EXAMPLE 2
`
`PI-75
`
`Evaluation of the Pharmacokinetic Profile
`of Gluteal Versus Deltoid Intramuscular
`Injections of Paliperidone Palmitate 100
`mg Equivalent in Patients with
`Schizophrenia
`
`
`
`EVALUATION OF THE
`PHARMACOKINETIC PROFILE OF
`GLUTEAL VERSUS DELTOID
`INTRAMUSCULAR INJECTIONS OF
`PALIPERIDONE PALMITATE 100 MG
`EQUIVALENT IN PATIENTS WITH
`SCHIZOPHRENIA.
`
`A. Cleton,1 S. Rossenu,1 D. Hough,2 H.
`Crauwels,1 A. Vandebosch,1 J. Berwaerts,2 M.
`Eerdekens,1 I. Francetic3; 1Johnson &
`Johnson Pharmaceutical Research &
`Development, Beerse, Belgium, 2Johnson &
`Johnson Pharmaceutical Research &
`Development, Titusville, NJ, 3 Institute of
`Clinical Pharmacology, Clinical Hospital
`Centre, Zagreb, Croatia
`
`
`
`BACKGROUND:
`
`This study was performed to characterize and
`compare the pharmacokinetic profile of
`paliperidone palmitate (formulated as
`described above) following four
`intramuscular injections in the deltoid or
`gluteal muscle.
`
`The aim of this study was to compare the PK
`profile of paliperidone palmitate 100 mg eq.
`administered into the deltoid (n=24) or gluteal
`muscle (n=25).
`
`Method
`
`METHODS:
`
`In this multiple-dose, open-label, parallel-
`group study, patients with schizophrenia were
`randomized to receive 4 consecutive
`injections (Days 1, 8, 36 and 64).
`
`In this multiple-dose, open-label, parallel-
`group study, patients with schizophrenia were
`randomized to receive four consecutive
`intramuscular injections (days 1, 8, 36 and 64)
`of paliperidone palmitate 100 mg-eq.
`administered into either the deltoid (n=24) or
`gluteal muscle (n=25). Plasma samples for
`pharmacokinetic analyses were collected. The
`total paliperidone concentration was
`calculated as the sum of both enantiomers.
`
`Janssen Ex. 2009
`Mylan v. Janssen
`IPR2020-00440
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`Results
`
`RESULTS:
`
`The median Cmax for paliperidone was higher
`in the deltoid versus the gluteal muscle after
`the second (31.3 versus 24.1 ng/mL) and
`fourth (23.7 versus 22.3 ng/mL) injections.
`
`The median Cmax was higher in deltoid vs.
`gluteal muscle after the 2nd (31.3 vs. 24.1
`ng/mL) and 4th (23.7 vs. 22.3 ng/mL)
`injections.
`
`After four injections, median AUC∞ was
`similar for both injection sites; Cmax and
`AUCτ for paliperidone were 30% (90% CI =
`100.56 % - 168.93 %) and 20% (90% CI =
`93.09 % - 154.69 %) higher in deltoid versus
`gluteal muscle, respectively.
`
`Median Tmax was similar between injection
`sites after the second (10 day versus 10 day)
`and fourth injections (5 versus 6.5 days).
`
`After four injections, the median peak-to-
`trough ratio was higher (2.3 versus 1.9), with
`a larger intersubject variability for deltoid
`versus gluteal injection.
`
`An increase in median predose plasma
`concentration between days 8, 36 and 64 for
`both sites suggested subjects were not
`completely at steady state after four
`injections. Relative exposure after the fourth
`injection was slightly lower than after the
`second injection in both the deltoid and
`gluteal muscle.
`
`Most commonly reported adverse events
`(combined injection sites) were orthostatic
`hypotension (24%), hypotension (14%),
`diastolic hypotension (12%) and injection site
`pain (14%). There were four serious adverse
`events (worsening of psychosis) that led to
`discontinuations. There were no deaths in the
`study.
`
`After 4 injections, the median fluctuation
`index (FI) was higher (71.9 vs. 56.2%), with a
`larger intersubject variability for deltoid vs.
`gluteal injection.
`
`
`
`Median Tmax was similar between injection
`sites after the 2nd (10 vs. 10 days) and 4th
`injections (5 vs. 6.5 days). The median
`concentration-time profile was higher
`following deltoid injection.
`
`After 4 injections, median AUC∞ was similar
`for both injection sites; Cmax and AUCτ for
`paliperidone were 30% (90%CI=100.56-
`168.93) and 20% (90%CI=93.09-154.69)
`higher in deltoid vs. gluteal muscle,
`respectively.
`
`Increased median predose plasma
`concentrations on Days 8, 36 and 64
`suggested subjects were not completely at
`steady state after 4 injections.
`
`
`
`
`
`Most commonly reported adverse events
`(combined injection sites) were orthostatic
`hypotension (24%), hypotension (14%),
`diastolic hypertension (12%) and injection
`site pain (14%). Four patients discontinued
`due to psychosis.
`
`Janssen Ex. 2009
`Mylan v. Janssen
`IPR2020-00440
`
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`Paliperidone palmitate was well tolerated with
`more favorable local tolerability profile in the
`gluteal versus deltoid; mean injection site
`pain VSA score was 3.3 for gluteal versus
`10.8 for deltoid muscle (day 1, 8 hours after
`injection.
`
`Paliperidone palmitate was well tolerated,
`with a mean injection site pain VAS score of
`3.3 for gluteal vs. 10.8 for deltoid muscle
`(Day 1, 8 hours after injection).
`
`Conclusion
`
`CONCLUSION:
`
`Paliperidone palmitate 100 mg-eq. injections
`resulted in an increased AUCτ higher Cmax,
`greater FI, but similar Tmax following four
`consecutive injections into the deltoid versus
`gluteal muscle.
`
`Paliperidone palmitate 100 mg-eq., had an
`increased AUCτ, higher Cmax and greater FI
`when injected into the deltoid vs. gluteal
`muscle, although similar Tmax was noted, for
`both injection sites.
`
`Paliperidone palmitate 100 mg-eq. was
`systemically and locally well tolerated in this
`study.
`
`Paliperidone palmitate 100 mg-eq. was well
`tolerated.
`
`
`
`Janssen Ex. 2009
`Mylan v. Janssen
`IPR2020-00440
`
`Page 3 of 6
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`

`

`EXAMPLE 3
`
`PI-74
`
`Assessment of the Dose Proportionality of
`Paliperidone Palmitate 25, 50, 100, and 150
`mg eq. Following Administration in the
`Deltoid or Gluteal Muscles
`
`
`
`ASSESSMENT OF THE DOSE
`PROPORTIONALITY OF PALIPERIDONE
`PALMITATE 25, 50, 100 AND 150 MG EQ.,
`A NEW LONG-ACTING INJECTABLE
`ANTIPSYCHOTIC FOLLOWING
`ADMINISTRATION IN THE DELTOID OR
`GLUTEAL MUSCLES.
`
`A. Cleton,1 S. Rossenu,1 D. Hough,2 H.
`Crauwels,1 J. Berwaerts,2 S. Gopal,2 A.
`Vandebosch,1 C. Rosso Fernandez3; 1Johnson
`& Johnson Pharmaceutical Research &
`Development, Beerse, Belgium, 2Johnson &
`Johnson Pharmaceutical Research &
`Development, Titusville, NJ, 3 Clinical Trial
`Unit, University Hospital of Bellvitge,
`Barcelona, Spain
`
`
`
`BACKGROUND:
`
`This study evaluated dose proportionality of
`paliperidone palmitate injections when
`administered into either the gluteal or deltoid
`muscle.
`
`Study evaluated dose proportionality of
`paliperidone palmitate injections administered
`in either gluteal or deltoid muscle.
`
`Method
`
`METHODS:
`
`A single-dose, open label, parallel-group
`study of 201 randomized schizophrenia
`subjects was performed. The subjects were
`assigned into eight treatment groups:
`paliperidone palmitate 25 (n=48), 50 (n=50),
`100 (n=51) or 150 (n=52) mg-eq. injected into
`either the deltoid or gluteal muscle.
`
`Serial plasma samples were collected for
`pharmacokinetic evaluation over 126-day
`period. The total paliperidone concentration
`was calculated as the sum of both
`enantiomers.
`
`A single-dose, open-label, parallel-group
`study randomized 201 schizophrenia subjects
`(safety set) into eight treatment groups:
`paliperidone palmitate 25 (n=48), 50 (n=50),
`100 (n=51) or 150 (n=52) mg-eq. injected into
`deltoid or gluteal muscle.
`
`
`
`Janssen Ex. 2009
`Mylan v. Janssen
`IPR2020-00440
`
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`

`Dose proportionality was assessed by linear
`regression model, for each injection site, with
`log-transformed dose-normalized AUC∞ and
`Cmax as dependent variables and log-
`transformed dose as predictor, respectively of
`Cmax and AUC∞ ratios of the enantiomers were
`documented.
`
`Paliperidone dose proportionality was
`assessed by a linear regression model, for
`each injection site, with log-transformed
`dose-normalized AUC∞ and Cmax as
`dependent variables and log-transformed dose
`as predictor, respectively. Cmax and AUC∞
`ratios of enantiomers [R078543(+)/R078544(-
`)] were documented.
`
`Results
`
`RESULTS:
`
`Slopes for log-transformed dose-normalized
`AUC∞ were not significantly different from
`zero for deltoid (slope -0.06; p=0.036) and
`gluteal injections (slope -0.02; p=0.760
`indicating a dose-proportional increase in
`AUC∞, Tmax, was comparable between doses
`but slightly earlier for deltoid (13-14 days)
`versus gluteal injections (13-17 days).
`
`Median Cmax was higher with deltoid (range
`5.3-11.0 ng/mL) versus gluteal (range 5.1-8.7
`ng/mL) injections except for the 100 mg-eq.
`deltoid (slope −0.22, p=0.0062) and gluteal
`(slope -0.31; p<0.0001) injections, indicating
`a less than dose-proportional increase in Cmax.
`Results of Cmax and AUC were confirmed
`using pairwise comparisons. Plasma
`concentrations of (+)-enantiomer were
`consistently higher than (−)-enantiomer;
`(+)/(−) plasma concentrations ratio was
`approximately 2.4 shortly after administration
`and decreased to ~1.7 for both injection sites,
`independent of dose.
`
`AUC∞ slopes were not significantly different
`from zero for deltoid (slope -0.06; p=0.36)
`and gluteal injections (slope -0.02; p=0.76)
`indicating dose proportional increase in
`AUC∞, Tmax was comparable for doses but
`slightly earlier for deltoid (13-14 d) vs gluteal
`injections (13-17 d).
`
`Median Cmax (range 5.1-11.0ng/mL) was
`higher with deltoid vs gluteal injections
`except for 100 mg eq. dose. Cmax slopes were
`significantly different from zero for deltoid
`(slope -0.22, p=0.0062) and gluteal (slope -
`0.31; p<0.0001) injections, indicating a less
`than proportional increase in Cmax with dose.
`Median (+)/(-) Cmax and AUC∞ ratios were
`~1.7.
`
`After a single dose of paliperidone palmitate,
`subjects received concomitant oral
`antipsychotics. Treatment-emergent AEs
`(TEAs) included tachycardia (10%), headache
`(7%), schizophrenia (6%), insomnia (5%).
`Only 2% of subjects discontinued due to
`TEAs. No deaths were reported.
`
`After a single dose of paliperidone palmitate,
`subjects received concomitant oral
`antipsychotics. Treatment-emergent AEs
`(TEAEs) included tachycardia (10%),
`headache (7%), schizophrenia (6%), insomnia
`(5%), weight gain (5%). Only 2% of subjects
`discontinued due to TEAEs.
`
`Janssen Ex. 2009
`Mylan v. Janssen
`IPR2020-00440
`
`Page 5 of 6
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`

`

`Conclusion
`
`CONCLUSION:
`
`AUC∞ increased proportionality with
`increasing paliperidone palmitate doses (5-
`150 mg-eq.), regardless of gluteal or deltoid
`injection. Overall, deltoid injection was
`associated with a higher Cmax (except for 100
`mg-eq.) and slightly earlier Tmax compared
`with gluteal injections.
`
`Data indicate AUC∞ increased proportionally
`with increasing paliperidone palmitate doses
`(25-150 mg-eq.), regardless of gluteal or
`deltoid injection. Cmax was less than dose
`proportional for doses >50 mg-eq. Overall,
`deltoid injection was associated with a higher
`Cmax (except for 100 mg-eq.) and slightly
`earlier tmax vs gluteal injection.
`
`
`
`Janssen Ex. 2009
`Mylan v. Janssen
`IPR2020-00440
`
`Page 6 of 6
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`