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`
`Page 1
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`RB Ex. 2016
`BDSI v. RB PHARMACEUTICALS LTD
`IPR2014-00325
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`

`ÕÕÖ
`
`662
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`Elkader é? Sproule
`
`The pharmacokinetic and pharmacodynamic properties of buprenorphine
`allow it to be a feasible option for substitution therapy in the treatment of opioid
`dependence.
`
`cy and also crosses into breast milk. Buprenorphine dosage does not need to be
`significantly adjusted in patients with renal impairment; however, since CYP3A
`activity may be decreased in patients with severe chronic liver disease, it is
`possible that the metabolism of buprenorphine will be altered in these patients.
`Although there is limited evidence in the literature to date, drugs that are known to
`inhibit or induce CYP3A4 have the potential to diminish or enhance bupre-
`norphine N—dealkylation. It appears that the interaction between buprenorphine
`and benzodiazepines is more likely to be a pharmacodynamic (additive or syner-
`gistic) than a pharmacokinetic interaction. The relationship between buprenor-
`phine plasma concentration and response in the treatment of opioid dependence
`has not been well studied.
`
`WOXRTPUV×V`aUbcOP
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`+,-./0 1  23*, 4. . 5 -*
`   
`

 
`
`Buprenorphine is a semi—synthetic opioid derived
`from thebaine, a naturally occurring alkaloid of the
`opium poppy, Papaver somm'ferum. Buprenorphine
`is used clinically as an analgesic and as substitution
`therapy for opioid dependence. This review focuses
`on the pharmacokinetics of buprenorphine as they
`relate to its use in the treatment of opioid depen—
`dence.
`
`Both opioid receptor agonists (e.g. methadone
`and levacetylmethadol
`[LAAM;
`levo—oc—acetyl—
`methadol]) and antagonists (e.g. naltrexone) have
`been used in the treatment of opioid dependence.
`The pharmacology of buprenorphine is unique in
`that it is a partial agonist at the opioid u receptor.[1’2]
`Its opioid u receptor agonist properties produce
`clinical effects similar to methadone, including anal—
`gesia, sedation, euphoria and respiratory depression.
`However, as a partial agonist, buprenorphine has
`maximal opioid effects lower than those of full
`agonists, providing a wider safety margin.[3] For
`example, in France, where buprenorphine has been
`available for several years, a retrospective evalua—
`tion of sudden deaths that were attributed to the
`
`misuse of buprenorphine or methadone estimated a
`3—fold higher yearly death rate associated with meth—
`adone than with buprenorphine despite the fewer
`restrictions on buprenorphine prescribing!“ A po—
`tential contributing factor to the increased safety
`profile of buprenorphine compared with methadone
`and LAAM could be the apparent lower risk of QT
`interval prolongation and cardiac toxicity.[5]
`
`Buprenorphine has a long receptor fixation half—
`life of 40 minutes (compared with milliseconds for
`morphine),[2] which probably contributes to its pro—
`longed duration of action. This allows for the effec—
`tive use of less than daily dose administrationfm
`similar to LAAM or naltrexone but unlike metha—
`
`done. As a partial opioid receptor agonist with a
`long duration of action, buprenorphine may also
`have the advantage of being associated with a
`delayed and less severe withdrawal syndrome com—
`pared with other opioids.[8’9]
`Several studies have demonstrated the efficacy of
`sublingually administered buprenorphine as substi—
`tution therapy in the treatment of opioid depen—
`dence.[7’1‘H5] Initial clinical trials used a sublingual
`alcohol (ethanol) solution of buprenorphine, where—
`as subsequent trials have used a sublingual tablet
`that is now available on the market in several coun—
`
`tries. A disadvantage buprenorphine shares with
`other opioid receptor agonists is a potential for
`abuse. To reduce this risk, buprenorphine is also
`marketed as a combination sublingual tablet con—
`taining both buprenorphine and naloxone in a ratio
`of 4 : l. The rationale is that when taken as intended,
`
`appreciable amounts of naloxone are not absorbed;
`however, if the tablets are crushed and injected,
`naloxone will exert its opioid receptor antagonist
`properties. There is some experimental research
`support for this rationale: opioid—dependent individ—
`uals using the combination product sublingually did
`not exhibit withdrawal
`symptoms;[16’17]
`bupre—
`norphine and naloxone administered in combination
`
`© 2005 Adis Data Information BV. All rights reseNed.
`
`Clin Phormocokine’r 2005; 44 (7)
`
`Page 2
`
`Page 2
`
`

`

`Buprenorphine Pharmacokinetlcs
`
`663
`
`this a feasible route of administration for the treat—
`
`ment of opioid dependence. Studies utilising specif—
`ic assays have reported buprenorphine sublingual
`solution’s mean bioavailability of 28—5 1% (table
`I).[34’35] The plasma bioavailability of the sublingual
`tablet has been estimated as 49—63% that of the
`
`the
`sublingual solution (table I).[36’37] However,
`clinical significance of these differences in bioavai—
`lability may be limited, based on recent investiga—
`tions that reported similar opioid—receptor binding
`changes in subjects (n = 3) taking buprenorphine
`sublingual liquid (2 and 16mg) compared with sub—
`j ects (n = 5) taking buprenorphine sublingual tablets
`(2 and 16mg).[38’39]
`
`Although this demonstrates that buprenorphine is
`rapidly absorbed into the oral mucosa, absorption
`into the systemic circulation is slower. The mean
`
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`+,-./0 1  23*, 4. . 5 -*
`   
`

 
`
`A number of factors could possibly influence
`sublingual absorption and bioavailability. At physi—
`ological pH, opioids can exist in ionised and non—
`ionised forms. By increasing the pH of the oral
`environment, more of the drug would be in the non—
`ionised form, therefore potentially enhancing ab—
`sorption. In a study of the sublingual absorption of
`selected opioids, it was found that methadone ab—
`sorption increased from 34% at a saliva pH of 6.5 to
`75% at pH 8.5. A similar test could not be done with
`buprenorphine because of the difficulty of dissolv—
`ing it in basic pH.[47] One study found a significant
`but low correlation, suggesting that as saliva pH
`increased, the recovery of buprenorphine in saliva
`decreased (r = —0.33; p = 0.05), indicating increased
`absorption.[351 In contrast, in another study the same
`group found no significant correlation between sali—
`va pH and buprenorphine area under the plasma
`concentration—time curve (AUC)
`[r = 0.33; p =
`0.52156] Likewise, the length of time the dose is
`held under the tongue seems to have minimal effect
`on the absorption of buprenorphine, as demonstrated
`by the bioequivalence of 3— and 5—minute sublingual
`solution holds,[351 and the similar absorbed fractions
`after 2.5— and 10—minute sublingual solution holds,
`under controlled study conditions.[47] It is not known
`if this is the case for the sublingual tablets. Of
`course, very short hold times would be likely to
`reduce the amount absorbed, which may be of con—
`cern in some patients who are unwilling to wait for
`complete tablet dissolution.
`
`parenterally to non—physically dependent individu—
`als attenuated (but did not block) the subjective
`effects of buprenorphine;[18’19] and the combination
`administered parenterally to physically dependent
`opioid
`users
`precipitated withdrawal
`symp—
`toms.[17’2°'24] The fact that naloxone did not com—
`
`pletely block buprenorphine subjective effectsm’m
`is probably explained by the relatively high affinity
`of buprenorphine for the opioid 0 receptor. The
`other important clinical implication is that in the
`case of buprenorphine overdose, naloxone may not
`be effective at reversing respiratory depression.[25]
`
`I. Buprenorphine Pharmacokinetics
`
`One challenge in the study of buprenorphine
`pharmacokinetics has been in the availability of
`appropriate assays to quantify buprenorphine con—
`centrations. Buprenorphine is 25—40 times more po—
`tent than morphine;[26] therefore, acute doses and
`resulting buprenorphine plasma concentrations are
`very low, often falling below 1 ng/mL. A radioim—
`munoassay (RIA) was used in the earlier pharma—
`cokinetic studies;[27] however, it has been shown
`
`that this assay may be incapable of distinguishing
`between buprenorphine and its metabolite, nor—
`buprenorphine.[28] When this was all that was avail—
`able, it was accepted for use in single—dose studies,
`since metabolite contributions in this setting may be
`less than with multiple—dose studies. Newer assays
`involving mass spectrometry or tandem mass spec—
`trometry, usually coupled to a gas chromatograph or
`liquid chromatograph, are very specific and are
`capable of quantifying very low plasma levels
`(<1.0 ng/mL).[29'31] Therefore, buprenorphine phar—
`macokinetics have been studied with different as—
`
`saying techniques over the years, which is likely to
`have contributed to the variable results obtained and
`
`reported in this review.
`
`1 .1 Absorption
`
`Buprenorphine undergoes extensive first—pass
`metabolism and therefore has very low oral bioavai—
`lability.[2] Absorption of buprenorphine
`trans—
`dermally is also limited,[32] although a new trans—
`dermal matrix patch has been developed for use in
`patients with pain.[331 The bioavailability of bupre—
`norphine sublingually is extensive enough to make
`
`© 2005 Adis Data Information BV. All rights reseNed.
`
`Clin Phormocokine’r 2005; 44 (7)
`
`Page 3
`
`Page 3
`
`

`

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