing and education, weekly counseling sessions, and a referral for further treatment when their participation in this study ended. Participants were paid for their time.
2.2. Drugs Buprenorphine HCl (NIH/NIDA/MDD, Chemistry and Pharmaceutics Branch, Rockville, MD) was provided packaged into 1-ml plastic containers in concentrations of 2, 4 and 8 mg/ml, and as an 8-mg sublingual tablet. Uncoated tablets for sublingual administration (Batch 06001/069) contained 8 mg of buprenorphine
base per tablet (as the HCl salt). Each tablet also contained lactose, mannitol, corn starch, povidone K30, citric acid, sodium citrate, and magnesium stearate. For detoxification, 0 and 1 mg/ml solutions were prepared from buprenorphine HCl powder using a 30% ETOH vehicle. These doses were placed in 1.0-ml syringes. Each dose was placed under the tongue and held in place for at least 5 min. Tablet doses were generally kept under the tongue until they had completely dissolved which could sometimes take longer than 5 min. Buprenorphine administrations were observed and timed by a staff member.
2.3. Procedures All participants were maintained on daily buprenorphine doses using ascending doses of 2, 4, 8 mg liquid, and 8 mg tablet before being detoxified. They participated in four test sessions, one at the end of each of these dosing phases. Participants were maintained on each dose for at least 7 days before each of the test sessions. In the event of a missed dose, dosing was extended to ensure that the participant received at least five consecutive daily doses before each test session. After the last 8-mg tablet dose, participants were detoxified by receiving 4, 2, 1 and 0 mg buprenorphine for at least 1 week at each dose. Urine samples were collected three times per week and analyzed using an Abbott ADx system (model c 1689-96) to determine the participants’ use of opiates, methadone, cocaine, benzodiazepines, and barbiturates. During weeks when the participants had no test sessions, urine samples were collected and analyzed on Monday, Wednesday and Friday. During weeks when the participants had a test session, urine samples were analyzed during the first 2 days of the session, and 1 other day that week. If a participant’s urine indicated use of any drug (including methadone) other than opiates, that session was rescheduled. Test sessions took place over a 3-day period. On the first day, a urine and a plasma sample were collected 15 min before administering the participant’s daily buprenorphine dose (24 h before the next day’s dose). During the second day, a urine sample was first collected. The participant then blew into an alcohol breathalyzer to determine recent alcohol consumption. If the participant was sober (breath alcohol level5 0.003%) and the urine drug test indicated no recent drug use other than opiates, the session was continued. A plasma sample was collected 15 min before the buprenorphine dose was administered as well as 30, 60, 120, 180, 240 and 360 min after the dose. On the third day, a plasma sample was collected 15 min before the buprenorphine dose (approximately 24 h after the previous day’s dose).
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Blood samples were collected into 10-ml Vacutainers containing the anticoagulant heparin (green top tubes) using ‘butterfly’ or straight needles. The tubes were inverted several times and then centrifuged for 15 min. The plasma was siphoned using plastic, disposable pipettes, placed into plastic tubes, and kept frozen at − 20°C. Plasma concentrations were determined by the Center for Human Toxicology at the University of Utah using liquid chromatography/tandem mass spectrometry. Sensitivity of this method is demonstrated by a 0.1-ng/ml lower limit of quantitation. Results of acceptable quality control samples were accurate within 14% of their target concentrations, and precise percent coefficients of variance did not exceed 14%.
2.4. Data analysis Buprenorphine plasma concentration raw data were analyzed using a two-way repeated-measures analysis of variance (ANOVA) with buprenorphine dosing phase and time as factors. Post-hoc tests were conducted to compare dosing phase within each time point using two-tailed matched-pairs t-tests. Raw data were also used to obtain AUCs for each buprenorphine dosing phase. The AUCs were calculated based upon the plasma concentrations produced by one buprenorphine dose. Therefore, the plasma concentrations from the − 24-h and −15-min timepoints were not included. The pre-existing trough levels were not subtracted. The last timepoint was not extrapolated to infinity. The concentrations from + 30 min to +24 h were weighted based upon the time intervals between data points. The weight of each timepoint was one-half the distance between it and the previous point plus one-half the distance between it and the next point. The first and last timepoints were weighted only with one-half the distance between them and the contiguous points. The plasma samples collected during the first and third day and the first sample of the second day were averaged to obtain the trough concentrations at each dosing phase. Peak concentrations, AUCs, and trough concentrations were analyzed using one-way repeated-measures ANOVAs. To determine if participants who had high (or low) plasma concentrations during a particular dosing phase also had high (or low) concentrations during the other dosing phases, concentrations produced by the three ascending liquid doses and the tablet dose were rank ordered from 1 (participant with the highest concentration at each dosing phase) to 14 (participant with the lowest concentration at each dosing phase). The rank orders were analyzed using a two-tailed Spearman correlation coefficient. Lastly, to determine if plasma concentrations produced by the dosing phases could predict the number of opioid-positive urine samples (e.g. did participants with the highest buprenorphine plasma concentrations have the fewest
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opioid-positive urine samples), plasma concentrations averaged over the four dosing phases were rank ordered from 1 (participant with the highest average concentration) to 14 (participant with the lowest average concentration) and were correlated with rank ordered % opioid positive urine samples. Again, a two-tailed Spearman Correlation Coefficient was used.
3. Results The two-way ANOVA indicated significant dosing phase effects [F(3,39)= 32.02; PB 0.001)], time effects [F(8,104)= 56.44; P B 0.001)], and a dosing phase× time interaction [F(24,312)= 8.19; P B 0.001)]. Visual inspection of the data indicates that the 8-mg liquid produced the highest plasma concentrations (Fig. 1). For all doses, average concentrations peaked 120 min after buprenorphine administration at which time the average plasma concentrations were 1.99, 2.37, 5.22 and 2.87 ng/ml for the 2-, 4-, 8-mg liquid, and the 8-mg tablet doses, respectively. Therefore, at the 120 min time point the plasma concentrations produced by the 8-mg tablet were 55% of those produced by the 8-mg liquid. Post-hoc tests comparing the plasma concentrations produced by each dosing phase within each time point indicate that the 8-mg liquid dosing phase produced plasma concentrations significantly higher than the other dosing phases at nearly all of the time points. Specifically comparing the 8-mg liquid and tablet, the liquid produced plasma concentrations significantly greater than the tablet at all time points except 24 h and 15 min before the dose, and 24 h after the dose. The 8-mg tablet produced concentrations greater than the 2-mg dose at all time points and greater than the 4-mg dose at 24 h and 15 min before the dose, and at 360 min and 24 h after the dose. The 4-mg dose produced
Fig. 1. Mean buprenorphine plasma concentrations ( 9standard errors) at each of the nine time points for each of the four dosing phases.
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Fig. 2. Mean peak plasma concentrations, mean AUC, and mean trough concentrations for each of the four dosing phases.
concentrations greater than the 2-mg dose at 24 h before the dose and 120, 240 and 360 min, and 24 h after the dose. Average peak concentrations were 2.04, 2.74, 5.83 and 3.02 ng/ml for the 2-, 4-, 8-mg liquid, and the 8-mg tablet doses, respectively (Fig. 2). A significant dosing phase effect was detected with a one-way ANOVA [F(3,39)= 30.71; PB 0.001]. Matched-pairs t-tests of peak concentrations indicated that all doses were significantly different from the others excepting the 4-mg liquid and 8-mg tablet doses. Average peak concentrations of the 8-mg tablet were 52% of the 8-mg liquid. For the areas-under-the-curve, the one-way ANOVA indicated a significant dosing phase effect [F(3,39)= 24.08; PB 0.001]. Matched-pairs t-tests showed that each dosing phase produced plasma concentrations significantly different from all others (Fig. 2). Mean AUC were 0.70, 0.87, 1.93 and 1.24 ng/ml for the 2-, 4-, 8-mg liquid, and 8-mg tablet dosing phases, respectively. Thus, the mean AUC for the tablet was approximately 64% of the mean liquid AUC.
Trough concentrations were calculated by averaging the concentrations from plasma samples collected approximately 24 h before, 15 min before, and 24 h after the test dose (i.e. plasma samples were collected just prior to the daily dose for 3 consecutive days). These three samples were each collected approximately 24 h after each previous dose. Mean trough concentrations were 0.25, 0.36, 0.77 and 0.64 ng/ml for the 2-, 4-, 8-mg liquid, and 8-mg tablet dosing phases, respectively (Fig. 2). Repeated measures ANOVA indicated a significant dosing phase effect [F(3,39)= 14.53; PB0.001]. Matched-pairs t-tests revealed that each dosing phase produced trough concentrations significantly different from the others, excepting the 8-mg liquid and tablet doses which did not significantly differ. The 8-mg tablet produced trough plasma concentrations that were 83% of those produced by the 8-mg liquid. The mean data obscures the substantial individual variability in the plasma concentrations obtained. As shown in Fig. 3, peak plasma concentrations after the 8-mg liquid dose ranged from 3.28 to 13.39 ng/ml. Peak plasma concentrations after the 8-mg tablet ranged from 1.86 to 5.00 ng/ml. When concentrations were rank ordered, significant correlations were found. The 2-mg dose versus the 4- and 8-mg liquid doses had Spearman r values of 0.81 and 0.85, respectively, with P valuesB 0.001. The 4-mg dose versus the 8-mg liquid dose had an r value of 0.80, with P= 0.001. These results indicate that subjects tended to have the same rank ordering of plasma concentrations (e.g. lower, intermediate, or higher concentrations) with each of the three liquid doses. In contrast, none of the correlations were significant when the three liquid doses were each compared with the 8-mg tablet dose indicating that the plasma concentrations produced by the liquid are not predictive of those produced by the tablet. Urine samples were generally collected three times per week and tested to determine illicit drug use. Opioids were present in 70.4% of all urine samples. For individual subjects, percent of urine samples containing opioids ranged from 8 to 100%. To determine if illicit opioid use could be predicted based upon the plasma buprenorphine concentrations, concentrations were rank ordered and were correlated with rank ordered % opioid positive urine samples. The Spearman r value was 0.29 (P= 0.31) indicating no significant correlation between the two variables.
4. Discussion This study was conducted to compare the plasma concentrations produced by three buprenorphine sublingual liquid doses with those of a buprenorphine sublingual tablet dose. Results indicate that the 8-mg buprenorphine liquid produced plasma concentrations
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significantly higher than any of the other dosages, both lower liquid doses and the 8-mg tablet. Mean concentration at the 120-min time point, mean peak concentration, and AUC of the 8-mg tablet were 55, 52 and 63%, respectively, of the 8-mg liquid concentrations. These data suggest that the buprenorphine tablet dose might have to be adjusted to produce plasma concentrations equivalent to those of the liquid. Similar results have been found in other studies. Mendelson et al. (1996) found that the buprenorphine tablet yielded about 50–60% of the 8-mg solution yield. However, in the present study the trough concentrations of the 8-mg tablet and 8-mg liquid doses were not significantly different. Trough concentrations of the 8-mg tablet were 83% of the 8-mg liquid dose. There were large individual differences in the plasma concentrations produced by the buprenorphine doses.
Fig. 3. Individual data from each of the 14 participants showing the buprenorphine plasma concentrations produced by each of the four dosing phases. In order to prevent flattening of the time point curves, the Y-axis values are not equivalent.
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These differences do not appear to be related to body weight or gender. The highest buprenorphine concentrations were produced by the 8-mg liquid in subjects 235 and 534. These subjects were males of nearly average weight. In comparison, subject 642 was a very heavy male and subject 981 was a light female; however, these subjects had comparable plasma concentrations that were below the group average. Of the three females, two had plasma concentrations below the group average, while one had concentrations above the average. It is possible these individual differences could be due to the pH in the participants’ mouths, producing more absorption in some participants. However, this cannot be verified because pH was not measured. It is interesting to note that large individual differences in buprenorphine plasma concentrations have also been observed in other studies (Kuhlman et al., 1996). It is also noteworthy that there were two subjects (188 and 772) for whom the 8-mg liquid and the 8-mg tablet produced nearly equivalent plasma concentrations. Furthermore, there were significant correlations between the plasma concentrations produced by the three liquid doses. For example, participants who tended to have the highest (or lowest) concentrations after one dose of the liquid also tended to have the highest (or lowest) concentrations after the other two liquid doses. However, the concentrations produced by the liquid doses were not predictive of those produced by the 8-mg tablet dose. These data suggest stable individual differences with the liquid doses but an influence of environmental factors with the tablet dose. The data from the present study are relevant for determining the optimal clinical dose of buprenorphine. Although there have been numerous attempts to determine optimal dose from clinical trials using the liquid dose, these data might not be helpful if there is now a switch from liquid doses to tablet doses. Given the lack of within-subject correlation between the liquid and tablet plasma concentrations, it will be difficult to ascertain the optimal tablet dose from the available data with the liquid form. However, it is interesting to note that the 8-mg liquid and tablet doses did not produce significantly different trough concentrations. Six hours after administration, the plasma concentrations produced by the 8-mg liquid were significantly higher than those produced by the tablet. However, by 24 h post-administration the concentrations did not differ. The present study did not ascertain the time at which the concentrations were no longer different, but if the trough concentrations are more important than peak concentrations for clinical efficacy, the 8-mg tablet might be as efficacious as the 8-mg liquid dose. It is interesting to note that in France, where the buprenorphine tablet is used clinically, the mean dose is reported to be 11 mg/day. The most commonly prescribed dosage is 6–8 mg. Nearly 80% of patients receive 4–16
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mg/day which was mostly taken once daily (56%), although this dose was split into two or more parts in 43% of cases (Bouchez and Vignau, 1998). In conclusion, this study indicates that the 8-mg buprenorphine tablet does not produce plasma concentrations equal to the 8-mg and is nearly 50% lower. If the 8-mg tablet is not altered, the different plasma concentrations produced by these two dosing forms must be considered when using the buprenorphine tablet in clinical settings.
Acknowledgements The authors thank Pamela Gary, L.P.N, Ja’Near Mathis, Jill Kuennen, M.A., Loraine DiCerbo, B.A., Debra Kish, B.A., and Kirsten Hines, B.S. for technical services, Mark Greenwald, Ph.D. for assistance with preparing the manuscript, John Hopper, M.D. and Rickie Hardaway, M.D. for medical supervision, Nora Chiang, Ph.D. for assistance with the study design, Reckitt & Colman for supplying buprenorphine, David Moody, Ph.D. and The University of Utah Center for Human Toxicology where the plasma samples were analyzed, and James Woods, Ph.D., the principal investigator of NIH grant, DA00254 from the National Institute on Drug Abuse, that supported the study. This study was supported by a research grant (Joe Young, Sr.) from the state of Michigan.
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