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`Volume 83 l Supplement 1 | March 200.8 "
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`www.nature.comlcpt
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`PublishedfortheAmerican Societyfor
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`

`

`
`m material may he Drowned thaDVngh: law (nae 17 u 5 Cadel
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`nature publishing group
`,———w
`
`RESULTS: Mean pharmacokinetic results are reported below:
`
`AUC (lig‘l‘niin/ml.)
`Cmax (rig/ml.)
`'I'max (min)
`Mean
`(Iiiiil-
`SJ). CV'lir max)CV94: MeanSJ).(Irouptnzs) Mean SJ). CV‘J’o
`
`
`
`
`Naralriptan
`(12851
`1729‘)
`28
`1052
`303
`2‘)
`27(15<3())
`7
`25
`Alone
`
`34
`5
`13*(5—15)
`37
`490
`1315
`13
`9377
`73568
`Naralriptan/
`CairicrA
`
`Naralriplan/
`57587
`18231
`32
`9-10
`320
`3—1
`‘)""(5-15)
`5
`(11
`Carrier II
`
`* Naralriptan and car ricr combination versus control tNaratriplan alone). [1:002
`
`CONCLUSION: Peak naratriptan concentrations following drug-
`carrier combination were reached significantly earlier than when
`naratriplan was administered alone. The extent of absorption, mew
`surcd as AUC and Cmax, was not substantially affected by the admin-
`istration of the combination.
`
`PI-74
`
`ASSESSMENT OF THE DOSE PROPORTIONALITY OF PALI-
`PERIDONE PALMITATE 25, 50, 100 AND 150 MG EQ., A NEW
`LONG-ACTING INJECTABLE ANTIPSYCHOTIC FOLLOWING
`ADMINISTRATION IN THE DELTOID OR GLUTEAL MUSCLES.
`A. Cleton,l S. Rossemi,l D. I’Iough,2 H. Crauwels,l J. Berwaerts,2
`S. Gopal,2 A. Vandebosch,' C. Rosso Fernandez]; |Johnson & Johnson
`Pharmaceutical Research & Development, Beerse, Belgium, 2Johnson
`& Johnson Pharmaceutical Research & Development, Titusville, NJ,
`3Clinical Trial Unit, University Hospital ofBellvitge, Barcelona, Spain
`BACKGROUND: Study evaluated dose proportionality of pali-
`peridone palmitate injections administered in either gluteal or deltoid
`muscle.
`METHODS: A single-dose, open-label. parallel—group study ran-
`domized 201 schizophrenia subjects (safety set) into eight treatment
`groups: paliperidone palmitate 25 (11:48), 50 (11:50), 100 (11:51) or
`150 (11:52) mg eq. injected into deltoid or gluteal muscle. Paliperi-
`done dose proportionality was assessed by a linear regression model,
`for each injection site, with log-transformed dose—normalized AUCM
`and Cmax as dependent variables and log-transformed dose as predic—
`tor, respectively. Cmax and AUC“ ratios of enantiomers 1R078543(+)/
`R()78544(-)] were documented.
`RESULTS: AUCW slopes were not significantly different from
`zero for deltoid (slope -().06;p:0.36) and gluteal
`injections (slope
`—().02;p:0.76) indicating dose proportional
`increase in AUCm. Tmax
`was comparable for doses but slightly earlier for deltoid (13—l4d) Vs
`gluteal injections (13—17(1). Median Cm,“ (range 5.1-11.()ng/111L) was
`higher with deltoid vs gluteal injections except for 100mg eq. dose.
`Cmux slopes were significantly different from zero for deltoid (slope
`-().22, p:0.()062) and gluteal (slope -().3l;p<0.0001) injections, iridi-
`cating a less than proportional increase in Cmax with dose. Median
`(+)/(—) CM)( and AUCm ratios were ~l.7. After a single dose of pali-
`peridone palmitate, subjects received concomitant oral antipsychotics.
`Treatment-emergent AEs (TEAEs) included tachycardia (10%), head-
`ache (7%), schizophrenia (6%), insomnia (5%), weight gain (5%).
`Only 2% of subjects discontinued due to TEAEs.
`CONCLUSION: Data indicate AUCM increased proportionally
`with increasing paliperidone palmitate doses (25-150mg eq.), regard-
`less of gluteal or deltoid injection. Cmax was less than dose propor-
`tional for doses >50mg eq. Overall, deltoid injection was associated
`with a higher Cmax (except for 100mg eq.) and slightly earlier tmax vs
`gluteal injection.
`
`PI-75
`EVALUATION OF THE PHARMAC
`‘
`,
`GLUTEAL VERSUS DELTOID INTCITAMIUSICULXEFILE OF
`TIONS OF I’ALIPERIDONE PALMITATE 100 MG E INJEC-
`LENT IN PATIENTS WITH SCHIZOPI—IRENIA A (CHIVAI
`S. Rossenu,l D.HoughPH.Crauwels,‘ A.Vandebosch .1] Ee' CIR-NE
`M. Eerdekens,I
`I. Francctic3;
`lJohnson & Johnson ’Pharnihgdu'ti:
`Research & Development, Beerse, Belgium, ZJolmson‘ &‘J:lu“-Ldl
`Pharmaceutical Research & Development, Titusville NJ 3lnstitnt1=50n‘
`Clinical Pharmacology, Clinical Hospital Centre, Zagreb, Croati'Lil L 01
`BACKGROUND: The aim of this study was to compare tlie PK
`profile of paliperidone palmitate 100 mg eq, administered into the d ‘1
`toid (n:24) or gluteal muscle (11:25).
`L —
`METHODS:
`111
`this multiple-dose, open-label, parallel-urou )
`study, patients with schizophrenia were randomized to receive ifconl—
`secutrve injections (Days 1, 8, 36 and 64).
`RILSULIS: The median Cmax was higher in deltoid vs. "luteal
`muscle alter the 2nd (31.3 vs. 24.lng/mL) and 4111 (23.7 vs 252 3110/
`mL) injections. After 4 injections, the median fluctuation iridexu(FT)
`was higher (71.9 vs. 56.2%), with a larger intersubject variabilit
`for
`deltoid vs. gluteal injection. Median Tnm was similar between ih'ec-
`tion sites after the 211d (10 vs. 10 days) and 4th injections (5 vs J6 5
`days). The median concentration-time profile was higher follow-
`jng lglelltoid injection. After 4 injections, median AUC was similar
`or
`011 injection sites; C .
`, and AUC '
`~
`2
`'
`-'
`.0
`L
`->
`‘1
`(90‘/r;CI=l()0.56-168.93) a'llii‘ 20% (90¢72c1i:<lejjgej$25))wlfilfiw33f/o
`deltoid vs. gluteal muscle, respectively. Increased ~median Staci:
`plasma concentrations on Days 8, 36 and 64 suggested subjects were
`not completely at steady state al'ter 4 injections. Most common]
`reported adverse events (combined injection sites) were orthostatiz
`hypotension (24%), hypotension (14%), diastolic hypertension (12%)
`and injection site pain (14%). Four patients discontinued due to psy-
`chosis. Paliperidone palmitate was well tolerated, with a mean injec—
`tion site pain VAS score of 3.3 for gluteal vs. 10.8 for deltoid muscle
`(Day 1, 8 hours after injection).
`i
`. CONCLUSION: Paliperidone palmitate 100 mg cq., had an
`increased AUCI, higher C1me and greater Fl when injected into the
`deltoid vs. gluteal muscle, although similar T , was noted for both
`injection sites. Paliperidone palmitate 100 mg 16?th was well tolerated.
`
`PI—76
`OF
`PHARMACOKINETIC MODEL
`RECIRCULATORY
`FENTANYL AEROSOL IN VOLUNTEERS. M. J. Avram, PhDl
`T. K. Henthorn, MD,2 D. A. Spyker, PhD, MD,3 J. V. Cassella, PhDi;
`:Northwestern University Feinberg School of Medicine, Chicago, IL,
`“University of Colorado Health Sciences Center, Denver, CO, 3Alexza
`Pharmaceuticals, Inc, Palo Alto, CA
`BACKGROUND/AIMS: A thermalIy-generated aerosol (TGA)
`system can deliver pure drug reliably to the alveoli, resulting in rapid
`systemic drug absorption.l This study determined the pharniacokinet-
`ics (PK) of fentanyl from the moment of administration as a TGA and
`as a rapid intravenous (IV) infusion to volunteers and absolute TGA
`bioavailability.
`METHODS: Fentanyl disposition was determined twice in each
`of 10 healthy volunteers (5 males, 5 females, mean x SD age 25.3 t
`4.0 yr and weight 77.7 i 7.4 kg) in this IRE-approved 2-period cross—
`over study. Studies were condtlcted after a 5 5 IV (25 pg) infusion and
`after aTGA (25 ug coated dose) via Staccato® Fentanyl for Inhalation,
`Alexza Pharmaceuticals, Palo Alto, CA, delivered in a single breath.
`Twenty-five arterial blood samples were collected from 15 sec to 8 h
`after drug administration. Plasma fentanyl concentrations were inca-
`sured by liquid chromatography—tandem mass spectrometry. IV and
`TGA PK were characterized simultaneously by a recirculatory PK
`model.2
`RESULTS: TGA fentanyl administration produced plasma arte-
`rial drug concentrations similar to those produced by rapid IV infu-
`sion. The good simultaneous fit of the recirculatory model to arterial
`
`Mylan V. Janssen (IPR2020-00440) Exhibit 1003 p.003
`CLINICAL PHARMACOLOGY & THERAPEUTICS 1 VOLUME 83 SUPPLEMENT 1
`1 MARCH 2008
`S31
`
`