Page 1
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`RB Ex. 2035
`BDSI v. RB PHARMACEUTICALS LTD
`IPR2014-00325
`
`

`
`Absolute bioavailability of oral naloxone
`
`361
`
`Very little information regarding the ab-
`solute bioavailability of naloxone has been
`published to date. This study therefore aimed
`to investigate the absolute bioavailability of
`naloxone across a wide range of oral doses,
`ranging from 5 mg to 120 mg, and to assess
`the pharmacokinetic implications of the rec-
`tal administration of naloxone.
`
`Materials and methods
`
`Study design
`
`This was an open-label, single-centre,
`single-dose, 7-treatment, 5-period, random-
`ized incomplete crossover study. The proto-
`col for this study was approved by the Office
`for Research Ethics Committee Northern
`
`Ireland (ORECNI). The study was con-
`ducted in accordance with the International
`Conference on Harmonization Good Clini-
`
`cal Practice guideline [10], the Declaration
`of Helsinki [11], and applicable regulatory
`requirements.
`
`28 healthy men and women, aged 18 — 55
`years, gave their written informed consent to
`participate and were enrolled into the study.
`Female subjects had to use a highly effective
`method of contraception throughout the study.
`Subjects were excluded from participation if
`they had evidence of any clinically relevant
`medical condition or had used opioid-contain-
`ing medication within 30 days before the start
`of the study. The use of any prescription or
`non-prescription drug (excluding acetamino-
`phen/paracetamol), vitamins, herbal and/or
`mineral supplements, and drugs of abuse were
`prohibited throughout the study. Caffeine and
`xanthine containing beverages were prohib-
`ited from 48 h before each dose and while
`
`resident in the study unit, and alcohol was
`prohibited from 48 h before until 72 h afier
`each dose.
`
`Subjects were randomized to receive five
`of the following seven single doses of nal-
`oxone with at least a 7 day washout period
`between each dose: 1 mg (0.4 mg/ml) admin-
`istered over 30 min as an intravenous (i.v.)
`infusion (reference treatment), orally admin-
`istered prolonged release tablets 5 mg, 20 mg
`(2 x 10 mg tablets), 40 mg, 80 mg (2 X 40
`mg tablets) and 120 mg (3 X 40 mg tablets),
`and a rectally administered 40 mg prolonged
`
`release tablet. The naloxone tablets were de-
`
`veloped specifically for the study, and their
`release profile was controlled in such a inan-
`ner that it reflected the release profile of nal-
`oxone in commercially available oxycodonef
`naloxone tablets.
`
`In each study period subjects attended the
`study unit on the day before dosing and were
`dosed the following morning. Study medica-
`tion was administered in open-label fashion.
`Subjects fasted from food from 8 h before
`until 4 h after dosing in each study period.
`Subjects also had restricted fluid (240 ml wa-
`ter at the time of dosing) from 1 hour before
`until 1 hour after each dose. A 1ow—fat lunch
`
`(< 30% fat), dinner and an evening snack
`were provided at 4, 10 and 14 h post-dose,
`respectively. Menus were standardized while
`subjects were resident in the study unit and
`were the same for each study period. Sub-
`jects remained resident in the study unit until
`36 h post-dose, and returned to the study unit
`for 48 and 72-h post-dose procedures follow-
`ing the oral and rectal doses. Subjects also
`underwent clinical evaluations within 21
`
`days before the first dose and 3 — 7 days after
`the last dose.
`
`Pharmacokinetic methods
`
`Blood samples (6 ml) were drawn from a
`forearm vein into tubes containing potassium
`ethylenediaminetetraacetic acid pre-dose and
`at 15, 30, 32, 35, 40 and 45 min and 1, 1.25,
`1.5, 2, 3, 4, 6, 8, 12, 16 and 24 h post-dose
`for the i.v. dose, and pre-dose and at 0.5, 1,
`1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 9, 12, 16, 24, 32,
`36, 48 and 72 h post-dose for all oral and rec-
`tal doses. Samples were centrifuged within
`30 min of collection at 1,500 g for 15 min at
`4 °C and the plasma frozen in polypropylene
`tubes at -20 °C within 1 hour of sampling.
`
`Naloxone was extracted from plasma by
`liquid-liquid extraction. Samples were ana-
`lyzed using a validated bioanalytical assay
`employing liquid chromatography and elec-
`trospray ionization with tandem mass spec-
`trometric detection. The precision of the assay
`was within 8% and accuracy within 5% over
`an extended quality control concentration
`range of 30 — 4,000 pg/ml. The quality con-
`trol samples were initially at concentrations of
`30, 450 and 850 pg/ml, however many sample
`
`Page 2
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`Page 2
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`

`
`Smith, Hopp, Mundin et al.
`
`362
`
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`Page 3
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`

`
`Absolute bioavailability of oral naloxone
`
`363
`
`Table 2. Absolute bioavailability (%) of orally and rectally administered pro-
`longed release naloxone compared with intravenous naloxone.
`
`_
`
`‘Dose-adjusted. "Estimate from mixed-effects linear model. Natural log param-
`eter estimates calculated by transforming the log-scale estimates back to the
`linear scale, that is estimates of ratios. “90% confidence intervals obtained by
`transforming the confidence intervals on the log-scale to the ratio scale.
`
`concentrations were above the upper limit of
`quantitation, therefore two additional quality
`control samples were added at concentrations
`of 2,000 and 4,000 pg/ml. Similarly, the cali-
`bration range was extended from 10 — 1,000
`pg/ml to 10 — 5,000 pg/ml. Specificity testing
`showed that there was no interference from a
`
`range of analytes in the chromatographic re-
`gions of interest for naloxone.
`
`Pharmacokinetic parameters for naloxone
`were calculated using the WinNonlin Enter-
`prise Edition version 4.1 software (Pharsight
`Corporation, St. Louis, MO, USA). From
`each individual plasma profile, the area un-
`der
`the plasma concentration-time curve
`measured from the time of dosing to the last
`measurable concentration (AUC;) was calcu-
`lated using the linear trapezoidal method. The
`maximum observed plasma concentration
`(Cam) and time of the maximum observed
`plasma concentration (tmx) were directly
`observed from the concentration-time curve.
`
`The terminal phase rate constant (LambdaZ)
`was estimated using those points determined
`to be in the tenninal log-linear phase. The
`terminal phase half-life (t, 2) was determined
`from the ratio of In 2 to LambdaZ. The area
`
`under the plasma concentration-time curve
`
`__90°/a—_"=
`mParameterTi—\la‘|o><oiie treat_rneificomp_aris_on's_“_ W Testl
`Confidence 3
`Reference”
`"1‘e_“’_a'°
`..
`___. __.____
`._ ._
`_
`__ __ ._
`_5_rng oral vs_._1 mg _i.v. infu_sion _ Oi __ ‘___ 0.6; _1_.2__
`_
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`.6‘-9m_9_°_ra' v:- Lr_fié_!-v-.i.:I7usi°n
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`_2-°___ _L4:_2-_6__
`80 mg oral vs. 1 mg_i.\fln_f_usio_ri_ _ 2.0
`£,_g._9_
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`1 4, 2.8_
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`_.5_rnqo'r'aIrs'.Tms iv. infusio_n
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`'1F_g i.v_.infusion i _ __1.g1; _.°_._._s _ _
`_f_0 mg o_ra_l_v1mg i.v._in_fusion F
`2._O ___ 1.5; 2.8_ _
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`. 40 nlg rectal vs. 1 mg i.v. infus_ion
`_
`15.8_
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`_40 mg oralvs._1 mg i.v. infusion_
`0.2 __ _ _0_.1£2_ _
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`_
`120 mg__oraE._1 _mg i.v._infusion __ __0.2T _
`0 1; 0.2
`__Jflg_recta| vs. 1_m_g i.v. infusion_ J______ _2.0______1_5;__2._6_|
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`_._
`_
`‘AUC,
`
`___
`Aucm
`
`I
`
`Cm
`
`__
`
`between the time of dosing and extrapolated
`to infinity (AUC,-,,,—) was calculated from the
`ratio of the final observed plasma concentra-
`tion to LambdaZ. This was then added to the
`
`AUC, to yield AUC,,,f.
`Absolute systemic bioavailabilities were
`calculated from the ratios afier dose adjust-
`ment of AUC, and, where possible, AUC,-nf
`values, using the i.v. dose as the reference
`treatment.
`
`Safety assessments
`
`Adverse events were recorded throughout
`the study, including details of severity and re-
`lationship to study medication. Vital signs (su-
`pine blood pressure, pulse rate and respiration
`rate) were measured and electrocardiograms
`(ECGs) were recorded at intervals throughout
`the study. Hematology, blood chemistry and
`urinalysis assessments were performed at the
`first and last study visits.
`
`Statistical methods
`
`Log transformed data of the AUC,,
`AUC,,,f (if available) and Cm.‘ for nalox-
`one were modeled using a mixed effect lin-
`ear model, with fixed terms for treatment,
`log(dose), period and sequence. The term
`“log(dose)” refers to the natural log. Treat-
`ment ratios/differences and their associated
`90% confidence intervals were calculated
`
`from the least square means. The primary
`comparisons of interest were each of the oral
`tablet doses versus the i.v. infusion. A sec-
`
`ondary comparison of interest was the rectal
`tablet administration versus the i.v. infusion.
`
`All reported contrasts between treatments
`(Table 2) were scaled by the ratio of the dos-
`es in the treatments under consideration as a
`
`form of dose-adjustrnent to aid the interpre-
`tation of the results.
`
`In the subset of oral administered treat-
`
`log transformed data of the AUC,,
`ments,
`AUCM (if available) and Cmax for naloxone
`were modeled using a mixed effect linear
`model, with a linear tenn for log(dose) with
`fixed terms for period and sequence, and a
`correlated error-structure, otherwise referred
`to as a power model. The estimated coef-
`ficient for log (dose) was compared to the
`
`Page 4
`
`Page 4
`
`

`
`Smith, Hopp, Mundin et al.
`
`364
`
`88
`
`§
`
`88
`
`2000
`
`
`
`PlasmaConcentration(pglml) 88
`
`
`
`
`
`1500 ‘
`
`1000
`
`500
`
`10
`
`20
`
`28
`
`32
`
`24
`Time (h)
`-0-NLX PR tab 5mg
`-fi—NLX PR tab 40 mg
`-D—NLX PRmbs 20 mg
`—)(—NLX PR tabs 80 mg %K—NLX PR tab: 120 mg —0—NLX IV lnluslon 1 mg
`
`38
`
`40
`
`4448
`
`Figure 1. Mean naloxone (NLX) plasma concen-
`tralion-time profiles: oral and intravenous doses.
`
`3500
`
`3000
`
`2500
`
`2000
`
`1500
`
`1000
`
`500
`
`
`
`
`
`PlasmaConcentration(pglml)
`
`4
`
`8
`
`12
`
`16
`
`20
`
`24
`
`28
`
`32
`
`38
`
`404448
`
`Time (h)
`-0-NLX IV infusion 1 mg —l—NLX PR tab 40 mg per rectum
`
`Figure 2. Mean naloxone (NLX) plasma concen-
`tration-time profiles: rectal and intravenous doses.
`
`Table 3. Statistical results of log transformed naloxone pharrnacokinetic pa-
`rameters regressed on log (dose).
`
`‘LParameter Tcbeificientj Tfifiea (SE)
`AUC,
`Intercept
`___ 3._5_6 (0.269)
`__
`Log dose
`% 1.26 (o_.o57)
`Auc},,,_
`Intercept
`_«_1g§_(o.315)
`_
`,
`;Log dose_
`j 1.00 (o.o_e_1)
`‘cm
`grtercept
`}__z;_1_o(o.1a4)
`
`_
`
`___
`
`Log dose
`
`9l)%_c<_:r1'fi_denceinte—r\/_a|_:
`3.10; 4.02
`1.17;1.35
`3.31;4.e9
`0.89; 1.11
`1.79; 2.42
`
`_
`
`_
`
`0.88; 1.01 ______
`
`_
`
`_
`=
`T
`
`__
`
`0.95 (0.037)
`
`‘Estimates from mixed-effects linear model. SE: standard error.
`
`reference value of 1 as a global test of dose-
`proportionality.
`This was a pharmacokinetic study that
`was designed to have an overall power of
`more than 90% to demonstrate dose-propor-
`
`tionality,
`
`in terms of the absolute bioavail-
`
`ability of naloxone-3-glucuronide, of any
`pair of oral doses considered. Assuming
`a within-subject standard deviation (SD,
`on the log-scale) of 0.2 and a true ratio of
`1 (100%) between test and reference treat-
`
`ments, this was achievable with 28 complet-
`ing subjects, which equated to 20 subjects
`per treatment group. The within-subject SD
`of 0.2 was based on preliminary data from
`a single dose food effect study of oxycodo-
`ne/naloxone 10/5 mg and 40/20 mg, which
`showed within-subject SDs on the log-scale
`of 0.163 — 0.192 for AUC and Cm,‘ of nalox-
`one-3-glucuronide.
`
`Statistical programming and analyses
`were performed using SAS® version 9.1 soft-
`ware (SAS Institute Inc., Cary, NC, USA).
`
`Results
`
`Subject disposition
`
`28 subjects were randomized into the
`study; 27 of these subjects completed all
`five study periods. One subject withdrew
`due to subject choice and did not receive
`the 5 mg and 40 mg oral tablet doses. A to-
`tal of 19 or 20 subjects received each study
`treatment. The study population comprised
`9 female and 19 male subjects, with a mean
`age of31 years (range 21 — 53 years), mean
`weight of 72.5 kg (range 55 — 96 kg) and
`a mean body mass index of 24.5 (range 20
`— 28.5). Two female subjects and one male
`subject were Black; all other subjects were
`Caucasian.
`
`Pharmacokinetic refl/ts_
`
`The mean observed plasma concentra-
`tion-time profiles for naloxone are shown
`in Figures 1 and 2. The mean absolute bio-
`availability of naloxone from the orally
`administered PR tablets, based on the dose-
`adjusted AUC, values, ranged from 0.9%
`for the 5 mg dose to 2.0% for the 40, 80 and
`120 mg doses (Tables 1 and 2). The pharma-
`cokinetics of naloxone were linear across
`
`the range of oral doses, confirmed by linear
`regression of the log(phannacokinetic pa-
`rameter) against log(dose); the 90% confi-
`
`Page 5
`
`Page 5
`
`

`
`Absolute bioavailabilily of oral naloxone
`
`365
`
`Incidence of common adverse events (reported by > 1 subject overall) by MedDRAT"" system organ class (SOC) and pre-
`Table 4.
`ferred term.
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`: 80 mg oral
`120 mg oral [40 mg rectal: 1mg infusion
`20 mg oral
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`
`.
`
`.-.
`
`_
`
`.
`._.__
`_ _
`
`Subjects could have reported more than one adverse event during a treatment period. As this was a crossover study. subjects could
`have reported the same adverse event in different treatment periods.
`
`dence intervals for the log(dose) coefficient
`in AUCM and Cmax included unity (0.89 —
`1.11 and 0.88 — 1.01, respectively) (Table
`3). Mean oral absolute bioavailability based
`on the dose-adjusted AUC,,,{ values con-
`firmed the results based on AUC,, ranging
`from 1.9% to 2.2%, although due to low and
`variable plasma concentrations of naloxone
`it was not possible to estimate the absolute
`bioavailability of naloxone from the 5 mg
`tablet based on the AUCi,,f values. Mean
`Cm“ values of up to 17% of that observed
`following the infusion were recorded fol-
`lowing oral dosing. However, after dose-
`adjustment, each oral dose achieved only
`0.2% of the peak plasma concentration of
`the infusion. Mean half-lives for the oral
`
`doses ranged from 11.3 h for the 80 mg dose
`to 16.6 h for the 20 mg dose; the half-life
`could only be estimated for 1 subject fol-
`lowing the 5 mg dose.
`
`Following the rectal administration of a
`40 mg naloxone PR tablet, the availability of
`naloxone increased compared with oral ad-
`ministration, confinning a partial avoidance
`of the hepatic first-pass effect. However, the
`mean absolute bioavailability remained low
`at 15% compared with the i.v. infusion. The
`mean dose-adjusted Cum ratio for naloxone
`from the 40 mg rectally administered PR tab-
`let compared with the i.v. infusion was also
`
`very low at 2%. Administering the nalox-
`one PR tablet via the rectal route resulted in
`
`shorter mean half-life (6.9 h) than following
`oral administration.
`
`Safety results
`
`Headache and nausea were the most
`
`common adverse events, each reported by 4
`subjects overall (Table 4). All other adverse
`events were reported by three or fewer sub-
`jects overall. Adverse events were reported
`by 10 subjects (50%) following the 80 mg
`oral dose and between 4 and 6 subjects (20
`— 32%) following the other test treatments.
`Headache and nausea are consistent with
`
`the expected adverse event profile of nal-
`oxone. All adverse events were of mild or
`
`moderate intensity, except for three instanc-
`es of severe syncope; one following the 40
`mg rectal dose and two following the 1 mg
`i.v.
`infusion. All adverse events resolved
`
`without complication.
`No serious adverse events were reported
`and no subjects discontinued the study due to
`adverse events. There were no clinically no-
`table changes in laboratory tests, vital signs
`or ECGs during the study.
`
`Page 6
`
`Page 6
`
`

`
`Smith, Hopp, Mundin et al.
`
`366
`
`Yophi!re¢e;xu' O oxycodone
`
`(.3 Naloxme
`
`| oxycodone/naloxone
`IS taken orally: both
`prolonged release
`oxycodone and
`prolonged release
`naloxone enteritis
`gut
`
`I Oxycodone/naloxone
`provides etlectrvo
`analgesia in the
`central nervous
`system
`
`the receptor site
`
`I Natoxone
`prelerentially binds to
`opioid receptors on the
`GI tract. thereby
`counteracting the
`action at oxycodone at
`
`3
`0
`V
`
`Q
`
`I Highoxycodone
`oral bioavailability:
`most oxycodone
`molecules pass
`through the
`healthy liver
`unchanged
`I Nalnxone has no
`sagmlncanl systemic ellect
`
`Figure 3. Mechanism of action of oxycodone/nal-
`oxone tablets.
`
`Discussion
`
`Opioid therapy is a mainstay in the man-
`agement of chronic pain. Prolonged release
`opioids have been shown to be effective
`agents in pain management; however,
`the
`ability to properly titrate and treat pain with
`opioids can be limited by adverse events.
`OIBD is a common and distressing adverse
`event in up to 90% of patients treated with
`opioids [12]. Current therapy recommends
`the administration of laxatives; however,
`many patients discontinue opioid therapy be-
`cause of ongoing problems with OIBD. It is
`therefore advantageous to minimize the de-
`velopment of OIBD or to reduce its severity.
`Oxycodone/naloxone tablets are a com-
`bination product of PR oxycodone/PR nal-
`oxone developed for the treatment of severe
`pain. The naloxone component in the fixed
`combination is indicated for the therapy and.‘
`or prophylaxis of OIBD. In this strategy, the
`high first-pass effect of naloxone is regarded
`as an advantage:
`improved bowel function
`can be accomplished through the local action
`of naloxone in the gut, while the central, an-
`algesic activity of oxycodone is not antago-
`nized due to the low systemic availability of
`naloxone (Figure 3).
`The mean oral absolute bioavailability
`of naloxone in this study was 5 2% at doses
`ranging from 5 to 120 mg, with naloxone
`showing linear pharmacokinetics. Thus the
`absolute bioavailability of oral PR nalox-
`one remains low even at doses far exceed-
`
`ing those currently used in combination with
`oxycodone (5, 10 and 20 mg). Indeed, the
`results of patient studies have demonstrated
`
`that oxycodone/naloxone PR tablets pro-
`vide comparable pain relief to oxycodone
`PR tablets, whilst significantly improving
`bowel function [13, 14, I5, 16], for doses of
`oxycodone/naloxone PR up to 120/60 mg/d
`[15, 17]. No loss of analgesic efficacy was
`observed in any of the reported trials and col-
`lectively data suggest that, even following
`high doses of oxycodone/naloxone PR, the
`amount of naloxone present in the systemic
`circulation and entering the central nervous
`system is very low and not sufficient to affect
`the analgesic efficacy of oxycodone.
`Given the lo\v and variable concentra-
`
`tions of naloxone, particularly at the lower
`doses, it was not possible to calculate abso-
`lute bioavailability based on AUC,,,f values
`for all of the treatments, therefore the results
`are based on AUC, values. Where AUC,,,f
`values were calculated, these confirmed the
`results based on AUC, values.
`the
`Following rectal
`administration,
`availability of naloxone was increased coin-
`pared with oral administration. This increase
`is to be expected as rectal administration
`avoids the first-pass metabolism of the liver;
`however the absolute bioavailability of the
`40 mg rectal dose remained low at 15% com-
`pared with the l mg i.v. infusion. The dose-
`adjusted Cm,‘ from the rectal administration
`was higher than from the oral administration
`of naloxone, but was still only 2% of that
`from the i.v. infusion.
`
`From a safety aspect the combination of
`naloxone and oxycodone neither increases
`the potential risk of expected opioid-specific
`(or naloxone-specific) reactions nor leads to
`new safety relevant findings that have to be
`taken into consideration when treatment of
`
`severe pain is necessary for patients. In the
`current study, all study treatments were well
`tolerated. The most frequently reported ad-
`verse events (n = 4) were headache and nau-
`
`sea, which are consistent with the expected
`adverse event profile of opioid analgesics.
`
`Conclusions
`
`the bio-
`Following oral administration,
`availability of naloxone was very low, with
`mean absolute bioavailabilities
`(based on
`AUC,) of 0.9 — 2.0% over a dose range of 5
`— 120 mg administered orally as prolonged
`
`Page 7
`
`Page 7
`
`

`
`Absolute bioavailability of oral naloxone
`
`release tablets. Following rectal administra-
`tion, the absolute bioavailability of naloxone
`increased compared with oral administration,
`consistent with a partial avoidance of the he-
`patic first-pass effect, although it remained
`low at 15%. Naloxone showed linear phanna-
`cokinetics over the oral dose range studied.
`
`Acknowledgments
`
`Writing assistance was provided by Karen
`Paine (Muiidipliarma Research Limited), a
`member of the European Medical Writers
`Association (EMWA),
`in accordance with
`the CONSORT statement. and EMWA and
`
`Good Publication Practice guidelines. The
`study was funded by Mundipharma Research
`GmbH & Co. KG.
`
`gonflictpf interest
`
`K. Smith, M. Hopp, G. Mundin, P. Bailey
`and J. Woodward are employed by Mundi-
`phamia Research.
`
`Trade mark __s_tatement
`
`Targin'3‘, Targinact“ and Targiniq“ are
`registered trade marks.
`
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