`

`provide clinical efficacy by increasing the availability
`of catecholamines, primarily dopamine, in the CNS 5 •
`hnn1ediate-release
`formulations of sti1nulants,
`particularly methylphenidate HCl, have been used to
`control ADHD symptoms for the past 30 years.
`However, there are some limitations of immediate(cid:173)
`release formulations: the short half-life and duration
`of efficacy, which result in the need for multiple daily
`dosing and, therefore, the involvement of the school
`system in remedicating. These limitations have led to
`the development of once-daily, extended-release
`formulations of methylphenidate HCl"-8 and mixed
`amphetamine saltss '1•
`CONCERTA®
`is an osmotic, controlled-release,
`OROS" formulation of methylphenidate HCl that
`controls ADHD symptoms effectively through 12 hw
`and ADDERALL XR™ is an extended-release, bead
`formulation of dextroamphetamine and amphetamine
`salts that provides long acting control of symptoms.
`Consistency in drug delivery and absorption from
`extended-release formulations is essential to reduce
`variability in plasma drug concentrations.
`The
`effect of
`food on extended-release
`formulations is typically quantified during product
`development, because gastrointestinal pH and
`changes in transit time can cause variability in drug
`release
`and/ or
`absorption.
`The
`standard
`bioavailability measures of maximum
`drug
`concentration (peak exposure) and total amount of
`drug absorbed (total exposure) are determined in the
`presence or absence of food. However, for once-daily
`formulations dosed in the morning, the consistency
`of
`drug exposure in children or adults, who may
`or may not have eaten breakfast, is also important.
`This is
`true
`exposure
`encompasses the first 8 h of the school or work day.
`Although the effect of food on early drug exposure is
`requirement
`for product
`stimulants, this
`in plasma
`4-8 h in
`
`conducted at PPD Development Inc, Austin, Texas in
`accordance with the ethical principles of the
`Declaration of Helsinki (amended 1996, South Africa)
`and those of Good Clinical Practice. Thirty-nine
`healthy subjects (21 women and 18 men) between 18
`and 50 years of age were enrolled. All subjects gave
`written, informed consent before participating.
`Subjects underwent a physical examination
`including an electrocardiogram and clinical laboratory
`profile.
`Subjects who
`had
`a
`history
`of
`gastrointestinal, cardiovascular, metabolic disease, or
`any other chronic disease; who had a history of
`analgesic, alcohol, barbiturate, amphetamine, or
`narcotic abuse; who were allergic to methylphenidate
`or amphetamine; or who participated in another
`clinical study within 30 days were excluded. In
`addition, subjects who tested positive for hepatitis B
`antigen or hepatitis C antibodies, drugs of abuse, or
`pregnancy were excluded.
`Eligible subjects reported to the clinical centre the
`evening before each study period and began an
`overnight fast. In the morning, they received a single
`dose of either 36 mg CoNCERTA@' or 20 mg
`in a fasted state (fasted) or 15
`ADDERALL XR1 M
`minutes after consuming a high-fat breakfast (fed).
`The standard high-fat breakfast consisted of two eggs
`fried in butter, two slices of toast with butter, two
`strips of bacon, 4 oz of hash brown potatoes and 8 oz
`of whole milk11 • Subjects participated in a supervised
`fast until lunch.
`(7 ml) were
`Blood
`collected
`samples
`venipuncture into anticoagulant (sodium heparin) pre-
`dose and at 1, 2, 2.5, 3, 3.5, 4, 5, 6,
`7, 7.5, 8,
`9, 12, 15, 24 and 28 h after the dose and
`were then
`until processed. Blood
`and plasma was collected for storage at -20°C.
`Subjects were monitored
`the study for
`allowed to leave the
`
`Methods
`
`0.25-25.0
`
`aho
`with
`gas
`detection. Calibration curves
`were linear within a nominal range of 0.25-50.0
`
`31
`
`Hfects of Foocl on Early Exposure to CoNcmrA and AoomALL XR
`
`/\uiier
`
`a!.
`
`Page 2
`
`

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`

`formulations where early exposure includes 8 h, the
`length of a school and work day. Significant effects of
`food on drug release and absorption may affect
`therapeutic efficacy, so the reliability of treatment
`may depend on whether the child or adult has eaten.
`Moreover, because breakfast diets may change each
`day, an extended-release stimulant with a delivery
`system susceptible to alteration by food may result in
`clinically-relevant, day-to-day fluctuations in plasma
`levels, which may affect the response to the drug.
`Such an effect has not yet been reported.
`This study showed large decreases in amphetamine
`plasma levels over the first 8 h when ADDERALL XR1 M
`was dosed after a high-fat breakfast. Mean decreases
`of 55.5C)b, 42.5% and 35.0% for early amphetamine
`exposure over 4, 6 and 8 h, respectively, were
`significantly different ( p < 0.000 l) from mean
`increases of 3%, 9.2% and 10.0% for early
`methylphenidate exposure.
`Plasma levels of methylphenidate over the first 8 h
`were independent of food. The unique, osmotic(cid:173)
`controlled OROS®
`tablet provided consistent,
`smooth methylphenidate release which was not
`affected by a high-fat breakfast. The reliability of
`CONCERTA~116 is an important clinical consideration
`when choosing a once-daily stimulant formulation to
`control symptoms of ADHD over a 12-hour period
`and certainly over the full school or work day,
`regardless of morning eating habits.
`
`Conclusions
`
`of mixed amphetamine salts from
`The
`ADDERALL XR™ was markedly slowed with food
`in
`led to
`amphetamine exposure over the first 8 h after the
`dose.
`contrast,
`exposure from the CoNCERTA'' OROS® tablet was
`unaffected
`food intake. This latter
`is
`to result in minimal
`variations in
`patterns vary and
`that
`
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`in the
`in chil-
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`316 Effects of Food on Early Exposure !o GoNCERT!l and AooER!ILL XR
`
`.1\.uiler el a!.
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`Page 6
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