WashingtonUniversitySchoolofMedicine
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`Journal Title: CNS Spectrums
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`Volume: 10
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`Issue: Supplement 820
`llllonthIYear: Dec 2005
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`Pages: 6-15
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`Article Author: Clause, Susan B
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`Article Title: Single- and multiple-dose
`pharmacokinetics of an oral mixed
`amphetamine salts extended~re|ease
`formulation in adults.
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`Imprint:
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`Call #:
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`Location: L4
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`ltem #:
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`CUSTOMER HAS REQUES'l'ED:
`Mail to Address
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`Karla Morris-Holmes (morrish)
`Husch, Blackwell. Sanders
`190 Carondolet Plaza, Ste. 600
`St. Louis, MO 63105
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`Amerigen Ex. 1045, p. 1
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`Single- and l\/Iultiple-Dose
`Pharmacokinetics of an Oral Mixed
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`Amphetamine Salts Extended-Release
`’
`Formulation in Adults
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`By Susan B. Clausen, PhD, Stephanie C. Read, MS, and Simon J. Tulloch, MD
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`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-
`tip|e—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
`(D-amphetamine) to levoamphetamine (L-amphet-
`amine) was observed for AUC,},, and Cmax. Time to
`maximum observed drug concentration (Tmax) was
`~5 hours for each isomer, and plasma concentra-
`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—arnphetamine to
`L—amphetamir1e was observed for AUC9_,,, and Cmax;
`Tmax was just over 4 hours for each isomer.
`- The concentrations of D—and L-amphetamine rise
`rapidly after single— and multiple—dose administra-
`tion due to the imrnediate—release component in
`MAS XR. Tmax occurs at ~5 hours. Drug concen-
`trations decrease slowly between 5 and 12 hours,
`likely reflecting the continuing absorption of
`delayed-release MAS XR pellets during this time.
`
`ABSTRACT
`
`Objectives: A.ssess the bioavailability of mixed
`amphetamine salts extendedxrelease (MAS XR) 30—mg
`capsules and the dose proportionality of pharmacolcinetic
`measures for MAS XR 20, 40, and 60 mg.
`Methods: Study A, an open—label single—peri0d
`study, and Study B, a randomized, operklabel, three-
`
`way crossover study, were conducted in healthy adults in
`a clinical research unit. I11 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 separated by 7—l4—day
`washout periods.
`Findings: Plasma dextroamphetamine (D—amphet—
`amine) and levoamphetamine (L—amphetamine) concen-
`trations were measured using a validated LC-MS/MS
`method. In Study A, a 3:1 ratio of D—amphetamine to
`L-amphetamine was observed for AUCOJ, and Cm”.
`Tm, was 4.2 and 4.3 hours for D—amphetamine to L—
`amphetamine, respectively. ln Study B, for D- and L—
`amphetamine, statistically significant differences were
`observed for AUCO_,, AUCOM, and Cm“ between
`all doses; there was a linear relationship between phar-
`macolcinetic variables and dose and T
`was similar
`for each isomer (range: 4.5-5 .3 hoursrlmiuith all given
`MAS XR doses.
`
`Conclusion: The extent of exposure as assessed
`by mean AUCO44 and Cum reflected the 3:1 ratio of
`D-amphetamine to barnphetamine in MAS XR 30—mg
`capsules. The phannacolcinetic profiles of MAS XR 20,
`40, and 60 mg are close proportional for the isomers.
`CNS Spectr. 2005;IO(l2 Suppl 20) :6-15
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`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 65% of
`children with a diagnosis of ADHD will continue
`to display behavioral problems and symptoms of
`the disorder into their adult lives? Epidemiologic
`
`Aclcnowledgments: The authors would like to thank Irving E. Weston, MD (MDS Harris, Phoenix, AZ) and James C. Kisicla, MD
`(MDS Harris, Lincoln, NE) for conducting the studies, and Theresa Craven Giering, MS, for assistance with manuscript preparation.
`Please direct all correspondence to: Stephanie C. Read, MS, Shire Pharmaceuticals lnc., 725 Chesterbroolc Blvd, Wayne, PA 19087;
`Tel: 484595-8110; Fax: 484-595-8651; Email: sread@us.shire.com.
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`_ Volume 10- Number 12 (Suppl 20)
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`CNS Spectrums — December 2005
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`Single- and Mulfiple—Dose Pharmacokinetics of an Oral MAS XR Formulation in Adults
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`data indicate that the prevalence of adult ADHD
`according to Diagnostic and Statistical Manual of
`Mental Disorders, Fourth Edition criteria is ~5%.3"‘
`Given an adult population of 209 million in the
`US, a 5% prevalence rate suggests that as many as
`10 million adults may be affected by ADHD.‘ The
`core symptoms of ADHD—inattcntion, impulsiv-
`ity, and hyperactivity—are apparent in adults with
`ADHD, although hyperactive symptoms diminish
`with age.‘5 As in children with ADHD, adults show
`functional impairments in multiple domains. often
`including poor educational performance, occupa—
`tional problems, and relationship difficulties.
`Psychostimulant medications are well tolerated
`and are considered first—line medication for reduc-
`
`ing the core symptoms of ADI-lD.7'9 Although the
`specific mechanism of action has not been fully
`elucidated, stimulants both accentuate the release
`from and block the reuptake of the neurotransmit-
`ters dopamine and norepinephrine into presynaptic
`neurons.” The pharmacokinetic and pharinacody—
`namic effects of amphetamine have been described
`in adults and children.”"“ The absorption of
`amphetamine is rapid and complete from the gas»
`trointestinal tract, and maximum plasma concentra-
`tions are reached in 3-4 hours. Clinical behavioral
`
`effects are most apparent during the absorption
`phase and decrease after peak plasma concentra-
`tions are reached."'”
`
`lmmediate—release mixed amphetamine salts
`(MAS IR) is a formulation of neutral salts of D-
`amphetamine sulfate, amphetamine sulfate, D-
`amphetamine saccharate, and amphetamine
`aspartate. For each MAS IR tablet, the combina—
`tion of salts and D— and L—isomers results in a 3:1
`
`ratio of D—amphetamine to L—arnphetamine. The
`efficacy and tolerability of MAS IR in the treat-
`ment of children and adults with ADHD have been
`demonstrated in clinical studies.15'“
`The short duration of action of most stimulant
`
`medications has necessitated multiple daily closing
`to provide effective symptom management for many
`children.”'”’ The complexity and inconvenience
`of multiple dailytdose stimulant regimens can be
`problematic for a chronic disorder such as ADHD,
`and noncompliance has been well docu1ne11ted.27‘25
`Children and adults will benefit from the recent
`
`development of long»acting amphetamine formula-
`tions, which eliminate the need for multiple daily
`doses. The availability of once—daily dosage formula-
`tions for ADHD patients facilitates increased con-
`venience and Compliance, and is likely to increase
`treatment effectiveness and satisfaction.”
`
`Mixed amphetamine salts extended—release
`(MAS XR) capsules contain the same 3:1 ratio
`of D—amphetamine to L—amphetarnine present in
`MAS IR tablets. MAS XR is formulated for once-
`
`daily dosing via the inclusion of both immediate
`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 bioavaiiability and pharmacokinctic pro-
`files observed for both D— and L—amphetamine after
`once—daily dosing of MAS XR 20 mg are compa-
`rable with those observed after twice«daily dosing
`of MAS IR 10 mg with a 4«hour interval.” Because
`the immediate- and delayed—re1ease beads are dis«
`tributed in a 50:50 ratio uniformly throughout
`the capsule, MAS XR capsules can be opened and
`sprinkled on food without affecting bioavailabil—
`ity.” Food has little effect on plasma amphetamine
`levels, although gastrointestinal acidifying agents
`(eg, ascorbic acid) may decrease bioavailabiliry 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-
`blind, placebo-controlled studies of children with
`ADHD: one conducted in an analog classroom set-
`ting, and the other in a naturalistic home and school
`environment."-32 The long-term effectiveness and
`tolerabiiity of MAS XR have been demonstrated in
`a 2-year study.” 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—
`tained effectivcness.3“'35
`
`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-amphetamine may be relatively longer
`(by ~1—2 hours) in adults than in child:-en.”~” This
`raises the possibility for potential differences in the
`pharmacokinetic profile of MAS XR in adults rela-
`tive to what has already been well described in chil-
`dren. To better characterize the pharrnacokinctic
`profile of MAS XR in adults and to facilitate devel-
`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—arnphetamine after oral dosing of MAS XR 30 mg
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`Volume 10 — Number 12 (Suppl 20)
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`CNS Spectrums — December 2005
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`S.B. Clausen, S.C. Read, SJ. Tulloch.
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`-21'
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`in healthy adults. The objective of the second study
`was to assess the dose proportionality of D— and
`L—amphetarnine after single oral doses of MAS XR
`20, 40, and 60 mg in healthy adults.
`
`METHODS
`
`Subjects
`Men and women between 19 and 55 years of
`age with no clinically significant abnormal find-
`ings on physical examination, medical history, or
`clinical laboratory results during screening were
`admitted to the studies. Body weight was not more
`than 10% below or 20% above ideal weight for
`height and estimated frame adapted from the 1983
`Metropolitan Life lnsurance Tables.
`Major exclusion criteriawcre treatment with
`any known cytochrome P450 enzyme—altering
`agents (eg, barbiturates, phenothiazines, cimeti-
`dine) within 30 days before or during the study; use
`of any other prescription medicine within 14 days
`before or during the st_udy (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—
`nancy or lactation; history of clinically significant
`gastrointestinal, renal, hepatic, neurologic, hema-
`tologic, endocrine, oncologic, pulmonary, immuno-
`logic, psychiatric, or cardiovascular disease; or any
`other condition that, in the opinion of the investi-
`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—
`thine—containing product 48 hours before and dur—
`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 MDS Harris, Phoenix, AZ (Study
`A), and MDS Harris, Lincoln, NE (Study 13). Shire
`Pharmaceuticals Inc. supplied all study drugs.
`
`Stud;/A Design
`Study A was an operklabcl, single~period, mul-
`tiple—dose study in 20 healthy subjects. Each subject
`received a total of seven doses, administered as sin—
`gle MAS XR 30—mg capsules on seven consecutive
`
`mornings. The seventh (final) dose was adminis-
`tered after a 10-hour overnight fast.
`A 30—mg dose was selected to enable quanti—
`tation of anticipated blood levels of both D« and
`L—amphetarnine over the 60»hour time period.
`Furthermore, 30 mg is the highest dosage strength
`marketed for MAS XR capsules, and previous expe-
`rience suggested that this dose would be well toler-
`ated by healthy subjects.
`Drug Administration
`Subjects were admitted to the clinic in the eve—
`ning, at least 10 hours before the first scheduled
`dose. At checloin, subjects completed a brief writ»
`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 serum preg»
`nancy test. Subjects remained at the clinic until
`completion of the 36—hour postdose blood collec-
`tion on day 8 and returned to the clinic for the 48-
`and 60-hour postdose specimen collections.
`After checloin, each subject received a meal or
`an evening snack, and water was allowed ad libi-
`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 closing 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»
`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»
`istcred with 8 fl oz room—temperature tap water; a
`mouth check was performed after closing to ensure
`that the capsule was swallowed.
`Blood Collection
`
`A total of 24 biood samples (7 mL per sam-
`ple) were collected for determination of D— and
`I.-amphetamine 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 1, 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.
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`CNS Spectrums — December 2005
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`Sin;le- andMultil-ale-DosePharmacokinefics ofan OralMASXRFormulationinAdults
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`Blood samples were collected by venipuncture into
`tubes containing ethylenediaminetetraacetic acid
`(EDTA) and stored on ice before plasma was sepa-
`rated by centrifugation (~2,5OO 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-
`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-
`ing before closing.
`Statistical Analysis
`The pharmacokinetic variables for D- and
`L-amphetamine were tabulated using descriptive
`statistics (N, mean, standard deviation, median,
`and minimum and maximum values) for all sub-
`
`jects with evaluative data. Adverse events, blood
`pressure. and pulse were tabulated descriprively.
`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
`61?. (SAS Institute, Cary, NC).
`
`Study 8 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 IO-mg capsules),
`40 mg (2 X Z0-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-
`ning, at least 12 hours before the scheduled dose.
`At each treatment period check-in, subjects com-
`pleted a brief written questionnaire to affirm that
`exclusion criteria and restrictions had not been vio-
`
`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-
`tion (sitting or standing) to assure proper stomach
`emptying. A standard meal schedule resumed with
`lunch, dinner, and an evening snack for all sub-
`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
`D- and L-amphetamine levels. Beginning on each
`closing day, 19 blood samples were collected from
`each subject through the 60-hour postdose inter-
`val during each study period. Blood samples were
`collected 5 minutes before dosing and at 1. Z, 3, 4,
`5, 6, 7, 8, 9, 10, ll, 12, 14. I6, 24, 36, 48, and 60
`hours. Two additional blood samples were collected
`for the clinical laboratory evaluation at the screen-
`ing visit. For women, another 25 mL was collected
`at each check-in period for a senim 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 riondirected 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 D- and L-amphetamine
`were calculated for all pharmacokinetic variables
`for all subjects with evaluative data. An analy-
`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-
`mum observed drug concentration (Cum), time to
`maximum observed drug concentration (Tmax). and
`elimination half-life (ti/fl) to determine differences
`between the doses. The model included sequence,
`Subject within sequence, period, and close. Profile
`analysis was performed to test the differences in the
`least-square estimated means between each pair of
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`Volume 10 — Number 12 (Suppl 20)
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`CNS Spectrums — December 2005
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`S.B. Clausen, S.C. Read, SJ. Tulloch
`ll‘~m—
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`adjacent doses, using the t test procedure of mul-
`tiple mean comparisons.
`Regression analysis using a linear model was
`used to estimate the change in a variable as a func-
`tion of increase or decrease in dose for AUC and
`
`Cmx.“ From a clinical perspective, estimates from
`the fitted linear model were presented to show
`the amount of change in a pharinacokinetic vari-
`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 proce-
`dures” closely similar to those previously described
`for the enantiorneric separation of other R/S race—
`mic drugs.38=59 Amphetamine isomers and deuter-
`ated analogs as internal standards were extracted
`from plasma under alkaline conditions into organic
`solvent. The analytes were back-extracted into
`acid, alkalinized derivatized with benzoyl chloride,
`and re—eXtracted into organic solvent. After aque-
`ous wash to remove excess reagent, the organic
`extract was evaporated to dryness and reconsti—
`tuted in mobile phase. Analysis was performed by
`chiral high—performance liquid chromatography
`with tl.J.ITbO—lOI1Sp1‘E1V tandem mass spectrometry
`detection. For Study A, a weighted ([1/x], where
`x=concentration of compound) linear regression
`was used to determine slopes, intercepts, and cor—
`relation coefficients for D— and L—amphetamine con—
`centrations in study samples and internal standards.
`Concentrations of D— and L—amphetamine were lin-
`ear over the range of 0.5 to 50 ng/mL with a limit
`of quantitation (LOQ) of 0.5 ng/mL. For Study B, a
`weighted (1 /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—amphetamine
`were linear over the range of 0.5 to 75 ng/mL and
`1.0 to 125.0 ng/mL, respectively.
`
`Pharmacokinetic Analysis
`Pharmacokinetic parameters were determined for
`both D» and L—amphetamine by standard noncom—
`partmental methods. The primary pharmacokinctic
`variables included area under the drug concentra-
`tion—time curve from time 0 to t hour (A.UCO_t),
`where t was the last time point of the interval
`
`with a measurable drug concentration; area under
`the drug concentration—time curve from time 0 to
`infinity (AUC0_Oo); Cm“; Tmx; and tr/,. For both
`isomers, AUCO_t was calculated using the linear
`trapezoidal rule. The residual area under the curve
`between the last time point measured and infinity
`(AUCHO) was determined and added to AUCO_[ to
`obtain AUCOM. The AUCW,=Ct/ke, where Ct was
`the last measurable plasma concentration and ke
`was the terminal elimination rate constant detet—
`
`mined by linear regression of the terminal log linear
`phase of the plasma drug concentration versus time
`curve. The ti/i 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—amphetamine following drug administra-
`tion on day 7 are shown in Figure 1. Descriptive
`statistics of pharmacokinetic variables for D» and
`L—amphetamine isomers at steady state are 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
`
`(N=20)
`
`10 (50)
`10 (50)
`
`Study B
`
`(N=i.Z)
`
`5 (42)
`N58)
`
`31.8 (1845)
`
`32.5 (2246)
`
`Variable
`
`Gender, n (%)
`Male
`Female
`
`Age in years
`Mean (range)
`
`Race, n (%)
`
`White
`
`Black
`
`Hispanic
`
`14 (70)
`
`3 (15)
`
`3 (15)
`
`12 (100)
`
`0
`
`0
`
`Height in cm
`Mean (range)
`
`169.?
`(154.9a182.9)
`
`172.?
`(1575-1854)
`
`74.2
`68.1
`Weight in kg
`(60.9—97.’r‘)
`(51.8~85.0)
`Mean (range)
`Clausen 53, Read SC, Tulloch SJ. CNS Spectr. Vol 10, No 12 (Suppl
`20). 2005.
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`Single- and Multiple-Dose Pharmacokinetics of an Oral MAS XR Formulation in Adults
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`adverse events were headache (30% of subjects) and
`dizziness (25%). Others included insomnia (10%),
`anxiety (10%), and pain (10%; two subjects reported
`pain at venipuncture site). All others were reported
`by 5% of subjects (n=1). All events were mild
`(93.5%) or moderate (65%) 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 serious adverse events or deaths
`occurred during the study.
`Compared with baseline values (predose on day
`1), statistically significant increases in mean pulse
`(P<.Ol) were noted for days 2 through 7. The mean
`increases from baseline ranged from 6-12 bpm on
`these days. No statistically significant changes in
`systolic or diastolic blood pressure were noted.
`
`I o-Amphetamine
`
`I L-Amphetamine
`
`
`
`Concentration(rig./rnL)
`
`No clinically significant ECG abnormalities were
`observed on days l/7.
`
`Study 8
`Twelve subjects (mean age:3Z.5 years) were
`enrolled and randomized to treatment; 11 com-
`pleted all periods of the crossover study (Table 1).
`One subject withdrew from the study after receiv-
`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-
`files of D— and L-amphetamine for MAS XR 20, 4-0,
`and 60 mg are shown in Figure 2. A comparison of
`mean Cum values for the three doses are presented
`in Figure 3. Similar patterns of exposure were
`observed for AUCM, AUC0,,,c, Cum, Tam, and [LA
`for D—amphetamine and L-amphetamine (Tables 3
`and 4).
`
`EE1
`5c
`C
`
`'13._4-:I:inuc
`O{J
`
`fime (hrs)
`
`FIGURE 1. Mean plasma D- and L-amphetamine
`concentration versus time profiles for MAS XR
`30 mg at steady state
`MAS XR=rnixed amphetamine salts extended release.
`
`Clause-n SB, Read SC, Tulloch SJ. CNS Spectr. Vol 10, No 12 (Suppl
`20). 2005.
`
`O D-Amphetamine. 50 mg/day
`I D—Amphetamine, 40 mglclay
`A D-Amphetamine, 20 mg/day
`
`6 i.—Amphetamine, 60 mglday
`I L—Ampl1etarnine, 40 mglday
`A L-Amphetamine, 20 mglday
`
`FIGURE 2. Mean plasma D- 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.
`
`Clausen SB, Read SC, Tulloch SJ. CNS Spectr. Vol 10, No 12
`(Suppl 20). 2005.
`
`TABLE 2. STEADY-STATE Pl-IARMACOKINETIC PARAMETERS FOR d- AND l—A|VlPHETAM|NE
`FOLLOWING MUL1'lPLE-DOSE ADMINISTRATION OF MAS XR 30 MG ONCE DAILY (STUDY A)
`
`MAS XR
`
`30 mg (n=20)
`
`d—Amphetamine
`
`L-AM P HETAM we
`Data are mean:SD.
`
`AUCOQ4 (ng.h l./lTl
`9Z3.581l79.76
`
`32?.87:63.19
`
`AUCO_w (ng-hrlmL)
`
`1294.3 72290.45
`
`506.1 71125.05
`
`Cmax (ng/m L)
`66.881118
`
`Tmax (hr)
`
`4.18:1.I8
`
`ti/2 (hr)
`11.281112
`
`217214.60
`
`4.30:r1.12
`
`13.77t3.3
`
`MAS XR=mixed amphetamine salts extended release; AUC,,_24=area under the drug concentration time-curve from_tir_ne U_ to 24 hour post-
`dose; AUCn_,,,=AUC from time 0 to infinity; C,.,,,,,=maximum observed drug concentration; T,,,a,=time to Cma;
`t,,,=e|Immatlon half-life.
`Clausen SB, Read SC, Tulloch Sl. CNS Spectr. Vol 10, No 12 (Suppl 20). 2005.
`
`Volume 10 — Number 12 (Suppl 20)
`
`11
`
`CNS Spectrums — December 2005
`
`Amerigen Ex. 1045, p. 7
`Amerigen Ex. 1045, p. 7
`
`

`
`S.B. Clausen, S.C. Read, SJ. Tulloch
`
`
`The ANOVA results of the threezway crossover
`indicate statistically significant differences between
`the three dose groups in AUCO4, AUC0_m, and
`Cmax. The results of the multiple mean compari-
`sons demonstrated statistically significant differ»
`ences (P-10001) between the ZO— and 40—mg doses
`and between the 40- and 60—mg doses of MAS XR
`tor least—square mean values of AUCO_[, AUC0_w,
`and Cmax. These observations were consistent for
`both isomers. The linear regression model of dose
`versus plasma concentration revealed statistically
`significantly different slope values for AUCOJ3,
`AUC0_t, and Cm“ (P<.OO0l, respectively) for
`D» and L—amphetamine. Slope values fell within
`the 95% confidence intervals for slope for all three
`variables for both isomers. When the AUCO43
`was normalized to each dose, the resultant val-
`ues were similar (31 ng°hr/ml./g, 32 ng'hr/mL/
`g, and 33 ng'hr/ml./g obtained for the 20-, 40-,
`and 60—mg doses, respectively). The results of this
`study demonstrate that the extent and rate of drug
`absorption as assessed by AUCO'm and Cm“ were
`
`dose proportional in the range from 20—60—mg
`MAS XR. There were no statistical differences
`[T1 EIX
`
`between the observed T
`
`or tr/1 for the doses.
`
`I ti-Amphetamine
`
`I L-Amphetam ine
`
`MAS XR 20 mg
`
`MAS xn 40 mg
`
`MAS XR 60 mg
`
`FIGURE 3. Relationship between dose adminis-
`tered (mg) and observed mean maximum plasma
`0- and L—amphetamine concentrations
`*P<.00D1 compared with 20-mg dose.
`tP<.0[}O1 compared with 40-mg dose.
`Cm,=maximum observed drug concentration.
`Ciausen SB, Read SC, Tuiloch SJ. CNS Spectr. Vol 10, No 12 (Suppl
`
`TABLE 3. PHARMACOKINETIC PARAMETERS FOR d-AMPHETAMINE FOLLOWING A SINGLE 20-. 40-,
`AND 60-MG ORAL DOSE OF MAS XR (STUDY B)
`
`20). 2005.
`Clausen SB, Read SC, Tulloch SJ. CNS Spectr. Vol 10, No 12 (Suppl 20). 2005.
`Clausen SB. Read SC, Tulloch SJ. CNS Spectr. Vol 10, No 12 (Suppl 20). 2005.
`
`2,, T v v '
`
`
`
`
`
`_._
`
`I=|'W§
`
`
`
` -aw'-'
`
`_
`
`1
`
`i
`
`Dose of
`MAS XR
`
`AUC0_t
`(ng-hr/mL)
`
`20 mg (n=12)
`
`599.4:l6?.4
`
`40 mg (n=12)
`
`I241.5:207.9‘
`
`AUC04.
`(ng-hrlmL)
`
`615.m73.2
`1270.2-1220.8‘
`
`i927.s:441.4'
`
`1974. 1 :4-58.1
`
`CMBX
`(nglm L)
`
`Tmax (h r)
`
`tr/2 (h r)
`
`32.73:S.88
`
`4.9~_~1.l
`
`10.1: 1.3
`
`67.99.210.27‘
`l06.52:20.18’
`
`3021.1
`4.5«_=1.3
`
`io.3:1.5
`10.61~1.3
`
`so mg (n=11)
`Data are meanest).
`* P<.0001 compared with MAS XR 20 mg; ANOVA with (‘test for multiple mean comparisons.
`t P<.00O1 compared with MAS XR 40 mg; ANOVA with ttest for multiple mean comparisons.
`MAS XR=mixed amphetamine salts extended release; AUCM=area under the drug concentration time-curve from time 0 to t hour; AUC0_,=AUC
`from time 0 to infinity; C,,,a,=maximum observed drug concentration; T,,,a,=time to Cm“; t.,2=e|imination half-life; ANOVA=analysis of variance.
`
`TABLE 4. PHARMACOKINETIC PARAMETERS FOR I-AMPHETAMINE FOLLOWING A SINGLE 20-. 40-.
`AND 60-MG ORAL DOSE OF MAS XR (STUDY B)
`
`Dose of MAS XR
`
`20 mg (n=12)
`
`40 mg (n=12)
`
`AU Cm
`(ng-hr/m L)
`
`215.?:r_63.0
`
`AUCM,
`(ng-hr/mL)
`
`230.2:68.4
`
`CITIBX
`(ng/rnL)
`10.26:1.70
`
`Tmax (hr)
`5.0:1.4
`
`460.5:77.8'
`
`484.} 187.5‘
`
`2Z.14i3.81‘
`
`5.3tO.9
`
`t.,, (hr)
`12.5123
`
`121.712.]
`
`71131167.?‘
`
`749.71 1 79.9‘
`
`60 mg (n=11)
`Data are n‘Iean:t-SD.
`* P<.0001 compared with MAS XR 20 mg; ANOVA with ttest for multiple mean comparisons.
`T P-<.UOD1 compared with MAS XR 40 mg; ANOVA with t test for multiple mean comparisons.
`MAS XR:rni)<ed amphetamine salts extended release; AUC.;,_,=area under the drug concentration time—curve from time 0 to t hour; AUCQ_,=AUC
`from time 0 to infinity; Cma,=maximum observed drug concentration; T,..,a,.=time to Cmax; ty,=e|irnination half-life; ANOVA=ana|y-sis of variance.
`
`33.89:6.53'
`
`4.9:1.4
`
`13.0: 1 .8
`
`Volume 10 — Number 12 (Suppl 20)
`
`CNS Spectrum: — December 2005
`
`Amerigen Ex. 1045, p. 8
`
`
`Ameri en Ex. 104
`
`
`

`
`Sin le— and Multi le-Dose Pharmacokinetics of an Oral MAS XR Formulation in Adults
`
`
`
`Safety
`All three doses of MAS XR were suitably toler-
`ated. Twelve subjects reported a total of 156 adverse
`events during the crossover study. Thirteen of these
`adverse events (8.3%) were moderate in intensity,
`and all others (91.7%) were mild. Two of the events
`resolved or improved on the closing days, and the
`remainder resolved after the dosing period. The
`number of adverse events for individual subjects
`ranged from 1 to 25. The most common adverse
`events, reported by five or more subjects (42% of
`subject population) were anorexia (75%), asthe-
`nia (67%), dry mouth (42%), headache (58%),
`insomnia (58%), nausea (42%), paresthesia (42%),
`and somnolence (42%). Of the total