CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`022410Orig1s000
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`Page 1
`
`RB Ex. 2040
`BDSI v. RB PHARMACEUTICALS LTD
`IPR2014-00325
`
`

`

`4.1.7 Study 20-291-SA: A Single-Dose, 3-Period, 5-Treatment, 3-Way Crossover
`Dose Proportionality Study of Buprenorphine/Naloxone Film Strips Administered
`Sublingually under Fasting Conditions
`
`Study Design:
`
`Objectives:
`
`Protocol Number:
`Study Center(s):
`
`Study Period (days):
`Number of Subjects
`enrolled:
`
`Number of Subjects
`analyzed:
`Diagnosis and Main
`Criteria for Inclusion:
`
`Test Formulations:
`
`Single-dose, open-label, randomized, 3-period, 5-treatment,
`3-way crossover study in which 60 healthy adult subjects
`(under naltrexone block) were scheduled to receive three
`separate single-dose administrations of study drug after a 10-
`hour overnight fast.
`To compare the rate and extent of absorption of five dosages
`(2/0.5 mg, 4/1 mg (2 x 2/0.5 mg), 8/2 mg, 12/3 mg,
`and 16/4 mg) of buprenorphine/naloxone film strip
`(sublingual) investigational formulations, manufactured by
` for Reckitt Benckiser Pharmaceuticals
`Inc., following an overnight fast of at least 10 hours.
`20-291-SA
`
`ł(cid:190)(cid:247) ł(cid:236)(cid:247)
`
`ł(cid:190)(cid:247) ł(cid:236)(cid:247)
`
`34
`60 [14 (29.17%) Non-Hispanic/Latino Black or African
`American, 16 (33.33%) Non-Hispanic/Latino White, 17
`(35.42%) Hispanic/Latino White, and 1 (2.08%)
`Hispanic/Latino American Indian or Alaska Native subjects]
`50 [completed at least two treatments]
`
`Healthy adult male or non-pregnant, non-breastfeeding female
`volunteers, 18-45 years of age (inclusive), BMI between 18
`and 30 kg/m2 (inclusive) and weighed a minimum of 50 kg
`(110 lbs).
`Test Formulation 1: Treatment A
`Buprenorphine/naloxone
`Dose = 1 x 2/0.5 mg film strip administered sublingually
`Lot A08DW101-024
`Mfg Date 01/24/08 – 01/25/08
`
`Test Formulation 2: Treatment B
`Buprenorphine/naloxone
`Dose = 4/1 mg (2 x 2/0.5 mg) film strips administered
`sublingually
`Lot A08DW101-024
`Mfg Date 01/24/08 – 01/25/08
`
`Test Formulation 3: Treatment C
`Buprenorphine/naloxone
`Dose = 1 x 8/2 mg film strip administered sublingually
`Lot A08EJ103-025
`
`
`
`56
`
`Page 2
`
`

`

`Mfg Date 01/28/08
`Test Formulation 4: Treatment D
`Buprenorphine/naloxone
`Dose = 1 x 12/3 mg film strips administered sublingually
`Lot A08EY101-028
`Mfg Date 02/02/08 – 02/03/08
`
`Test Formulation 5: Treatment E
`Buprenorphine/naloxone
`Dose = 1 x 16/4 mg film strips administered sublingually
`Lot A08ET101-035
`Mfg Date 02/05/08 – 02/06/08
`Phase I
`Study Phase:
`1 April 2008
`Study Initiation Date:
`Study Completion Date: 5 May 2008
`Principal Investigator:
`
`ł(cid:190)(cid:247) ł(cid:236)(cid:247)
`
`ł(cid:190)(cid:247) ł(cid:236)(cid:247)
`
`ł(cid:190)(cid:247) ł(cid:236)(cid:247)
`
`ł(cid:190)(cid:247) ł(cid:236)(cid:247)
`
`ł(cid:190)(cid:247) ł(cid:236)(cid:247)
`
`
`Bioanalytical validation:
`
`Human EDTA plasma samples were analyzed for buprenorphine and norbuprenorphine
`according to
` procedure ATM-1336, Revision 1. The assay validation was
`finalized and reported under
`. The method used in this study was
`validated for a range of 0.0250 to 10.0 ng/mL for buprenorphine and 0.0200 to 8.00
`ng/mL for norbuprenorphine based on the analysis of 0.500 mL of human EDTA plasma.
`Human EDTA plasma samples were analyzed for naloxone according to
`
`procedure ATM-1268, Revision 1. The assay validation was finalized and reported under
`. The method used in this study utilized a range of 1.00 to 250
`pg/mL for naloxone, based on the analysis of 1.00 mL of human plasma. Quantitation
`was performed using separate weighted (1/x2) linear least squares regression analysis
`generated from calibration standards.
`
`For precision and accuracy, please refer to individual study review 1 for the 2 mg/ 0.5 mg
`SL strips.
`
`
`
`Drug Concentration Measurements:
`
`Blood (plasma) pharmacokinetic characteristics were assessed after each dose of study
`medication. Blood samples were drawn at 0 (pre-dose) and at 0.25, 0.5, 0.75, 1, 1.25,
`1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, and 144 hours after dose administration.
`
`
`
`
`
`
`
`57
`
`Page 3
`
`

`

`Table 1: Pharmacokinetic Parameters of Buprenorphine after Sublingual Administration
`of Suboxone
`(2 mg/0.5 mg through 16 mg/4 mg)
`
`ł(cid:190)(cid:247) ł(cid:236)(cid:247)
`
`
`Tmax [h]
`
`Cmax
`[ng/mL]
`AUClast
`[h x ng/mL]
`AUCinf
`[h x ng/mL]
`T1/2 (h)
`
`2/0.5
`1.54
`(0.68)
`1.07
`(0.525)
`7.178
`(2.836)
`8.434
`(3.207)
`22.71
`(13.01)
`
`4/1
`1.48
`(0.57)
`1.66
`(0.794)
`13.42
`(6.133)
`14.62
`(6.446)
`25.67
`(13.30)
`
`8/2
`1.40
`(0.45)
`3.55
`(1.23)
`28.71
`(8.826)
`30.66
`(9.241)
`36.55
`(16.38)
`
`12/3
`1.43
`(0.53)
`4.80
`(2.14)
`39.86
`(14.71)
`41.74
`(15.08)
`36.07
`(10.48)
`
`16/4
`1.29
`(0.37)
`6.05
`(2.42)
`50.32
`(16.38)
`53.40
`(18.58)
`40.37
`(17.22)
`
`ł(cid:190)(cid:247) ł(cid:236)(cid:247)
`
`
`Tmax [h]
`
`Cmax
`[pg/mL]
`AUClast
`[h x pg/mL]
`AUCinf
`[h x pg/mL]
`T1/2 (h)
`
`2/0.5
`0.73
`(0.19)
`48.5
`(25.9)
`100.6
`(41.30)
`105.1
`(14.08)
`2.01
`(1.03)
`
`4/1
`0.74
`(0.18)
`72.8
`(33.7)
`164.1
`(68.02)
`171.0
`(69.53)
`2.18
`(1.53)
`
`8/2
`0.79
`(0.23)
`193
`(84.6)
`442.9
`(134.4)
`454.8
`(135.0)
`5.15
`(3.66)
`
`12/3
`0.74
`(0.21)
`286
`(155)
`647.5
`(227.4)
`665.1
`(230.8)
`6.81
`(4.45)
`
`16/4
`0.78
`(0.19)
`401
`(226)
`937.9
`(368.8)
`958.4
`(372.6)
`7.00
`(3.45)
`
`
`Table 2: Pharmacokinetic Parameters of Naloxone after Sublingual Administration of
`Suboxone
`
`
`
`
`Table 3: Pharmacokinetic Parameters of Norbuprenorphine after Sublingual
`Administration of Suboxone
`
`
`
`ł(cid:190)(cid:247) ł(cid:236)(cid:247)
`
`2/0.5
`1.32
`(1.01)
`0.352
`(0.163)
`10.61
`(4.391)
`12.73
`(5.217)
`44.23
`(23.40)
`
`4/1
`1.35
`(0.80)
`0.679
`(0.270)
`22.68
`(10.54)
`25.96
`(12.46)
`42.46
`(19.47)
`
`8/2
`1.51
`(1.05)
`1.55
`(0.664)
`48.14
`(16.85)
`56.22
`(22.52)
`55.71
`(48.02)
`
`12/3
`1.87
`(1.74)
`2.19
`(1.59)
`69.46
`(38.20)
`77.42
`(41.72)
`45.74
`(17.22)
`
`16/4
`1.60
`(1.29)
`2.73
`(1.64)
`85.45
`(38.41)
`95.94
`(43.88)
`44.77
`(21.78)
`
`
`Tmax [h]
`
`Cmax
`[pg/mL]
`AUClast
`[h x pg/mL]
`AUCinf
`[h x pg/mL]
`T1/2 (h)
`
`
`
`
`
`
`58
`
`Page 4
`
`

`

`In general, peak exposure to buprenorphine was observed at approximately 1.5 h and
`mean ± SD estimates of maximum concentration (Cmax) ranged from 1.07 ± 0.525
`ng/mL (buprenorphine and naloxone 2/0.5 mg) to 6.05 ± 2.42 ng/mL (buprenorphine and
`naloxone 16/4 mg). Likewise, total systemic exposure of buprenorphine, based on
`AUClast, increased with dose. Concentrations of buprenorphine declined with an
`apparent t1/2 value of 22.71 to 40.37 h. As observed for buprenorphine, exposure to
`norbuprenorphine increased with the dose of buprenorphine in the soluble film. Mean ±
`SD peak exposure to norbuprenorphine was observed from 1.32 to 1.87 h, and mean ±
`SD estimates of Cmax ranged from 0.352 ± 0.163 ng/mL (buprenorphine and naloxone
`2/0.5 mg) to 2.73 ± 1.64 ng/mL (buprenorphine and naloxone 16/4 mg). Exposure to
`naloxone increased with dose of naloxone in the soluble film. Mean ± SD peak exposure
`to naloxone was observed at approximately 0.75 h, and mean ± SD estimates of Cmax
`ranged from 48.5 ± 25.9 pg/mL (buprenorphine and naloxone 2/0.5 mg) to 401 ± 226
`pg/mL (buprenorphine and naloxone 16/4 mg). Concentrations of naloxone declined with
`an apparent t1/2 of 2.01 to 7.00 h.
`
`In the linear regression plots of the dose-normalized values of Cmax, AUClast, and
`AUCinf, there was a negative slope in the regression line, suggesting a less than
`proportional increase in exposure to buprenorphine with increasing dose. The negative
`slope in the regression line appeared to be due to the first two dose levels, 2/0.5 and 16/4
`mg. For norbuprenorphine and naloxone, the slopes of the regression lines were small,
`almost parallel to the x-axis for AUClast and AUCinf, suggesting that overall systemic
`exposure to norbuprenorphine and naloxone were proportional to the administered dose
`in buprenorphine/naloxone film strips.
`
`Overall, the increases in Cmax and AUC for buprenorphine, norbuprenorphine and
`naloxone with increases in dose, were dose linear but somewhat less than dose
`proportional.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`59
`
`Page 5
`
`

`

`Table 4: Assessment of Dose Proportionality of Buprenorphine and Naloxone
`Sublingual Soluble Film (Dose Range 2/0.5 mg to 16/4 mg) Using Mixed-effects
`Statistical Model based on a Power Function (Study 20-291-SA)
`
`
`
`When all dose levels were included in the dose-proportionality assessment of
`buprenorphine using a mixed effects model based on a power function, the slope ( 1)
`estimates and associated 90% CIs are summarized in Table 4. The 1 estimates were
`closer to 1.0000 when the upper dose levels were considered in the power analysis.
`Exposure to buprenorphine, norbuprenorphine, and naloxone increased with increased
`dose of SL buprenorphine and naloxone soluble film. The power analysis results
`indicated that buprenorphine Cmax and AUCinf and naloxone Cmax were directly
`proportional to the SL administered dose of buprenorphine and naloxone soluble film
`over the dose range of 2/0.5 mg to 16/4 mg. Although the dose proportionality of
`naloxone AUCinf could not be confirmed over the entire 8-fold dose range, the power
`analysis indicated that this parameter was proportional over a 5.06-fold range.
`
`
`
`
`
`60
`
`Page 6
`
`