1. Can we give “hyperactive” children 8 tests across the day?

2. Swanson and Kinsbourne, 1978

3. DOSE PK C PD
EFFECT C E
E=E0 +
Emax • C
EC50 + C

4. Classroom Evaluations of Attention Deportment, and Performance

5. UCI Lab School Protocol
Time
Std
Exp
Classrm
0700
0730
BID1
dose 1
0800
0830
0900
peak
dose 2
Class 1
0930
dose 3
1000
dose 4
1030
dose 5
1100
trough
dose 6
Class 2
1130
BID2
dose 7
1200
dose 8
1230
dose 9
1300
dose 10
Class 3
1330
1400
1430
1500
Class 4
NAME______________________
DATE___________________
HOUR_________________ 2 7 4 6 1 3 5 + 9 8 -
10-minute Math Test
Getting started
Sticking with tasks
Completing work
Performing accurately
Careful and neat
Interacting with others
Remaining quiet
Staying seated
Complying with requests
Following the rules
SKAMP rating scale:
A repeatable probe for classroom manifestations (Academic and Deportment) of symptoms
At UC Irvine, we developed a way to evaluate the efficacy of different drug delivery profiles, which enabled use to compare several prototype profiles for Alza.
We identified 36 school-aged children with ADHD from clinical practices who were good responders to methylphenidate. These children volunteered to come to the UC Irvine Lab School each Saturday for 4 Saturdays in a row.
On each of these “test days”, the children took capsules very 30 minutes to allow us to establish several experimental drug delivery profiles, as well as their standard clinical regimes, under double-blind procedures. Across the day, the children (in groups of about 18) would shift back and forth between classroom period of about an hour and playground periods of about an hour.
We developed surrogate measures of response in the Lab School setting, where we could impose control over timing and context of serial assessments of response across the day. One measure was the SKAMP rating scale, designed to measure the classroom manifestations of ADHD behavior (see above) rather than the symptoms of the disorder (inattention, impulsivity, and hyperactivity).

6. Playground Evaluation of Behavior and Activity During Recess

7. Ritalin 10 mg TID vs Ascending Small Doses
Time Hr
10 mg Ritalin tid
Ascending
7:30 am
10 mg
8 mg
8:00 am
0.5
8:30 am
1.0
9:00 am
1.5
1.3 mg
9:30 am
2.0
10 ng/ml
1.4 mg
8 ng/ml
10:00
2.5
1.5 mg
10:30
3.0
1.6 mg
11:00
3.5
1.8 mg
11:30
4.0
6 ng/ml
1.9 mg
9 ng/ml
12:00
4.5
2.0 mg
12:30
5.0
2.1 mg
1:00 pm
5.5
2.2 mg
1:30 pm
6.0
12 ng/ml
2.3 mg
2:00 pm
6.5
2.4 mg
2:30 pm
7.0
2.5 mg
3:00 pm
7.5
2.6 mg
3:30 pm
8.0
11 ng/ml
4:00 pm
8.5
4:30 pm
9.0
5:00 pm
9.5
5:30 pm
10.0
14 ng/ml
6:00 pm
10.5
The optimal pattern of drug delivery in the “sipping study” for a typical ADHD child on a 10 mg TID regime of methylphenidate is shown, along with the serum concentrations of both the bolus and ascending profiles.
An initial bolus (8 mg) was administered to produce the full effect, and then small doses were administered to maintain the full effect.
The small doses started at about 2.5 mg per hour, and at the end of the day the “first order” (increasing) profile was delivering about 5.0 mg per hour.
The maximum serum concentrations of the new, optimum ascending drug delivery did not exceed the maximum serum concentrations of the old, standard bolus drug delivery.

8. Effects of Methylphenidate in LSP: 3 Settings and 3 Measures
At Desk
In Group
On Playground
Activity
Attention
Deportment

9. Evaluating the optimal MPH PK profile
Flat (zero order) profile
Ascending (first order) profile
Time after dose (h)
This study led us to re-evaluate the optimal PK profile for delivery of methylphenidate.
We know from clinical experience that some children would require low dose, some medium does, and some high does of medication, and that most of these children, regardless of the clinically optimal dose, would require doses to be administered about every 4 hours to maintain constant efficacy.
Instead of the zero-order (flat) profile shown on the left, this study by Swanson et al (1999) indicated that a first-order (ascending) profile would be required to maintain the optimal efficacy achieved at the peak of the initial bolus dose.
This provided a target PK profile to be evaluated in the next few studies, using the Lab School protocol.

10. Proof of product study: PK profiles for OROS-MPH (Concerta®) and IR-MPH (Ritalin®)
MPH Overcoat
Membrane
Polymer
MPH #2
MPH #1
Hole
Concerta®

11. Academic Productivity 10-minute Math Test2 3 5 7 9 10 11 12
1=Concerta™ QD
2=Ritalin® TID
3=Placebo
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Hours post initial dose
Mean deportment rating 50
100
150
200
250
# Math problems completed
Academic Productivity
10-minute Math Test
Classroom Behavior
SKAMP Rating Scale

12. Laboratory School Protocol

13. Dopfner et al, 2004, Eur Child Adolesc Psychiatry

14. New Formulations for Extended Delivery Osmotic Pump (Concerta) or Coated Beads (Equasym XL)
Extended Release (ER) MPH
Two ER MPH reservoirs
ER MPH coated beads
Laser-Drilled Hole
MPH Compartment #1
Tablet Shell
MPH Compartment #2
Swanson JM et al. Comparison of efficacy and safety of Concerta™ (methylphenidate HCl) with Ritalin® and placebo in children with ADHD. Presented at Region IX and X Annual Meeting of the Ambulatory Pediatric Association; February 12-13, 2000; Carmel, CA.
Schnipper’s notes:
This is what the ALZA technology team come up with
OROS technology
reliable/reproducible—used in products such as Padmixture rocardia XL
Overcoat—Immediate-release MPH
Semipermeable membrane
Polymer layer—water absorbed and expands the polymer compartment
Two concentrations of drug
Compartment 1—lower concentration
Compartment 2—delivered later in the day—higher concentration
Admixture between 1 and 2—mid-level concentration in midday
Drug pushed out of a very precisely laser-drilled hole at the top of the tablet
Technologically vary advanced/complex
Next step—test to make sure it produced target PK profile in vivo
OROS extended-release technology has been in use nearly 20 years and is used in
Ditropan XL®
Procardia XL®
Glucotrol XL®
Sudafed® 24-hour
Volmax® (in patients aged 6 years and older)
Tegretol®–XR (in patients of all ages)
Push Compartment
IR MPH overcoat
IR MPH uncoated beads
Immediate Release (IR) MPH

15. Proof of Concept Studies: Pharamacodynamic Profiles of Equasym XL (Wigal et al, J Applied Research, 2003) 20
MPH MR 30:70 15
MPH MR 40:60 10 5
Dose: 40 mg 2
3.5 5 6
7.5 9 10 12 13 15 16 18 19 21 22 24
Time After Dose (h)

16. Immediate Release (IR) MPH
Membrane
Hole
MPH #1
MPH Overcoat
MPH #2
Polymer
Immediate Release (IR) MPH
Extended Release (ER) MPH
EQXL

17. Non-Equivalence Study Equasym XL v Concerta
A Comparison of Once-Daily Extended-Release Methylphenidate Formulations in Children With Attention-Deficit/Hyperactivity Disorder in the Laboratory School (The Comacs Study)
Swanson JM et al PEDIATRICS Vol. 113, March 2004
Comparison of near-equal daily doses:
Low Dose Group: EQXL 20 mg vs CON 18 mg vs PLA
Med Dose Group: EQXL 40 mg vs CON 36 mg vs PLA
High Dose Group: EQXL 60 mg vs CON 54 mg vs PLA

18. Initial (IR) and Extended (ER) MPH Components (Swanson et al, 2002, J Attention Disorders, 6:s73–s88)
IR MPH
Concerta (IR + ER)
Equasym XL (IR + ER)
4 mg
18 mg (4 + 14)
6 mg
27 mg (6 + 21)
20 mg (6 + 14)
8 mg
36 mg (8 + 28)
10 mg
45 mg ( )
12 mg
54 mg ( )
40 mg ( )
14 mg
16 mg
18 mg
63 mg ( )
72 mg ( )
81 mg ( )
60 mg ( )
These are the equivalent doses of 3 formulations of methylphenidate that are now available in the US.

19. (Corrected for dose and surface area, N = 5)
MPH Concentration v Time for ‘Bioequivalent’ Doses of CON vs EQXL: 18 vs 20 mg; 35 vs 40 mg; 54 vs 60 mg
(Corrected for dose and surface area, N = 5) 1
EQXL MEAN
0.8
CON MEAN
MPH ng/ml/mg/m2
0.6
0.4
0.2
1.5 3
4.5 6
7.5 9
10.5 12
13.5
Time (h)

20. Non-Equivalence Design for Comparison of 2 Active Conditions: Equasym XL vs Concerta (Swanson et al, Pediatrics, 2004)
Dose level 2
Dose level 3 5 10 15
[Mean +/- SEM] ‡ *
Dose level 1
EQXL 5 10 15 * † 15
CON
PLA 10
SKAMP Deportment ‡ † * * *
EQXL 20mg (6+14)
CON 18mg (4+14)
EQXL 40mg (12+28)
CON 36mg (8+28)
EQXL 60mg (18+42)
CON 54mg (12+42) 16 4 8 12 16 ‡ * 16 12 12
SKAMP Attention
[Mean +/- SEM] † ‡ 8 8 ‡ *
These the PD profiles for a head-to-head comparison of Concerta and Metadate-CD.
Children who were responsive to low, medium or high doses of methylphenidate participated in this large, multisite Lab School study. * * 4 4
120
120 * *
0.0
1.5
3.0
4.5
6.0
7.5
9.0
10.5
12.0 40 60 80
100
120 ‡ †
100
100
Answered Correctly
PERMP #
[Mean +/- SEM] 80 80 † ‡ ‡ 60 60 40 40
0.0
1.5
3.0
4.5
6.0
7.5
9.0
10.5
12.0
0.0
1.5
3.0
4.5
6.0
7.5
9.0
10.5
12.0
Time post-dose (h)

21. Non-Equivalence Design for Comparison of 2 Active Conditions: Equasym XL vs Concerta (Swanson et al, Pediatrics, 2004)
Equasym
Concerta

22. A Comparison of Once-Daily Extended-Release Methylphenidate Formulations in Children With ADHD in the Laboratory School
Pediatrics, 2004, 113: s
James M. Swanson, PhD*; Sharon B. Wigal, PhD*; Tim Wigal, PhD*; Edmund Sonuga-Barke, PhD*; Laurence L. Greenhill, MD‡; Joseph Biederman, MD§; Scott Kollins, PhD; Annamarie Stehli Nguyen, MPH*; Heleen H. DeCory, PhD; Sharon J. Hirshey Dirksen, PhD; Simon J. Hatch, MD; and the COMACS Study Group
Conclusions. Once-daily doses of EQXL and CON produced statistically significantly different PD effects on surrogate measures of behavior and performance among children with attention-deficit/hyperactivity disorder in the laboratory school setting. As predicted by the PK/PD model, superiority at any point in time was achieved by the formulation with the highest expected plasma MPH concentration.

24. Effects of Time of Day on Classroom Behaviour of Children with ADHD (Antrop et al, 2005)

25. PET [11C]Methylphenidate
Volkow and Swanson, in press (Chapter 14, Rutter’s Child and Adolescent Psychiatry, 5th Edition)
Absorption (ka)
Distribution (ke)
Elimination (keo)
Ce(t)
Transporters
Enzymes
Receptors
Ee(t)
Emotion
Cognition
Side Effects
Synapse
Circuit
Blood
Brain
C(t)
E(t)
Pharmacokinetic
Pharmacodynamic
PET [11C]Methylphenidate
Brain T1/2= 1.5 hr 20 40 60 80
100 10 30 50 70
Time (min)
% Peak