December2005
`CNS spectrums
`DUP-Ge
`· ,
`OP.rat Collection
`W
`1 CN15
`V,10,no 12
`200S-OJ-(J1 ' suppl. 20 (Dec. 2005
`
`Volume 10 - Number 12 - Suppl 20
`
`~CTRUMS®
`
`The International Journal of Neuropsychiatric Medicine
`
`ACADEMIC SUPPLEMENT
`Mixed Amphetamine Salts Extended
`Release for the Treatment of ADHD
`in Adults: Current Evidence
`
`Introduction
`J. Bieder111a11
`
`Single- and Multiple-Dose Pharmacokinetics of an Oral Mixed
`Amphetamine Salts Extended-Release Formulation in Adults
`S.B. Clausen, S. C. Read, SJ. Tulloch
`
`long-Term Safety and Effectiveness of Mixed Amphetamine Salts
`Extended Release in Adults With ADHD
`j. Bieder111a11, TJ. Spence,; T.E. Wilens, R.H. Weis/er, S.C. Read, S.j. Tulloch
`
`An Interim Analysis of the Quality of Life, Effectiveness, Safety,
`and Tolerability (QU.E.S. T.) Evaluation of Mixed Amphetamine Salts
`Extended Release in Adults With ADHD
`D. IV. Gootl111a11, L. Ginsberg, R.H. f#isler, A.j. Cutler, R I:lodgki11s
`
`long-Term Cardiovascular Effects of Mixed Amphetamine Salts
`Extended Release in Adults With ADHD
`R.H. f#isler,j. Biederman, T.J. Spencer, T.E. Wilens
`
`Index Medicus/MEDLINE
`citation: CNS Spectr
`
`Page 1 of 12
`
`KVK-TECH EXHIBIT 1033
`
`

`

`CNS SPECTRUMS®
`
`The International Journal of Neuropsychiatric Medicine
`
`December 2005
`Volume 10 - Number 12 - Supplement 20
`
`5
`
`6
`
`16
`
`26
`
`Introduction
`By Joseph Biederman, MD
`
`Single- and Multiple-Dose Pharmacokinetics of an
`Oral Mixed Amphetamine Salts Extended-Release
`Formulation in Adults
`By Susan B. Clausen, PhD, Stephanie C. Read, MS,
`and Simon J. Tulloch, MD
`
`Long-Term Safety and Effectiveness of Mixed
`Amphetamine Salts Extended Release in Adults
`WithADHD
`By Joseph Biederman, MD, Thomas J. Spencer, MD,
`Timothy E. Wilens, MD, Richard H. Weisler, MD,
`Stephanie C. Read, MS, and Simon J. Tulloch, MD,
`on behalf of the SLl381.304 Study Group
`
`An Interim Analysis of the Qyality of Life,
`Effectiveness, Safety, and Tolerability (QU.E.S.T.)
`Evaluation of Mixed Amphetamine Salts
`Extended Release in Adults With AD HD
`By David W. Goodman, MD, Lawrence Ginsberg, MD,
`Richard H. Weisler, MD, Andrew J. Cutler, MD, and
`Paul Hodgkins, PhD, PMP, RAC
`
`Founded in 1996, CNS Spectrums is an Index
`Medicus journal and is available on MEDLINE
`under the citation CNS Spectr. It is available
`online at www.cnsspectrums.com. CNS Spec(cid:173)
`trums is also distributed to all CINP members and
`is accredited for international CME by EACIC.
`
`CNS Spectrums (ISSN 1092-8529) is published
`monthly by MBL Communications, Inc., 333
`Hudson Street, 7th Floor, New York, NY 10013.
`
`One-year subscription rates: domestic $140;
`foreign $195; in-training $85. For subscrip(cid:173)
`tions: Phone: 212-328-0800; Fax: 212-328-0600;
`Web: www.cnsspectrums.com.
`Postmaster: Send address changes to CNS Spec(cid:173)
`trums do MMS, Inc, 185 Hanson Court, Suite 110,
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`
`For editorial inquiries, please fax us at 212-328-
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`Opinions and views expressed by authors are
`their own and do not necessarily reflect the
`views of the publisher, MBL Communications,
`Inc., or the editorial advisory board. Advertise(cid:173)
`ments in CNS Spectrums are accepted on the
`basis of adherence to ethical medical standards,
`but acceptance does not imply endorsement by
`CNS Spectrums or the publisher.
`
`CNS Spectrums is a registered trademark of
`CNS Spectrums, LLC, New York, NY. Permission
`to reproduce articles in whole or part must be
`obtained in writing from the publisher.
`
`BPA member since July 2005.
`
`35
`
`Long-Term Cardiovascular Effects ofMixedAmphet(cid:173)
`amine Salts Extended Release in Adults With ADHD
`By Richard H. Weisler, MD, Joseph Biederman, MD,
`Thomas J. Spencer, MD, and Timothy E. Wilens, MD
`
`MIL
`
`I! I 1, ff ~J '.i ,': J
`
`f, '
`
`Copyright ©2005 by MBL Communications, Inc.
`All rights reserved. Printed in the United States.
`
`Disclaimer
`
`This acac.lemic supplement is sponsorec.l by Shire Pharmaceuticals Inc. Sponsorship of this review c.loes not imply the sponsor's agree(cid:173)
`ment with the views cxpressec.l herein. Although every effort has been mac.le to ensure that c.lrug <loses anc.l other information arc
`presentcc.l accurately in this publication, the ultimate responsibility rests with the prescribing physician. Neither the publisher, the
`sponsor, nor the authors can be helc.l responsible for errors or for any consequences arising from the use of information contained
`herein. Readers are strongly urgcc.l to consult any relevant primary literature. No claims or endorsements arc made for any c.lrug or
`compound currently under clinical investigation. This supplement may contain information concerning a use or dosage schedule
`that has not been approved by the US Fooc.l and Drug Administration.
`
`Volume 10- Number 12 (Suppl 20)
`
`4
`
`CNS Spectrums - December 2005
`
`This material wasco,pied
`atthe NLM and m:ay b,a
`5ubject US Copyright Laws
`
`Page 2 of 12
`
`

`

`Academic Supplement
`
`Single- and Multiple-Dose
`Pharmacokinetics of an Oral Mixed
`Aniphetamine Salts Extended-Release
`Formulation in Adults
`
`By Susan B. Clausen, PhD, Stephanie C. Read, MS, and Simon J. Tulloch, MD
`
`FOCUS POINTS
`• Psychostimulant medications are well tolerated
`and are considered first-line medications for
`reducing the core symptoms of attention-deficit/
`hyperactivity disorder.
`• Two studies described here assessed single- and mul(cid:173)
`tiple-dose pharmacokinetics of mixed amphetamine
`salts extended release (MAS XR) in healthy adults.
`• Following a single oral dose of MAS XR (20, 40,
`or 60 mg), a 3:1 ratio of dextroamphetamine
`(o-amphetamine) to levoamphetamine (L-amphet(cid:173)
`amine) was observed for AUC0•00 and Cmax· Time to
`maximum observed drug concentration (T maxl was
`-5 hours for each isomer, and plasma concentra(cid:173)
`tions and extent of exposure for o-amphetamine
`and L-amphetamine were dose proportional.
`• Following multiple-dose administration of MAS
`XR 30 mg/day, a 3:1 ratio of o-amphetamine to
`L-amphetamine was observed for AUC0•00 and Cmax;
`T max was just over 4 hours for each isomer.
`• The concentrations of o-and L-amphetamine rise
`rapidly after single- and multiple-dose administra(cid:173)
`tion due to the immediate-release component in
`MAS XR. T max occurs at -5 hours. Drug concen(cid:173)
`trations decrease slowly between 5 and 12 hours,
`likely reflecting the continuing absorption of
`delayed-release MAS XR pellets during this time.
`
`ABSTRACT
`Objectives: Assess the bioavailability of mixed
`amphetamine salts extended-release (MAS XR) 30-mg
`cafJsules and the dose pro/)ortionality of /Jharmacol<inetic
`measures for MAS XR 20, 40, and 60 mg.
`Methods: Study A, an a/Jen-label single-period
`study, and Study B, a randomized, a/Jen-label, three-
`
`way crossover study, were conducted in healthy adults in
`a clinical research unit. In Study A, 20 subjects received
`a single MAS XR 30-mg capsule by mouth daily for 7
`days. In Study B, 12 subjects received single oral doses
`of MAS XR 20, 40, and 60 mg se/)arated by 7-14-day
`washout /)eriods.
`Findings: Plasma dextroamfJhetamine ( D-amphet(cid:173)
`amine) and levoam/Jhetamine (L-am/Jhetamine) concen(cid:173)
`trations were measured using a validated LC-MS/MS
`method. In Study A, a 3: 1 ratio of D-am/)hetamine to
`L-am/Jhetamine was observed for AUCo.oo and cmax·
`Tmax was 4.2 and 4.3 hours for o-am/Jhetamine to L(cid:173)
`amphetamine, respectively. In Study B, for D- and L(cid:173)
`amphetamine, statistically significant differences were
`observed for AUC0_tt AUC0_00 , and Cmax between
`all doses; there was a linear relationshi/J between /Jhar(cid:173)
`macol<inetic variables and dose and T max was similar
`for each isomer (range: 4 .5-5. 3 hours) with all given
`MAS XR doses.
`Conclusion: The extent of exposure as assessed
`by mean AUC0_24 and Cmax reflected the 3: 1 ratio of
`D-am/)hetamine to L-amphetamine in MAS XR 30-mg
`cafJsules. The pharmacol<inetic profiles of MAS XR 20,
`40, and 60 mg are dose pro/Jortional for the isomers.
`CNS Spectr. 2005; 10( 12 Su/J/)l 20) :6-15
`
`INTRODUCTION
`Attention-deficit/hyperactivity disorder (ADHD)
`is a neurobehavioral disorder that is one of the most
`prevalent chronic health conditions in children,
`affecting 2 % to 18% of school-age youth in the
`United States.' Although ADHD traditionally has
`been considered a pediatric disorder, up to 6Sc¼1 of
`children with a diagnosis of ADHD will continue
`to display behavioral problems and symptoms of
`the disorder into their adult lives. 2 Epidemiologic
`
`Acknowledgments: The authors would like to thank Irving E. Weston, MD (MDS Harris, Phoenix, AZ) and James C. Kisicki, ~D
`(MOS Harris, Lincoln, NE) for conducting the studies, and Theresa Craven Giering, MS, for assistance with manuscri/it Jire/iaratwn.
`Please direct all corres/iondence to: Ste/ihanie C. Read, MS, Shire Pharmaceuticals Inc., 725 Chesterbrook Blvd, Wayne, PA 19087;
`Tel: 484-595-8110; Fax: 484-595-8651; E-mail: sread@us.shire.com.
`Volume 10- Number 12 (Suppl 20)
`6
`
`CNS Spectrums - December 2005
`
`Th is mate ria I was Hipcied
`at the NLM and may b,e
`~ubject US Copyright Laws
`
`Page 3 of 12
`
`

`

`_______ S_i_n,...,g'--lc_-_a_n_d_M_u_l_ti_._p_lc_-_D_o_s_c_I_>J_1_ar_m_ac_o_ki_._n_c_ti_cs_o_fa_, n_O_r_al_MA __ S_X_R_~_·o_r_m_u_la_a_· o_n_in_A_d_u_l_ts _____ ...,r
`
`data indicate that the prevalence of adult ADHD
`according to Diagnostic and Statistical Manila/ of
`Mental Disorders, Fourth Edition criteria is -S(¼i. 1·4
`Given an adult population of 209 million in the
`US, a 5% prevalence rate suggests that as many as
`IO million adults may be affected by ADHD.; The
`core symptoms of ADHD-inattcntion, impulsiv(cid:173)
`ity, and hyperactivity-arc apparent in adults with
`ADI-ID, although hyperactive symptoms diminish
`with agc. 6 As in children with ADHD, adults show
`functional impairments in multiple domains, often
`including poor educational performance, occupa(cid:173)
`tional problems, and relationship difficulties.
`Psychostimulant medications arc well tolerated
`and arc considered first-line medication for reduc(cid:173)
`ing the core symptoms of ADHD. 7·'1 Although the
`specific mechanism of action has not been fully
`elucidated, stimulants both accentuate the release
`from and block the rcuptakc of the neurotransmit(cid:173)
`ters dopamine and norcpincphrinc into prcsynaptic
`ncurons. 10 The pharmacokinctic and pharmacody(cid:173)
`namic effects of amphetamine have been described
`in adults and childrcn. 11 - 14 The absorption of
`amphetamine is rapid and complete from the gas(cid:173)
`trointestinal tract, and maximum plasma concentra(cid:173)
`tions arc reached in 3-4 hours. Clinical behavioral
`effects arc most apparent during the absorption
`phase and decrease after peak plasma concentra(cid:173)
`tions arc rcachcd. 11 -14
`Immediate-release mixed amphetamine salts
`(MAS IR) is a formulation of neutral salts of D(cid:173)
`amphctaminc sulfate, amphetamine sulfate, [)(cid:173)
`amphetamine saccharatc, and amphetamine
`aspartatc. For each MAS IR tablet, the combina(cid:173)
`tion of salts and[)- and L-isomcrs results in a 3:1
`ratio of [)-amphetamine to L-amphctaminc. The
`efficacy and tolerability of MAS IR in the treat(cid:173)
`ment of children and adults with ADHD have been
`24
`demonstrated in clinical studics. 11
`·
`The short duration of action of most stimulant
`medications has necessitated multiple daily dosing
`to provide effective symptom management for many
`children. 25,2 6 The complexity and inconvenience
`of multiple daily-dose stimulant regimens can be
`problematic for a chronic disorder such as ADHD,
`28
`and noncompliance has been well documcntcd. 27
`•
`Children and adults will benefit from the recent
`development of long-acting amphetamine formula(cid:173)
`tions, which eliminate the need for multiple daily
`doses. The availability of once-daily dosage formula(cid:173)
`tions for ADHD patients facilitates increased con(cid:173)
`venience and compliance, and is likely to increase
`1
`treatment effectiveness and satisfaction. 2
`'
`
`Mixed amphetamine salts extended-release
`(MAS XR) capsules contain the same 3: 1 ratio
`of [)-amphetamine to L-amphctamine present in
`MAS IR tablets. MAS XR is formulated for once(cid:173)
`daily dosing via the inclusion of both immediate(cid:173)
`release beads, which release the first half of the dose
`upon ingestion, and delayed-release beads, which
`begin to release the second half of the dose 4 hours
`later. The bioavailability and pharmacokinetic pro(cid:173)
`files observed for both D- and L-arnphctaminc after
`once-daily dosing of MAS XR 20 mg arc compa(cid:173)
`rable with those observed after twice-daily dosing
`1 Because
`of MAS IR 10 mg with a 4-hour interval. 1
`l
`the immediate- and dclaycd-rclcasc heads arc dis(cid:173)
`tributed in a 50:50 ratio uniformly throughout
`the capsule, MAS XR capsules can be opened and
`sprinkled on food without affecting bioavailabil(cid:173)
`ity.10 Food has little effect on plasma amphetamine
`levels, although gastrointestinal acidifying agents
`(cg, ascorbic acid) may decrease bioavailability by
`reducing absorption.
`The efficacy, safety, and extended duration of
`action of MAS XR 10-, 20-, and 30-mg capsules
`were demonstrated in two randomized, double(cid:173)
`blind, placebo-controlled studies of children with
`ADHD: one conducted in an analog classroom set(cid:173)
`ting, and the other in a naturalistic home and school
`cnvironmcnt. 31 •32 The long-term effectiveness and
`tolerability of MAS XR have been demonstrated in
`a 2-ycar study. 11 In addition, a well-controlled study
`of MAS XR 20, 40, and 60 mg once daily in adults
`with ADHD demonstrated significant symptom
`improvement and 12-hour duration of action in
`this population, and long-term results show sus(cid:173)
`tained effectiveness. 14· 15
`Detailed pharmacokinetic studies of MAS XR have
`been limited primarily to the pediatric population!!
`and as such may not generalize to the adult ADHD
`population. Earlier studies of amphetamine agents
`suggest, for instance, that the elimination half-life of
`both D- and L-amphctamine may be relatively longer
`14 This
`(by -1-2 hours) in adults than in childrcn. 13
`'
`raises the possibility for potential differences in the
`pharmacokinctic profile of MAS XR in adults rela(cid:173)
`tive to what has already been well described in chil(cid:173)
`dren. To better characterize the pharmacokinctic
`profile of MAS XR in adults and to facilitate devel(cid:173)
`opment of MAS XR as a first-line treatment for
`adults with ADHD, two separate studies in healthy
`adult volunteers using doses up to 60 mg/day were
`conducted. The objective of the first study was
`to assess the steady-state bioavailability of D- and
`L-amphctaminc after oral dosing of MAS XR 30 mg
`
`Volume 10- Number 12 (Suppl 20)
`
`7
`
`CNS Spectrums - December 2005
`
`This material wase1:Ipied
`atthe NLM and may bE
`5'ubject US Copyright Laws
`
`Page 4 of 12
`
`

`

`S.B. Clausen, S.C. Read, S.J. Tulloch
`
`in healthy adults. The objective of the second study
`was to assess the dose proportionality of D- and
`L-amphctaminc after single oral doses of MAS XR
`20, 40, and 60 mg in healthy adults.
`
`METHODS
`
`Subjects
`Men and women between 19 and 5 5 years of
`age with no clinically significant abnormal find(cid:173)
`ings on physical examination, medical history, or
`clinical laboratory results during screening were
`admitted to the studies. Body weight was not more
`than I 0% below or 20<¾1 above ideal weight for
`height and estimated frame adapted from the 1983
`Metropolitan Life Insurance Tables.
`Major exclusion criteria were treatment with
`any known cytochrome P450 enzyme-altering
`agents ( cg, barbiturates, phcnothiazines, cimcti(cid:173)
`dine) within 30 days before or during the study; use
`of any other prescription medicine within 14 days
`before or during the study ( excluding hormonal
`contraceptive or hormonal replacement therapy for
`women); use of any over-the-counter agent within
`7 days before or during the study; history of allergic
`or adverse response to amphetamine or any related
`drug; positive urine screen for alcohol or drugs of
`abuse or a history of drug or alcohol abuse; preg(cid:173)
`nancy or lactation; history of clinically significant
`gastrointestinal, renal, hepatic, neurologic, hema(cid:173)
`tologic, endocrine, oncologic, pulmonary, immuno(cid:173)
`logic, psychiatric, or cardiovascular disease; or any
`other condition that, in the opinion of the investi(cid:173)
`gator, would jeopardize the safety of the subject or
`affect the validity of the study results.
`Subjects were prohibited from ingesting food or
`beverages containing alcohol, caffeine, or any xan(cid:173)
`thine-containing product 48 hours before and dur(cid:173)
`ing each period of confinement; from ingesting fruit
`or juices (including grapefruit) containing ascorbic
`acid during confinement; and from participating in
`strenuous exercise during confinement.
`All subjects gave written, informed consent,
`and the studies were approved by the institutional
`review boards of MOS Harris, Phoenix, AZ (Study
`A), and MOS Harris, Lincoln, NE (Study B). Shire
`Pharmaceuticals Inc. supplied all study drugs.
`
`Study A Design
`Study A was an open-label, single-period, mul(cid:173)
`tiple-dose study in 20 healthy subjects. Each subject
`received a total of seven doses, administered as sin(cid:173)
`gle MAS XR 30-mg capsules on seven consecutive
`
`mornings. The seventh (final) dose was adminis(cid:173)
`tered after a I 0-hour overnight fast.
`A 30-mg dose was selected to enable quanti(cid:173)
`tation of anticipated blood levels of both D- and
`L-amphctamine over the 60-hour time period.
`Furthermore, 30 mg is the highest dosage strength
`marketed for MAS XR capsules, and previous expe(cid:173)
`rience suggested that this dose would be well toler(cid:173)
`ated by healthy subjects.
`Drug Administration
`Subjects were admitted to the clinic in the eve(cid:173)
`ning, at least 10 hours before the first scheduled
`dose. At check-in, subjects completed a brief writ(cid:173)
`ten questionnaire to affirm that exclusion criteria
`and restrictions had not been violated since the
`screening period. A urine sample was collected
`to test for alcohol and drugs of abuse, and a blood
`sample was collected from women for a scrum preg(cid:173)
`nancy test. Subjects remained at the clinic until
`completion of the 36-hour postdose blood collec(cid:173)
`tion on day 8 and returned to the clinic for the 48-
`and 60-hour postdosc specimen collections.
`After check-in, each subject received a meal or
`an evening snack, and water was allowed ad libi(cid:173)
`tum. On days 1 through 6, subjects received clinic
`meals of breakfast, lunch, dinner, and an evening
`snack according to a standard schedule and menu.
`All subjects observed a supervised fast for at least
`10 hours before dosing on day 7. Water was allowed
`ad libitum during this time, except for 1 hour before
`and 1 hour after dosing on day 7. For 4 hours after
`drug administration on day 7, subjects were required
`to continue fasting and to remain in an upright
`position (sitting or standing) to assure proper stom(cid:173)
`ach emptying. The standard meal schedule was
`resumed with lunch on day 7. On day 8, water was
`allowed ad libitum, and all subjects received clinic
`meals of breakfast, lunch, and dinner according to
`the standard schedule. Each daily dose was admin(cid:173)
`istered with 8 fl oz room-temperature tap water; a
`mouth check was performed after dosing to ensure
`that the capsule was swallowed.
`Blood Collection
`A total of 24 blood samples ( 7 mL per sam(cid:173)
`ple) were collected for determination of D- and
`L-amphctamine plasma levels. On days 1, 5, and
`6, only predose blood samples were collected. On
`day 7 (steady state), blood samples were collected 5
`minutes before dosing and at I, 1.5, 2, 2.5, 3, 3.5, 4,
`5, 6, 7, 8, 9, 10, 12, 14, 16, 24, 36, 48, and 60 hours.
`At the screening visit, 15 ml of blood was collected
`for clinical laboratory evaluations; for women, an
`additional 5 ml was collected to test for pregnancy.
`
`Volume 10- Number 12 (Suppl 20)
`
`8
`
`CNS Spectrums - December 2005
`
`la
`
`This material was «Ipied
`at the NLM :and m:ay be
`5ubje,:t US Copyright Laws
`
`Page 5 of 12
`
`

`

`_______ S_i_n_..g'-lc_-_a_n_d_M_u_l_t ... ip_l_c-_D_o_sc_·_P_h_ar_m_a_c_o_ki_·n_c_t_ic_s_o_f_a_n_O_ral_MA __ S_X_R_~_o_r_m_u_l_att_·_o_n_i_n_A_d_u_l_t_s ______ , . .,.
`
`Blood samples were collected by venipuncture into
`tubes containing ethylcnediaminetetraacetic acid
`(EDTA) and stored on ice before plasma was sepa(cid:173)
`rated by centrifugation (-2,500 rpm x 15 minutes
`at 4°C). All plasma samples were frozen and stored
`at -20°C until assay was performed.
`Safety Evaluations
`Adverse event data were obtained by obser(cid:173)
`vation and unsolicited reporting throughout the
`study. A 12-lead electrocardiogram (ECG) was
`obtained, and sitting vital signs (blood pressure and
`pulse) were measured at screening and each morn(cid:173)
`ing before dosing.
`Statistical Analysis
`The pharmacokinetic variables for [)- and
`L-amphetamine were tabulated using descriptive
`statistics (N, mean, standard deviation, median,
`and minimum and maximum values) for all sub(cid:173)
`jects with evaluative data. Adverse events, blood
`pressure, and pulse were tabulated descriptively.
`There were no statistical comparisons of adverse
`events; vital signs were compared using a paired t
`test. All statistical analyses (for both studies) were
`performed using SAS statistical software, version
`6.12 (SAS Institute, Cary, NC).
`
`Study B Design
`Study B was an open-label, three-way crossover
`study designed to assess the dose proportionality of
`MAS XR following single 20-, 40-, and 60-mg doses.
`A standard 3 x 3 Latin square was used to assign the
`12 subjects to treatment sequences, with four subjects
`per sequence. In each sequence, subjects received a
`single dose of MAS XR 20 mg (2 x 10-mg capsules),
`40 mg (2 x 20-mg capsules), or 60 mg (2 x 30-mg
`capsules) after an overnight fast. Subjects received
`the other treatments during subsequent study periods
`according to the randomization scheme. A washout
`period of 7 days separated each study period.
`Drug Administration
`Subjects were admitted to the clinic in the eve(cid:173)
`ning, at least 12 hours before the scheduled dose.
`At each treatment period check-in, subjects com(cid:173)
`pleted a brief written questionnaire to affirm that
`exclusion criteria and restrictions had not been vio(cid:173)
`lated since the screening or previous study period.
`A urine sample was collected to test for alcohol and
`drugs of abuse, and a blood sample was collected
`from women for a serum pregnancy test. Subjects
`remained at the clinic until completion of the 24-
`hour postdose blood collection and returned to
`the clinic for the 36-, 48-, and 60-hour postdose
`collections. After check-in, each subject received
`
`a standard evening meal -12 hours before drug
`administration. Intact capsules were administered
`and a mouth check was performed after dosing to
`ensure that capsules were swallowed. Water was
`allowed ad libitum during the study, except for 1
`hour before and 1 hour after dosing. For 4 hours
`after drug administration, subjects were required to
`continue fasting and to remain in an upright posi(cid:173)
`tion (sitting or standing) to assure proper stomach
`emptying. A standard meal schedule resumed with
`lunch, dinner, and an evening snack for all sub(cid:173)
`jects. This schedule of events was followed for each
`of the three treatment periods.
`Blood Collection
`A total of 57 blood samples per subject (7 ml per
`sample) were collected for determination of plasma
`[)- and L-amphetamine levels. Beginning on each
`dosing day, 19 blood samples were collected from
`each subject through the 60-hour postdose inter(cid:173)
`val during each study period. Blood samples were
`collected 5 minutes before dosing and at 1, 2, 3, 4,
`5, 6, 7, 8, 9, IO, 11, 12, 14, 16, 24, 36, 48, and 60
`hours. Two additional blood samples were collected
`for the clinical laboratory evaluation at the screen(cid:173)
`ing visit. For women, another 25 ml was collected
`at each check-in period for a serum pregnancy test.
`Samples were collected by venipuncture into tubes
`containing EDTA and stored on ice before plasma
`was separated by centrifugation (-3,000 rpm x 10
`minutes at 4°C). All plasma samples were stored at
`-20°C until analysis was performed.
`Safety Evaluations
`Adverse event data were obtained by the use
`of nondirected questioning at preselected times in
`addition to spontaneous reports throughout the
`study. Vital signs (sitting blood pressure and pulse)
`were measured at screening and at five other times
`at every dosing period ( immediately before dosing
`and at 2, 4, 24, and 60 hours postdose).
`Statistical Analysis
`Descriptive statistics of[)- and L-amphetamine
`were calculated for all pharmacokinetic variables
`for all subjects with evaluative data. An analy(cid:173)
`sis of variance (ANOVA) model for a three-way
`crossover design with a general linear approach
`was applied to area under the curve (AUC), maxi(cid:173)
`mum observed drug concentration (C 111aJ, time to
`maximum observed drug concentration (TmaJ, and
`elimination half-life (t½) to determine differences
`between the doses. The model included sequence,
`subject within sequence, period, and dose. Profile
`analysis was performed to test the differences in the
`least-square estimated means between each pair of
`
`Volume 10- Number 12 (Suppl 20)
`
`9
`
`CNS Spectrums - December 2005
`
`This material was co,pcied
`at the NLM and may be
`5'ubject USCopcyright Laws
`
`Page 6 of 12
`
`

`

`S.B. Clausen, S.C. Read, S.J. Tulloch
`
`adjacent doses, using the t test procedure of mul(cid:173)
`tiple mean comparisons.
`Regression analysis using a linear model was
`used to estimate the change in a variable as a func(cid:173)
`tion of increase or decrease in dose for AUC and
`Cmax· 16 From a clinical perspective, estimates from
`the fitted linear model were presented to show
`the amount of change in a pharmacokinetic vari(cid:173)
`able that was expected as a function of increase or
`decrease in dose.
`Adverse events, blood pressure, and pulse were
`tabulated descriptively. There were no statistical
`comparisons of adverse events; vital signs were
`compared using a paired t test.
`
`Analytical Methods
`Plasma samples were analyzed by validated procc(cid:173)
`dures17 closely similar to those previously described
`for the cnantiomeric separation of other R/S race(cid:173)
`19 Amphetamine isomers and dcuter(cid:173)
`mic drugs. 18
`•
`atcd analogs as internal standards were extracted
`from plasma under alkaline conditions into organic
`solvent. The analytcs were back-extracted into
`acid, alkalinized derivatizcd with benzoyl chloride,
`and re-extracted into organic solvent. After aque(cid:173)
`ous wash to remove excess reagent, the organic
`extract was evaporated to dryness and reconsti(cid:173)
`tuted in mobile phase. Analysis was performed by
`chiral high-performance liquid chromatography
`with turbo-ionspray tandem mass spectrometry
`detection. For Study A, a weighted ([1/x], where
`x=conccntration of compound) linear regression
`was used to determine slopes, intercepts, and cor(cid:173)
`relation coefficients for D- and L-amphctaminc con(cid:173)
`centrations in study samples and internal standards.
`Concentrations of D- and L-amphetaminc were lin(cid:173)
`ear over the range of 0.5 to 50 ng/mL with a limit
`of quantitation (LOQ) of 0.5 ng/mL. For Study 13, a
`weighted (l/x2) quadratic regression was used with
`the same LOQ for both analytes. Because three
`different doses were administered in this study,
`the method was validated over two concentration
`ranges. Concentrations of D- and L-amphctamine
`were linear over the range of 0.5 to 75 ng/mL and
`1.0 to 125.0 ng/mL, respectively.
`
`Pharmacokinetic Analysis
`Pharmacokinctic parameters were determined for
`both D- and L-amphetamine by standard noncom(cid:173)
`partmental methods. The primary pharmacokinctic
`variables included area under the drug concentra(cid:173)
`tion-time curve from time O to t hour (AUCo_r),
`where twas the last time point of the interval
`
`with a measurable drug concentration; area under
`the drug concentration-time curve from time O to
`infinity (AUC0_00 ); Cmaxi Tmaxi and t½. For both
`isomers, AUC0_r was calculated using the linear
`trapezoidal rule. The residual area under the curve
`between the last time point measured and infinity
`(AUCr_ 00 ) was determined and added to AUCo-r to
`obtain AUC0_"" The AUCr_ 00=CJkc, where Cr was
`the last measurable plasma concentration and kc
`was the terminal elimination rate constant deter(cid:173)
`mined by linear regression of the terminal log linear
`phase of the plasma drug concentration versus time
`curve. The t½ for each isomer equalled 0.693/ke.
`
`RESULTS
`
`Study A
`Twenty subjects (mean age, 31.8 years) were
`enrolled and completed the study (Table 1 ).
`Pharmacokinetic Parameters
`Mean plasma concentration-time profiles for
`D- and L-amphctamine following drug administra(cid:173)
`tion on day 7 are shown in Figure 1. Descriptive
`statistics of pharmacokinetic variables for D- and
`L-amphctamine isomers at steady state arc reported
`in Table 2.
`Safety
`The MAS XR 30-mg dose was well tolerated.
`Nine subjects reported a total of 31 adverse events
`between days 1 and 8. The most commonly reported
`
`TABLE 1. SUBJECT DEMOGRAPHICS AND
`BASELINE CHARACTERISTICS
`Study A
`Study B
`
`Variable
`
`(N=20)
`
`(N=12)
`
`Gender, n (%)
`Male
`Female
`
`Age in years
`Mean (range)
`
`Race, n (%)
`
`10 (SO)
`10 (50)
`
`5 (42)
`7 (58)
`
`31.8 (18-55)
`
`32.5 (22-46)
`
`White
`
`Black
`
`Hispanic
`
`14 (70)
`3 (15)
`
`3 (15)
`
`12 (100)
`
`0
`
`0
`
`Height in cm
`Mean (range)
`
`169.7
`(154.9-182,9)
`
`172.7
`(157.5-185.4)
`
`Weight in kg
`Mean (range)
`
`68.1
`(51.8-85.0)
`Clausen SB, Read SC, Tulloch SJ. CNS Spectr. Vol 10, No 12 (Suppl
`20). 2005.
`
`74.2
`(60.9-97.7)
`
`Volume 10- Number 12 (Suppl 20)
`
`10
`
`CNS Spectrums - December 2005
`
`L.
`
`Th is mate ria I was Hipied
`at the NLM and may be
`~ubject US Copyright Laws
`
`Page 7 of 12
`
`

`

`_______ S_i_n..,,.g'-le_-_a_n_d_M_u_l_t1 .... · p_lc_-_D_o_sc_I_>_h_ar_m_a_co_l_ci_n_c_ti_c_s _o_fa_, n_O_r_al_MA __ S_X_R_~_·o_r_m_ul_a_tt_· o_n_i_n_A_d_u_lt_s _____ .. --
`
`Z!t:111 Jf lfWBWlFEaIUVeifiAAA µu;cu.::zw1 ;J 11
`
`No clinically significant ECG abnormalities were
`observed on days 1-7.
`
`Study B
`Twelve subjects (mean agc=32.5 years) were
`enrolled and randomized to treatment; 11 com(cid:173)
`pleted all periods of the crossover study (Table l) ·
`One subject withdrew from the study after receiv(cid:173)
`ing the 20-mg dose of MAS XR (treatment A) and
`the 40-mg dose of MAS XR (treatment B) due to
`an elevated pulse. All information collected from
`this subject was included in the analyses.
`Pharmacokinetic Parameters
`Mean plasma concentrations versus time pro(cid:173)
`files of n- and L-amphetamine for MAS XR 20, 40,
`and 60 mg are shown in Figure 2. A comparison of
`mean Crnax values for the three doses arc presented
`in Figure 3. Similar patterns of exposure were
`observed for AUC0_t> AUC0_00 , Cmax• Trnax• and t½
`for D-amphetaminc and L-amphetaminc (Tables 3
`and 4 ).
`
`120 T'"'------------------i
`:::. 100
`
`t
`~ 80
`0 ·;:.
`~ 60
`C
`['j
`C
`3
`
`40
`
`20
`
`12
`
`48
`
`60
`
`36
`24
`nme (hrs)
`+ o-Amphetamine, 60 mg/day + L-Amphetamine, 60 mg/day
`a L-Amphetamine, 40 mg/day
`• o-Amphetamine, 40 mg/day
`.a. o-Amphetamine, 20 mg/day
`.a. L-Amphetamine, 20 mg/day
`FIGURE 2. Mean plasma o- and L-amphetamine
`concentrations for single 20-mg (n=12), 40-mg
`(n=12), and 60-mg (n=11) doses of MAS XR
`MAS XR=mixed amphetamine salts extended release.
`
`adverse events were headache (30(){> of subjects) and
`dizziness (25%). Others included insomnia ( 10%),
`anxiety ( 10%), and pain (10%; two subjects reported
`pain at vcnipuncturc site). All others were reported
`by 5% of subjects (n=l). All events were mild
`(93.5%) or moderate (6.5%) in intensity, and all
`resolved. Of the 31 events, 9 (29%) were unrelated
`to study medication and 22 (71 %) were related or
`possibly related to study medication. Twenty-five of
`the 31 reported events (81 %) occurred on or before
`day 5, and the remaining six events (19%) occurred
`on day 8. None of the adverse events occurring on
`day 8 was related to study medication. No subjects
`were withdrawn from the study as a result of adverse
`events, and no