Long-acting stimulants:
`development and dosing
`James M. Swanson, PhD1
`
`Until relatively recently, the choices of stimulant
`medications for children were limited. Amphetamines
`and immediate-release methylphenidate (MPH) have
`been used for several decades, but in their native
`"immediate release" (IR) formulations, both have rapid
`onsets and short durations of action, and must therefore
`be given at least twice daily for optimal clinical efficacy
`throughout the day. The challenge to the clinician using
`short-acting preparations was to find the optimum dosing
`regimen for each child—and dosing requirements could
`vary as much as sixfold between individual children.
`After a morning dose of MPH, peak concentration
`(Cmax) is reached about 2 hours after dosing, and
`concentrations have declined by half approximately 2
`hours later (T112). Higher doses will produce higher Cmax
`values, but do not affect the time of the peak (Tmax) or
`onset or T112. For several decades, it was assumed that the
`clinician merely had to find the Cmax that would produce
`the optimal clinical response 1 to 2 hours after dosing,
`and keep this constant throughout the day. Smaller
`doses were therefore used toward the end of the day;
`these were the "sculpted" dosing regimens of the early
`1990s. For example, children in the MTA study who
`were treated with an average MPH dose received MPH
`10 mg in the morning, 10 mg at noon, and 5 mg in the
`afternoon. However, after the 14-month treatment phase,
`compliance with drug treatment worsened considerably,
`in part because medicated children suffered teasing at
`the hands of their peers when called to the principal's
`office to take noontime medication doses. The longer
`formulations then available included Ritalin SR® and
`Dexedrine® spansules. Neither medication provided
`coverage for the whole day, and the reasons for this
`were a mystery. Several manufacturers
`therefore
`embarked on the development of more effective once-
`daily medications in collaboration with investigators at
`the University of California at Irvine laboratory school
`(analogue classroom) using surrogate measures of drug
`efficacy.
`Development of Concerta OROS-MPH
`An effective once-daily stimulant formulation should
`
`* All trademark rights used under licence.
`
`deliver medication in a pattern that produces optimum
`clinical effects that begin shortly after administration
`and are maintained for the desired duration. To find this
`pattern, a "sipping study"' was conducted among 36
`children with ADHD who were already being treated
`effectively with immediate-release MPH regimens.
`These children attended a laboratory school (the analog
`classroom) on several Saturdays, where they were given
`either active medication or placebo in various patterns
`every 30 minutes throughout the day. They were also
`evaluated multiple times throughout the day using the
`Swanson, Kotkin,Agler, M-Flynn, and Pelham (SKAMP)
`rating scale,2 which had been developed to measure not
`ADHD symptoms (inattention, overactivity, impulsivity,
`etc) but the classic behavioural manifestations of ADHD
`in the classroom (eg, getting started, staying on task,
`interacting with peers, working neatly, staying seated, or
`remaining quiet). Academic productivity was measured
`objectively by means of a 10-minute written math test
`containing problems of appropriate difficulty for the
`child—both number of problems attempted and number
`of correctly worked problems were tracked.
`The known pharmacokinetic profiles revealed that
`twice-daily administration of immediate release (IR)
`MPH produced a highly variable pattern of plasma
`MPH concentration (Figure 1A: left side, Ritalin bid),
`which was associated with a corresponding variability
`in SKAMP scores (Figure 1B: right side, Ritalin bid).
`Dosing IR-MPH as an initial bolus at 7:30 am followed
`by a small but constant dose every 30 minutes from
`8:30 am to 3:00 pm (with doses depending on the child's
`usual IR-MPH dose) produced a flat plasma profile
`(zero-order drug delivery; Figure 1A: left side, Flat) and
`SKAMP scores that showed full efficacy in the morning
`compared to the child's standard drug regimen. However,
`surprisingly, about 40% of the effect was lost later in the
`day (Figure 1B: right side, Flat). Finally, an experimental
`condition defined by dosing IR-MPH without a large
`initial bolus but ascending doses throughout the day
`(selected to produce high afternoon plasma levels that
`matched the afternoon peak of the tid regime) showed
`SHIRE EX. 2061
`KVK v. SHIRE
`IPR2018-00293
`
`1 Professor of Pediatrics, UCI Child Development Center, University of California at Irvine, Irvine, California
`Corresponding Author: jmswanso@uci.edu
`
`4
`
`Supplement 1 : The Canadian Chi ld and Adolescent Psychiatry Review August 2005 (14) :3
`Page 1
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`

`

`Figure 1A: Acute tolerance: Development of a concept
`Figure 1A: Acute tolerance: Development of a concept
`Simulated Plasma Profiles
`Simulated Plasma Pro!les
`
`Figure 1B: Acute tolerance: Development of a concept
`Figure 1B: Acute tolerance: Development of a concept
`Impact on SKAMP
`Impact on SKAMP
`
`SKAMP Deportment Index
`
`—
`
`_
`
`Ritalin bid
`Flat
`Ascending
`
`2.0
`
`0.8
`
`0.4 —
`
`4- Ritalin bid
`-e- Placebo
`Flat
`-.- Ascending
`
`Concentration (nglmL)
`
`0
`
`5
`
`Time (hours)
`
`10
`
`15
`
`0
`
`2
`
`4
`
`8
`6
`Time (hours)
`
`10
`
`12
`
`14
`
`Swanson J, et al. Clin Pharmacol Ther 1999;66:295.
`Swanson J, et al. Clin Pharmacol Ther 1999;66:295.
`Copyright © 1999, reprinted with permission from The American Society for Clinical Pharmacology & Therapeutics.
`Copyright © 1999, reprinted with permission from The American Society for Clinical Pharmacology & Therapeutics.
`
`A. Study 1: Simulated plasma methylphenidate concentrations
`A. Study 1: Simulated plasma methylphenidate concentrations
`for a 20 mg total daily dose delivered by twice daily (bid), at,
`for a 20 mg total daily dose delivered by twice-daily (bid), !at,
`and ascending dosing regimens.
`and ascending dosing regimens.
`
`B. Study 1: Peak and trough responses for an example ef cacy
`B. Study 1: Peak and trough responses for an example ef!cacy
`measure (attention subscale of the SKAMP rating scale) for the
`measure (attention subscale of the SKAMP rating scale) for the
`bid, at, ascending, and placebo treatments.
`bid, !at, ascending, and placebo treatments.
`
`no or low ef cacy during the morning, but full ef cacy
`no or low ef!cacy during the morning, but full ef!cacy
`in the afternoon (Figures lA and B: Ascending).
`in the afternoon (Figures 1A and B: Ascending).
`This laboratory school study had two important
`This laboratory school study had two important
`ndings. First, the decline in ef cacy with the at
`!ndings. First, the decline in ef!cacy with the !at
`plasma pro le suggested that acute drug tolerance
`plasma pro!le suggested that acute drug tolerance
`(tachyphylaxis) was developing in response to exposure
`(tachyphylaxis) was developing in response to exposure
`to relatively high drug levels over 3 to 4 hours. The
`to relatively high drug levels over 3 to 4 hours. The
`hypothesis of acute tolerance would explain why
`hypothesis of acute tolerance would explain why
`formulations such as Ritalin SR, which used a zero order
`formulations such as Ritalin SR, which used a zero-order
`drug delivery as a target, did not have the anticipated
`drug delivery as a target, did not have the anticipated
`long acting ef cacy. In the face of this acute tolerance,
`long-acting ef!cacy. In the face of this acute tolerance,
`the traditional dosing protocol (such as the "sculpted"
`the traditional dosing protocol (such as the “sculpted”
`procedure used in the MTA study) should be reversed:
`procedure used in the MTA study) should be reversed:
`once a morning bolus achieves its initial rapid effect,
`once a morning bolus achieves its initial rapid effect,
`afternoon doses should not be smaller than the morning
`afternoon doses should not be smaller than the morning
`dose (based on the hypothesis that some carryover
`dose (based on the hypothesis that some carryover
`would occur, and a smaller dose would thus maintain the
`would occur, and a smaller dose would thus maintain the
`initially effective plasma concentration at a constant level
`initially effective plasma concentration at a constant level
`across the day), but instead should be equal to or larger
`across the day), but instead should be equal to or larger
`than the initial bolus to produce higher concentrations
`than the initial bolus to produce higher concentrations
`in the afternoon than in the morning to maintain full
`in the afternoon than in the morning to maintain full
`ef cacy. Second, the experimental ascending condition
`ef!cacy. Second, the experimental ascending condition
`demonstrated that a bolus dose was not necessary to
`demonstrated that a bolus dose was not necessary to
`achieve full ef cacy, and that an appropriately designed
`achieve full ef!cacy, and that an appropriately designed
`continuous delivery of MPH could reach the same level
`continuous delivery of MPH could reach the same level
`of ef cacy as the afternoon ef cacy following multiple
`of ef!cacy as the afternoon ef!cacy following multiple
`bolus doses of equal size (which along with carryover
`bolus doses of equal size (which along with carryover
`produces an ascending series of peaks across the day).
`produces an ascending series of peaks across the day).
`Of course, to achieve rapid onset an initial bolus would
`Of course, to achieve rapid onset an initial bolus would
`
`be required, but if the decline from the peak of the
`be required, but if the decline from the peak of the
`initial bolus could be avoided, then perhaps it could be
`initial bolus could be avoided, then perhaps it could be
`slightly smaller than the typical initial bolus of a clinical
`slightly smaller than the typical initial bolus of a clinical
`regime based on the rationale that the rst bolus must
`regime based on the rationale that the !rst bolus must
`be suf cient to maintain adequate ef cacy of the drug
`be suf!cient to maintain adequate ef!cacy of the drug
`despite its short, 2 hour half life (for which the plasma
`despite its short, 2-hour half-life (for which the plasma
`concentrations fall by 50% over 2 hours).
`concentrations fall by 50% over 2 hours).
`These ndings were con rmed in a second proof
`These !ndings were con!rmed in a second proof-
`of-concept study3 with a randomized, double-blind
`of concept study3 with a randomized, double blind
`crossover design. In this trial, 32 con rmed MPH
`crossover design. In this trial, 32 con!rmed MPH
`responders received either placebo or lR MPH three
`responders received either placebo or IR-MPH three
`times daily, or an ascending delivery of small doses
`times daily, or an ascending delivery of small doses
`designed to maintain full ef cacy after an initial large
`designed to maintain full ef!cacy after an initial large
`bolus selected to achieve rapid onset of the effect; both
`bolus selected to achieve rapid onset of the effect; both
`active treatments produced similar signi cant reductions
`active treatments produced similar signi!cant reductions
`in SKAMP scores compared to placebo (Figure 2).
`in SKAMP scores compared to placebo (Figure 2).
`The next phase of development involved engineering
`The next phase of development involved engineering
`a way to deliver MPH in the ascending pattern. The
`a way to deliver MPH in the ascending pattern. The
`initial plan had been to use the original OROS system, a
`initial plan had been to use the original OROS system, a
`round pill designed for zero order drug delivery; instead,
`round pill designed for zero-order drug delivery; instead,
`because of the results described above, an oblong pill
`because of the results described above, an oblong pill
`was designed that achieved the desired rst order drug
`was designed that achieved the desired !rst-order drug
`delivery. This pill is coated with lR MPH in order to
`delivery. This pill is coated with IR-MPH in order to
`produce a bolus with a rapid onset of effect. The rest of
`produce a bolus with a rapid onset of effect. The rest of
`the total daily dose is contained in a reservoir, together
`the total daily dose is contained in a reservoir, together
`with a polymer that expands when it absorbs water
`with a polymer that expands when it absorbs water
`diffusing into the compartment. This expanding polymer
`diffusing into the compartment. This expanding polymer
`pushes the drug out of a laser drilled hole into the GI
`pushes the drug out of a laser-drilled hole into the GI
`tract, from whence it is absorbed. Prototypes with a
`tract, from whence it is absorbed. Prototypes with a
`
`Supplement 1: The Canadian Child and Adolescent Psychiatry Review August 2005 (141:3
`S u p p l e m e n t 1 : T h e C a n a d i a n C h i l d a n d A d o l e s c e n t P s y c h i a t r y R e v i e w A u g u s t 2 0 0 5 ( 1 4 ) : 3
`
`5
`5
`
`Page 2
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`Page 2
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`

`

`Figure 2: An ascending profile of MPH delivery maintains SKAMP attention scores
`Figure 2: An ascending pro!le of MPH delivery maintains SKAMP attention scores
`
`4 _
`
`3 _
`
`A Ascending condition
`•
`tid-treated condition
`•
`Placebo-treated condition
`
`Main effect of treatment (ANOVA) p < 0.001
`
`1
`9 am
`
`1
`1
`11 am
`1 pm
`Primary session time (h)
`
`1
`3 pm
`
`5 pm
`
`Swanson J, et al. Arch Gen Psychiatry 2003;60:204. Copyright © 2003, American Medical Association. All rights reserved.
`Swanson J, et al. Arch Gen Psychiatry 2003;60:204. Copyright © 2003, American Medical Association. All rights reserved.
`Results of the proof of concept study: the Attention and Performance subscales of the Swanson, Kotkin, Agler, Mylnn, and Pelham
`Results of the proof-of-concept study: the Attention and Performance subscales of the Swanson, Kotkin, Agler, Mylnn, and Pelham
`(SKAMP) rating scale and the percentage of errors made on the computerized mathematics test.
`(SKAMP) rating scale and the percentage of errors made on the computerized mathematics test.
`
`single compartment OROS reservoir did not reliably
`single compartment OROS reservoir did not reliably
`achieve the targeted ascending pro le, so a reservoir
`achieve the targeted ascending pro!le, so a reservoir
`with two drug compartments was developed, the second
`with two drug compartments was developed, the second
`containing a higher MPH concentration than the
`rst.
`containing a higher MPH concentration than the !rst.
`This formulation was shown to produce the desired initial
`This formulation was shown to produce the desired initial
`rapid rise in MPH plasma level and smooth ascending
`rapid rise in MPH plasma level and smooth ascending
`pharmacokinetic pro le produced by a gradient of MPH
`pharmacokinetic pro!le produced by a gradient of MPH
`concentrations that exit the laser drilled hole as the
`concentrations that exit the laser-drilled hole as the
`contents of the two reservoir compartments mix in the
`contents of the two reservoir compartments mix in the
`water that crosses the membrane3 (Figure 3).
`water that crosses the membrane3 (Figure 3).
`
`An additional proof of product study using this
`An additional proof-of-product study using this
`new formulation3 showed that SKAMP scores for both
`new formulation3 showed that SKAMP scores for both
`attention and deportment decreased dramatically in the
`attention and deportment decreased dramatically in the
`morning after the initial bolus, and these decreases were
`morning after the initial bolus, and these decreases were
`maintained for 12 hours after dosing (Figure 4). This
`maintained for 12 hours after dosing (Figure 4). This
`trial3 of OROS-MPH compared with placebo and
`trial3 of OROS MPH compared with placebo and
`IR MPH three times daily (as well as a parallel study
`IR-MPH three times daily (as well as a parallel study
`by another team of investigators4) was carried out in
`by another team of investigators4) was carried out in
`both the laboratory school and natural settings; in this
`both the laboratory school and natural settings; in this
`study, ratings on the Inattention/Overactivity subscale of
`study, ratings on the Inattention/Overactivity subscale of
`
`Figure 3: Proof of product study: PK profiles for OROS MPH (Concerta) and IR MPH (Ritalin)
`Concern:
`
`I
`
`0
`
`2
`
`4
`
`6
`Time (h)
`
`8
`
`10
`
`12
`
`B.
`
`(left side) A. Greenhill LL, et al. J Am Acad Child Adolesc Psychiatry 2003;42:1234
`(right side) B. Swanson JM, et al. Arch Gen Psychiatry 2003;60:204. Copyright © 2003, American Medical Association. All rights reserved.
`
`3B. The pharmacokinetic pro les from a 3 way crossover study of immediate release OROS methylphenidate hydrochloride adminis
`tered with a (high fat breakfast) and without (fasting) food, and tid (3 times daily) methylphenidate administered in the fasting state.
`OROS is a new oral once a day formulation to deliver methylphenidate by osmotic pump process based on OROS technology (ALZA
`Corp, Mountain View, Calif).
`
`Supplement 1: The Canadian Child and Adolescent Psychiatry Review August 2005 (14):3
`S u p p l e m e n t 1 : T h e C a n a d i a n C h i l d a n d A d o l e s c e n t P s y c h i a t r y R e v i e w A u g u s t 2 0 0 5 ( 1 4 ) : 3
`Page 3
`
`-
`
`111.Membrane
`e
`
`MPH #1
`
`Polymer
`
`44
`
`44
`44
`
`MPH
`Overcoat
`
`A.
`
`1 1
`i, ii-
`,
`
`/
`
`i
`
`/,'
`/,'
`/,'
`
`OROS high fat (n = 15)
`• Ritalin fasting (n = 15)
`OROS fasting (n = 15)
`
`

`

`Figure 4: Proof of product study: SKAMP scores for attention and deportment with OROS MPH and IR MPH
`Figure 4: Proof-of-product study: SKAMP scores for attention and deportment with OROS-MPH and IR-MPH
`
`3.0_
`
`2.5 _
`
`tn
`
`m .
`
`g 1.5 _
`
`tv,
`
`1.0 _
`
`1E
`
`E 8 0.5 _
`
`0.0
`A.
`A.
`
`p < 0.001 (either active treatment vs placebo)
`
`• OROS-methylphenidate hydrochloride-treated condition
`•
`tid-methylphenidate-treated condition
`A Placebo-treated condition
`
`1
`
`2
`
`3
`
`8
`7
`6
`5
`4
`Time after initial dose (h)
`
`9
`
`10
`
`11 12
`
`3.0_.
`
`2.5 _
`
`<1.)
`RS
`
`A 2.0_
`cy>„,
`
`Y1.5_
`
`u)E
` X01.0_
`
`0.5 _
`
`0.0
`B.
`B.
`
`p < 0.001 (either active treatment vs placebo)
`
`2
`
`3
`
`8
`7
`6
`5
`4
`Time after initial dose (h)
`
`9
`
`10
`
`11 12
`
`Swanson JM, et al. Arch Gen Psychiatry 2003;60:204. Copyright CD 2003, American Medical Association. All rights reserved.
`Swanson JM, et al. Arch Gen Psychiatry 2003;60:204. Copyright © 2003, American Medical Association. All rights reserved.
`
`Attention ratings using the Swanson, Kotkin, Agler, Mylnn, and Pelham (SKAMP) rating scale by the University of California,
`Attention ratings using the Swanson, Kotkin, Agler, Mylnn, and Pelham (SKAMP) rating scale by the University of California,
`Irvine, Laboratory School showing the onset and duration of OROS methylphenidate hydrochloride treated condition and tid (3
`Irvine, Laboratory School showing the onset and duration of OROS-methylphenidate hydrochloride-treated condition and tid (3
`times daily) methylphenidate treated condition in the proof of product study. OROS is a new oral once a day formulation to deliver
`times daily)-methylphenidate-treated condition in the proof-of-product study. OROS is a new oral once-a-day formulation to deliver
`methylphenidate by osmotic pump process based on OROS technology (ALZA Corp, Mountain View, Calif).
`methylphenidate by osmotic pump process based on OROS technology (ALZA Corp, Mountain View, Calif).
`A.
`A.
`OROS methylphenidate treated condition (n = 60)
`OROS-methylphenidate-treated condition (n = 60)
`tid methylphenidate treated condition
`(n = 61)
`tid-methylphenidate-treated condition
`(n = 61)
`Placebo treated corxlition
`(n = 60)
`Placebo-treated condition
`(n = 60)
`
`59
`59
`60
`60
`58
`58
`
`60
`60
`60
`60
`58
`58
`
`59
`59
`62
`62
`59
`59
`
`59
`59
`61
`61
`58
`58
`
`60
`60
`62
`62
`58
`58
`
`60
`60
`62
`62
`59
`59
`
`60
`60
`62
`62
`59
`59
`
`59
`59
`62
`62
`58
`58
`
`B.
`B.
`OROS methyphenidate treated condition
`OROS-methyphenidate-treated condition
`tid methylphenidate treated condition
`tid-methylphenidate-treated condition
`Placebo treated corxlition
`Placebo-treated condition
`
`(n = 60)
`(n = 60)
`(n = 61)
`(n = 61)
`(n = 60)
`(n = 60)
`
`59
`59
`62
`62
`59
`59
`
`58
`58
`61
`61
`58
`58
`
`60
`60
`62
`62
`58
`58
`
`60
`60
`62
`62
`59
`59
`
`60
`60
`62
`62
`59
`59
`
`59
`59
`62
`62
`58
`58
`
`59
`59
`60
`60
`59
`59
`
`60
`60
`60
`60
`58
`58
`
`the Inattention/Overactivity with Aggression Conners
`the Inattention/Overactivity with Aggression Conners
`(IOWA C) rating scale were well correlated with each
`(IOWA-C) rating scale were well correlated with each
`other and consistent with the results of the previous
`other and consistent with the results of the previous
`study (Figure 5).
`study (Figure 5).
`A large longer-term open-label study5 involved 407
`A large longer term open label study5 involved 407
`children aged 6 to 13 years with documented response
`children aged 6 to 13 years with documented response
`to MPH who had participated in previous of cacy
`to MPH who had participated in previous ef!cacy
`or pharmacokinetic studies of OROS MPH. The
`or pharmacokinetic studies of OROS-MPH. The
`effectiveness (as measured by the IOWA C rating scale,
`effectiveness (as measured by the IOWA-C rating scale,
`Global Assessment Scale, and teachers' ratings of peer
`Global Assessment Scale, and teachers’ ratings of peer
`interactions) and tolerability of OROS MPH was shown
`interactions) and tolerability of OROS-MPH was shown
`to be maintained throughout the 12 months of the
`to be maintained throughout the 12 months of the
`analysis. It is important to note that at the beginning
`analysis. It is important to note that at the beginning
`of the study, children were assigned to one of three
`of the study, children were assigned to one of three
`doses of OROS MPH to match their clinically effective
`doses of OROS-MPH to match their clinically effective
`doses established in the initial clinical trials (28.5% on
`doses established in the initial clinical trials (28.5% on
`18 mg daily, 47.4% on 36 mg daily, and 24.1% on 54 mg
`18 mg daily, 47.4% on 36 mg daily, and 24.1% on 54 mg
`daily). Doses could be adjusted upward or downward
`daily). Doses could be adjusted upward or downward
`(or interrupted for weekends or nonschool days) at the
`(or interrupted for weekends or nonschool days) at the
`discretion of the physician who reviewed the child at
`discretion of the physician who reviewed the child at
`
`the monthly clinic visits. After 12 months of treatment,
`the monthly clinic visits. After 12 months of treatment,
`only 15.0% were still taking 18 mg daily, while 40.0%
`only 15.0% were still taking 18 mg daily, while 40.0%
`took 36 mg daily and 45.0% took 54 mg daily. The
`took 36 mg daily and 45.0% took 54 mg daily. The
`average dose increased from 35 mg to 41 mg daily, and
`average dose increased from 35 mg to 41 mg daily, and
`mean total dose per kg of body weight increased
`mean total dose per kg of body weight increased
`from 1.09 mg/kg at baseline to 1.26 mg/kg at month
`from 1.09 mg/kg at baseline to 1.26 mg/kg at month
`12. Thus, in a study in which doses were carefully
`12. Thus, in a study in which doses were carefully
`monitored, almost half the participants required
`monitored, almost half the participants required
`OROS MPH doses of at least 54 mg daily to achieve
`OROS-MPH doses of at least 54 mg daily to achieve
`optimal effects. The authors noted that the increased
`optimal effects. The authors noted that the increased
`dosage over time was consistent with other studies such
`dosage over time was consistent with other studies such
`as the MTA trial,6'7 and might re ect a ne tuning of the
`as the MTA trial,6,7 and might re!ect a !ne-tuning of the
`dose after the initial response is manifested, an increase
`dose after the initial response is manifested, an increase
`in dose as the child matures and body size increases, or
`in dose as the child matures and body size increases, or
`differences in evaluation by parents and teachers of the
`differences in evaluation by parents and teachers of the
`optimal or maximum response.
`optimal or maximum response.
`t he development of Adderall Xr
`h
`v I prn
`A
`all X
`The pharmacokinetic and pharmacodynamic effects of
`The pharmacokinetic and pharmacodynamic effects of
`Adderall were tested in the analog classroom in studies
`Adderall were tested in the analog classroom in studies
`similar to those used for the development for Concerta.
`similar to those used for the development for Concerta.
`
`Supplement 1: The Canadian Child and Adolescent Psychiatry Review August 2005 (14):3
`S u p p l e m e n t 1 : T h e C a n a d i a n C h i l d a n d A d o l e s c e n t P s y c h i a t r y R e v i e w A u g u s t 2 0 0 5 ( 1 4 ) : 3
`
`Page 4
`
`Page 4
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`

`Figure 5: Mean I/O ratings from IOWA C
`Figure 5: Mean I/O ratings from IOWA-C
`
`• Concerta
`
`• Ritalin E Placebo
`
`14 _
`
`12 _
`
`10 _
`
`8 _
`
`6 _
`
`4 _
`
`2 _
`
`IOWA Conners Inattention/Overactivity scale
`
`0
`
`I
`
`Parent
`
`Lab schoolteacher
`
`Community
`school teacher
`< 0.05 vs placebo
`Adapted from Swanson JM, et al. Arch Gen Psychiatry 2003;60:204. Copyright © 2003, American Medical Association. All rights reserved.
`Adapted from Swanson JM, et al. Arch Gen Psychiatry 2003;60:204. Copyright © 2003, American Medical Association. All rights reserved.
`IOWA (Inattention and Overactivity With Aggression) Conners rating scale from 3 sources (parent, University of California, Irvine,
`IOWA (Inattention and Overactivity With Aggression) Conners rating scale from 3 sources (parent, University of California, Irvine,
`laboratory school teacher, and community school teacher) in the proof of product study of the OROS methylphenidate hydrochloride
`laboratory school teacher, and community school teacher) in the proof-of-product study of the OROS-methylphenidate hydrochloride-
`treated condition, tid (3 times daily) methylphenidate treated condition, and placebo treated condition.
`treated condition, tid (3 times daily)-methylphenidate-treated condition, and placebo-treated condition.
`
`A double blind, crossover comparison of 10 mg once
`A double-blind, crossover comparison of 10 mg once-
`daily with 10 mg twice daily Adderall (considered the
`daily with 10 mg twice-daily Adderall (considered the
`standard dosing regime for lR Adderall at the time of this
`standard dosing regime for IR Adderall at the time of this
`study) among 12 subjects8 found that with once-daily
`study) among 12 subjects8 found that with once daily
`administration, although high serum concentrations were
`administration, although high serum concentrations were
`maintained in the afternoon, clinical ef cacy waned,
`maintained in the afternoon, clinical ef!cacy waned,
`as predicted by the hypothesis of acute tolerance. The
`as predicted by the hypothesis of acute tolerance. The
`twice daily dosing produced approximately doubled
`twice-daily dosing produced approximately doubled
`afternoon plasma levels and maintained full ef cacy in
`afternoon plasma levels and maintained full ef!cacy in
`
`the afternoon (Figure 6).
`the afternoon (Figure 6).
`Because amphetamine has a long pharmacokinetic
`Because amphetamine has a long pharmacokinetic
`half life, doubling of serum concentration can be
`half-life, doubling of serum concentration can be
`achieved by giving a second bolus dose of amphetamine,
`achieved by giving a second bolus dose of amphetamine,
`as demonstrated in the above study. Also, the
`as demonstrated in the above study. Also, the
`technology of polymer coated beads can be used to
`technology of polymer-coated beads can be used to
`delay the release of the second dose after a morning
`delay the release of the second dose after a morning
`administration that contains an lR component (uncoated
`administration that contains an IR component (uncoated
`beads) and a delayed release component (coated beads).
`beads) and a delayed-release component (coated beads).
`
`Figure 6: Math problems attempted and solved with Adderall 10 mg q8am (left) or q8am and ql2pm (right)
`Figure 6: Math problems attempted and solved with Adderall 10 mg q8am (left) or q8am and q12pm (right)
`
`200-
`
`180-
`
`120_
`
`100
`
`A.
`A.
`
`Math Effect-Concentration-Time plot: 10 mg Adderall q8am
`
`0(chss 1) 1 (class 2) 2(dass 3) Nelms 4) 4(class 5) 5(none)
`
`13(cbss 6)
`
`7(none)
`
`8(class 7) 9(none) 10(cess B)
`
`Time [hours] post 1st dose (class #)
`
`50.00
`
`40.00 ":1'
`-a)
`
`30.008
`
`a)
`20.00 2
`0
`co
`10.00 2
`
`0 00
`
`Math Effect-Concentration-Time plot: 10 mg Adderall q8am & q12pm
`200-
`50.00
`
`40.00 a
`-a,
`30.00 g
`:171
`0)
`20.00 2
`S 0
`
`10.00 2
`
`0.00
`
`100
`
`B.
`B.
`
`0(class 1) 1(class 2) 2(ceiss 3) 9(dass 4) 4(cisss 5)
`
`5(none) 6(dass 6)
`
`7(nene) Nelms 7)
`
`9(none) 10(dass 6)
`
`Greenhill LL, et al. A pharmacokinetic/pharmacodynamic study comparing a single morning dose of Adderall to twice daily dosing in children with
`Greenhill LL, et al. A pharmacokinetic/pharmacodynamic study comparing a single morning dose of Adderall to twice-daily dosing in children with
`ADHD. J Am Acad Child Adolesc Psychiatry 2003;42:1234 1241.
`ADHD. J Am Acad Child Adolesc Psychiatry 2003;42:1234-1241.
`
`A.
`A.
`SKAMP score: pharmacokinetics and pharmacodynamics: 10 mg of Adderall given at 8 am.
`SKAMP score: pharmacokinetics and pharmacodynamics: 10 mg of Adderall given at 8 am.
`B.
`B.
`SKAMP score: pharmacokinetics and pharmacodynamics 10 mg of Adderall given at 8 am and noon.
`SKAMP score: pharmacokinetics and pharmacodynamics 10 mg of Adderall given at 8 am and noon.
`
`Supplement 1: The Canadian Child and Adolescent Psychiatry Review August 2005 (141:3
`S u p p l e m e n t 1 : T h e C a n a d i a n C h i l d a n d A d o l e s c e n t P s y c h i a t r y R e v i e w A u g u s t 2 0 0 5 ( 1 4 ) : 3
`Page 5
`
`Page 5
`
`

`

`Adderall XR—an extended-release formulation of mixed
`amphetamine salts—is composed of 50% immediate-
`release beads and 50% delayed-release beads designed
`to release medication after about 4 hours to mimic the
`effects of two doses of IR Adderall given 4 hours apart
`(Figure 7).8,9,10 The product is formulated in capsules
`containing 5 to 30 mg of drug, and can be sprinkled onto
`food for children who have difficulty swallowing pills.
`Adderall XR is currently unavailable in Canada.
`Proposed mechanisms of acute tolerance
`It is known that oral clinical doses of MPH act to block
`the dopamine transporter in the striatum, increasing
`the availability of dopamine at the synapse. It has
`
`been hypothesized that in response to this increased
`dopamine availability, postsynaptic dopamine receptors
`are inactivated by a process of internalization (retracting
`into the cell membrane).11 One way to overcome this
`mechanism of tolerance is to provide a medication-free
`interval; when synaptic dopamine concentrations return
`to baseline levels, the receptors re-emerge from the cell
`membrane, reverting to their normal sensitive states. A
`second way is to use a larger dose of MPH to produce
`a larger increase in synaptic dopamine concentration
`to compensate for the desensitization of the receptor.
`Studies to elucidate the mechanisms of acute tolerance
`to MPH and to amphetamine are underway.
`
`Figure 7: ADDERALL XR Pulse Delivery System
`
`Immediate-release bead
`
`Delayed-release bead
`
`ADDERALL XR Capsule
`Available in 5-, 10-, 15-, 20-, 25-mg, and 30-mg capsules
`Greenhill LL, et al. J Am Acad Child Adolesc Psychiatry 2003;42:1234
`
`REFERENCES
`1 Swanson J, Gupta S, Guinta D, et al. Acute tolerance
`to methylphenidate in the treatment of attention deficit
`hyperactivity disorder in children. Clin Pharmacol Ther
`1999;66:295-305.
`2 Swanson JM, Wigal SB, Udrea D, et al. Evaluation
`of individual subjects in the analog classroom setting I:
`examples of graphical and statistical procedures for within-
`subject ranking of responses to different delivery patterns
`of methylphenidate. Psychopharmacol Bull 1998;34:825-
`832.
`3 Swanson JM, Gupta S, Lam A, et al. Development
`of a new once-a-day formulation of methylphenidate
`for the treatment of attention-deficit/hyperactivity
`disorder: proof-of-concept and proof-of-product studies.
`Arch Gen Psychiatry 2003;60:204-211.
`4 Pelham WE, Gnagy EM, Burrows-MacLean L, et al.
`Once-a-day Concerta methylphenidate versus three-times-
`daily methylphenidate in laboratory and natural settings.
`Pediatrics 2001;107:e105.
`5 Wilens T, Pelham W, Stein M, et al. ADHD
`treatment with once-daily OROS methylphenidate:
`interim 12-month results from a long-term open-label
`study. J Am Acad Child Adolesc Psychiatry 2003;42:424-433.
`6 The MTA Cooperative Group. A 14-month
`
`randomized clinical trial of treatment