can we give “hyperactive” children 8 tests across the day?

Can we give hyperactive children 8 tests across the day?

Swanson and Kinsbourne, 1978

DOSEEFFECTPKPDC

CHART

0.420689766.47

5.9827586

10.7827586

12.003448379.07

11.0724138

75.93

7.6551724

69.1

60.06

2.6678571

63.94

1.6740741

dl 10 mg (Blood Level)

dl 10 mg (Math)

TIME POINTS

Blood Levels (ng/ml)

Math (% correct)

DATA

DESCRIPTIONdl 5 mgdl 10 mgdl 20 mgDESCRIPTIONd 2.5 mgd 5 mgd 10 mgMATHddl

000.420689700000165.0366.47

0.52.82592595.98275865.32413790.52.2370374.35862079.3423077

14.225925910.782758612.106896614.158.806896616.837037

1.54.418518512.003448314.80344831.54.2629639.18955216.912282.2679.07

24.270370411.072413815.027586223.93846158.631034515.6148148

2.5374.1375.93

3

3.5

42.94444447.655172412.503448343.00370375.686206911.732

4.5471.169.1

5

5.5

6

6.5561.660.06

7

7.5

80.84814812.66785713.853571480.67307691.84137933.812

8.5657.4263.94

9

9.5

100.29230771.67407412.1740741100.20.81724142.956522

Classroom Evaluations of AttentionDeportment, and Performance

UCI Lab School Protocol

Playground Evaluation of Behavior andActivity During Recess

_1046510577.doc

C-94-007-04: STUDY II, SWANSON: FINAL REPORT

FIGURE 1B

Mean 20-Minute Activity Level Time Profiles

Following Methylphenidate Treatments

SOURCE: C94007II\PKPD\FIGPGM\PLTMNBIN.SAS BNL (VER: 03/28/00 14:00)

A

c

t

i

v

i

t

y

L

e

v

e

l

0

50

100

150

200

250

300

Time

0700

1100

1500

1900

2300

0300

0700

1100

PQD (n=28)

TID (n=29)

PLACEBO (n=30)

Ritalin 10 mg TID vs Ascending Small Doses

Effects of Methylphenidate in LSP:3 Settings and 3 MeasuresAt DeskIn GroupOn PlaygroundActivityAttentionDeportment

Evaluating the optimal MPH PK profileFlat (zero order) profileAscending (first order) profile

Proof of product study:PK profiles for OROS-MPH (Concerta) and IR-MPH (Ritalin)

Laboratory School Protocol

Dopfner et al, 2004, Eur Child Adolesc Psychiatry

New Formulations for Extended Delivery Osmotic Pump (Concerta) or Coated Beads (Equasym XL) Tablet ShellPush CompartmentMPH Compartment #2IR MPH uncoated beadsER MPH coated beadsImmediate Release (IR) MPHIR MPH overcoatTwo ER MPH reservoirsExtended Release (ER) MPHLaser-Drilled HoleMPH Compartment #1

Proof of Concept Studies:Pharamacodynamic Profiles of Equasym XL (Wigal et al, J Applied Research, 2003)Dose: 40 mg05101520023.5567.5910121315161819212224Time After Dose (h)MPH MR 30:70 MPH MR 40:60

SKAMP DATA

SKAMP ATTENTIONPLACEBOBID

TimePlaceboBID (10mg/10mg)SEnSDSEnSD

1.51.391.250.1313640809230.630.12250.6

3.02.071.580.2408664914241.180.146250.73

4.52.161.770.2001738375230.960.172250.86

6.01.971.020.1605560988230.770.132250.66

7.52.251.250.148045234230.710.1857529722240.91

9.02.141.70.1236564155220.580.1751521078230.84

30/70 MIX20 MB40 MG

TimePlacebo20mg, (30/70, 6mg/14mg)40mg (30/70, 12mg/28mg)SEnSDSEnSD

1.51.391.081.350.1356773133120.470.2201032815110.73

3.02.071.281.070.141450816120.490.1115591975110.37

4.52.161.751.490.1598010126110.530.2472393026110.82

6.01.971.531.360.2915618859121.010.2592997563110.86

7.52.251.771.580.2626943725120.910.1748765799110.58

9.02.141.942.090.2078460969120.720.0434176336110.144

40/60 MIX20 MB40 MG

TimePlacebo20mg (40/60, 8mg/12mg)40mg (40/60, 16mg/24mg)SEnSDSEnSD

1.51.391.141.540.2340085469100.740.1328156617100.42

3.02.071.221.140.195982374110.650.1454647724100.46

4.52.161.451.340.2684678752120.930.14862705100.47

6.01.971.781.20.2165063509120.750.2466576575100.78

7.52.251.821.50.1905255888120.660.2150348809100.68

9.02.141.832.180.28867513461210.2371708245100.75

SKAMP DEPORTMENTPLACEBOBID


1.51.640.570.3044310445231.460.138250.69

3.01.691.10.2918975277241.430.2251

4.52.011.30.2648133059231.270.242251.21

6.02.010.790.2877498914231.380.188250.94

7.51.950.90.2731538824231.310.234742767241.15

9.02.21.430.2878209671221.350.2919201797231.4

30/70 MIX20 MB40 MG


1.51.640.220.510.0923760431120.320.2321637353110.77

3.01.690.790.980.28867513461210.3376927059111.12

4.52.010.821.180.2834206639110.940.4703576975111.56

6.02.011.951.250.4330127019121.50.5095541723111.69

7.51.951.21.180.3954849344121.370.4884483782111.62

9.02.21.781.640.3868246804121.340.4040252017111.34

40/60 MIX20 MB40 MG


1.51.640.420.260.1897366596100.60.1043551628100.33

3.01.690.510.340.1386952185110.460.167600716100.53

4.52.011.230.940.4099186911121.420.3604996533101.14

6.02.011.851.680.534048999121.850.4427188724101.4

7.51.951.11.220.1674315781120.580.474341649101.5

9.02.22.132.050.5022947342121.740.4522057054101.43

ATT BID

1.391.250.13136408090.12

2.071.580.24086649140.146

2.161.770.20017383750.172

1.971.020.16055609880.132

2.251.250.1480452340.1857529722

2.141.70.12365641550.1751521078

Placebo

BID (10mg/10mg)

Hour

Average Rating

SKAMP Attention20mg - BID

ATT BID 30-70

1.391.251.080.13136408090.13567731330.12

2.071.581.280.24086649140.1414508160.146

2.161.771.750.20017383750.15980101260.172

1.971.021.530.16055609880.29156188590.132

2.251.251.770.1480452340.26269437250.1857529722

2.141.71.940.12365641550.20784609690.1751521078

Placebo

BID (10mg/10mg)

20mg, (30/70, 6mg/14mg)

Hour

Average Rating

SKAMP Attention20mg - BID and 30/70

ATT 30-70

1.391.080.13136408090.1356773133

2.071.280.24086649140.141450816

2.161.750.20017383750.1598010126

1.971.530.16055609880.2915618859

2.251.770.1480452340.2626943725

2.141.940.12365641550.2078460969

Placebo

20mg, (30/70, 6mg/14mg)

Hour

Average Rating

SKAMP Attention20mg - 30/70

ATT P&20mgs

1.391.081.140.13136408090.13567731330.2340085469

2.071.281.220.24086649140.1414508160.195982374

2.161.751.450.20017383750.15980101260.2684678752

1.971.531.780.16055609880.29156188590.2165063509

2.251.771.820.1480452340.26269437250.1905255888

2.141.941.830.12365641550.20784609690.2886751346

Placebo

20mg, (30/70, 6mg/14mg)

20mg (40/60, 8mg/12mg)

Hour

Average Rating

SKAMP Attention20mg - 30/70 and 40/60

ATT 40-60

1.391.140.13136408090.2340085469

2.071.220.24086649140.195982374

2.161.450.20017383750.2684678752

1.971.780.16055609880.2165063509

2.251.820.1480452340.1905255888

2.141.830.12365641550.2886751346

Placebo

20mg (40/60, 8mg/12mg)

Hour

Average Rating


ATT P&40mgs

1.391.351.540.13136408090.22010328150.1328156617

2.071.071.140.24086649140.11155919750.1454647724

2.161.491.340.20017383750.24723930260.14862705

1.971.361.20.16055609880.25929975630.2466576575

2.251.581.50.1480452340.17487657990.2150348809

2.142.092.180.12365641550.04341763360.2371708245

Placebo

40mg (30/70, 12mg/28mg)

40mg (40/60, 16mg/24mg)

Hour

Average Rating


DEP BID

1.640.570.30443104450.138

1.691.10.29189752770.2

2.011.30.26481330590.242

2.010.790.28774989140.188

1.950.90.27315388240.234742767

2.21.430.28782096710.2919201797

Placebo

BID (10mg/10mg)

Hour

Average Rating

SKAMP Deportment20mg - BID

DEP BID 30-70

1.640.570.220.30443104450.1380.0923760431

1.691.10.790.29189752770.20.2886751346

2.011.30.820.26481330590.2420.2834206639

2.010.791.950.28774989140.1880.4330127019

1.950.91.20.27315388240.2347427670.3954849344

2.21.431.780.28782096710.29192017970.3868246804

Placebo

BID (10mg/10mg)

20mg, (30/70, 6mg/14mg)

Hour

Average Rating

SKAMP Deportment20mg - BID and 30/70

DEP 30-70

1.640.220.30443104450.0923760431

1.690.790.29189752770.2886751346

2.010.820.26481330590.2834206639

2.011.950.28774989140.4330127019

1.951.20.27315388240.3954849344

2.21.780.28782096710.3868246804

Placebo

20mg, (30/70, 6mg/14mg)

Hour

Average Rating

SKAMP Deportment20mg - 30/70

DEP P&20mgs

1.640.220.420.30443104450.09237604310.1897366596

1.690.790.510.29189752770.28867513460.1386952185

2.010.821.230.26481330590.28342066390.4099186911

2.011.951.850.28774989140.43301270190.534048999

1.951.21.10.27315388240.39548493440.1674315781

2.21.782.130.28782096710.38682468040.5022947342

Placebo

20mg, (30/70, 6mg/14mg)

20mg (40/60, 8mg/12mg)

Hour

Average Rating

SKAMP Deportment20mg - 30/70 and 40/60

DEP 40-60

1.640.420.30443104450.1897366596

1.690.510.29189752770.1386952185

2.011.230.26481330590.4099186911

2.011.850.28774989140.534048999

1.951.10.27315388240.1674315781

2.22.130.28782096710.5022947342

Placebo

20mg (40/60, 8mg/12mg)

Hour

Average Rating


DEP P&40mgs

1.640.510.260.30443104450.23216373530.1043551628

1.690.980.340.29189752770.33769270590.167600716

2.011.180.940.26481330590.47035769750.3604996533

2.011.251.680.28774989140.50955417230.4427188724

1.951.181.220.27315388240.48844837820.474341649

2.21.642.050.28782096710.40402520170.4522057054

Placebo

40mg (30/70, 12mg/28mg)

40mg (40/60, 16mg/24mg)

Hour

Average Rating


Sheet2

Sheet3

SKAMP DATA

SKAMP ATTENTIONPLACEBOBID


1.51.391.250.1313640809230.630.12250.6

3.02.071.580.2408664914241.180.146250.73

4.52.161.770.2001738375230.960.172250.86

6.01.971.020.1605560988230.770.132250.66

7.52.251.250.148045234230.710.1857529722240.91

9.02.141.70.1236564155220.580.1751521078230.84

30/70 MIX20 MB40 MG


1.51.391.081.350.1356773133120.470.2201032815110.73

3.02.071.281.070.141450816120.490.1115591975110.37

4.52.161.751.490.1598010126110.530.2472393026110.82

6.01.971.531.360.2915618859121.010.2592997563110.86

7.52.251.771.580.2626943725120.910.1748765799110.58

9.02.141.942.090.2078460969120.720.0434176336110.144

40/60 MIX20 MB40 MG


1.51.391.141.540.2340085469100.740.1328156617100.42

3.02.071.221.140.195982374110.650.1454647724100.46

4.52.161.451.340.2684678752120.930.14862705100.47

6.01.971.781.20.2165063509120.750.2466576575100.78

7.52.251.821.50.1905255888120.660.2150348809100.68

9.02.141.832.180.28867513461210.2371708245100.75

SKAMP DEPORTMENTPLACEBOBID


1.51.640.570.3044310445231.460.138250.69

3.01.691.10.2918975277241.430.2251

4.52.011.30.2648133059231.270.242251.21

6.02.010.790.2877498914231.380.188250.94

7.51.950.90.2731538824231.310.234742767241.15

9.02.21.430.2878209671221.350.2919201797231.4

30/70 MIX20 MB40 MG


1.51.640.220.510.0923760431120.320.2321637353110.77

3.01.690.790.980.28867513461210.3376927059111.12

4.52.010.821.180.2834206639110.940.4703576975111.56

6.02.011.951.250.4330127019121.50.5095541723111.69

7.51.951.21.180.3954849344121.370.4884483782111.62

9.02.21.781.640.3868246804121.340.4040252017111.34

40/60 MIX20 MB40 MG


1.51.640.420.260.1897366596100.60.1043551628100.33

3.01.690.510.340.1386952185110.460.167600716100.53

4.52.011.230.940.4099186911121.420.3604996533101.14

6.02.011.851.680.534048999121.850.4427188724101.4

7.51.951.11.220.1674315781120.580.474341649101.5

9.02.22.132.050.5022947342121.740.4522057054101.43

ATT BID

1.391.250.13136408090.12

2.071.580.24086649140.146

2.161.770.20017383750.172

1.971.020.16055609880.132

2.251.250.1480452340.1857529722

2.141.70.12365641550.1751521078

Placebo

BID (10mg/10mg)

Hour

Average Rating

SKAMP Attention20mg - BID

ATT BID 30-70

1.391.251.080.13136408090.13567731330.12

2.071.581.280.24086649140.1414508160.146

2.161.771.750.20017383750.15980101260.172

1.971.021.530.16055609880.29156188590.132

2.251.251.770.1480452340.26269437250.1857529722

2.141.71.940.12365641550.20784609690.1751521078

Placebo

BID (10mg/10mg)

20mg, (30/70, 6mg/14mg)

Hour

Average Rating

SKAMP Attention20mg - BID and 30/70

ATT 30-70

1.391.080.13136408090.1356773133

2.071.280.24086649140.141450816

2.161.750.20017383750.1598010126

1.971.530.16055609880.2915618859

2.251.770.1480452340.2626943725

2.141.940.12365641550.2078460969

Placebo

20mg, (30/70, 6mg/14mg)

Hour

Average Rating


ATT P&20mgs

1.391.081.140.13136408090.13567731330.2340085469

2.071.281.220.24086649140.1414508160.195982374

2.161.751.450.20017383750.15980101260.2684678752

1.971.531.780.16055609880.29156188590.2165063509

2.251.771.820.1480452340.26269437250.1905255888

2.141.941.830.12365641550.20784609690.2886751346

Placebo

20mg, (30/70, 6mg/14mg)

20mg (40/60, 8mg/12mg)

Hour

Average Rating


ATT 40-60

1.391.140.13136408090.2340085469

2.071.220.24086649140.195982374

2.161.450.20017383750.2684678752

1.971.780.16055609880.2165063509

2.251.820.1480452340.1905255888

2.141.830.12365641550.2886751346

Placebo

20mg (40/60, 8mg/12mg)

Hour

Average Rating


ATT P&40mgs

1.391.351.540.13136408090.22010328150.1328156617

2.071.071.140.24086649140.11155919750.1454647724

2.161.491.340.20017383750.24723930260.14862705

1.971.361.20.16055609880.25929975630.2466576575

2.251.581.50.1480452340.17487657990.2150348809

2.142.092.180.12365641550.04341763360.2371708245

Placebo

40mg (30/70, 12mg/28mg)

40mg (40/60, 16mg/24mg)

Hour

Average Rating


DEP BID

1.640.570.30443104450.138

1.691.10.29189752770.2

2.011.30.26481330590.242

2.010.790.28774989140.188

1.950.90.27315388240.234742767

2.21.430.28782096710.2919201797

Placebo

BID (10mg/10mg)

Hour

Average Rating

SKAMP Deportment20mg - BID

DEP BID 30-70

1.640.570.220.30443104450.1380.0923760431

1.691.10.790.29189752770.20.2886751346

2.011.30.820.26481330590.2420.2834206639

2.010.791.950.28774989140.1880.4330127019

1.950.91.20.27315388240.2347427670.3954849344

2.21.431.780.28782096710.29192017970.3868246804

Placebo

BID (10mg/10mg)

20mg, (30/70, 6mg/14mg)

Hour

Average Rating

SKAMP Deportment20mg - BID and 30/70

DEP 30-70

1.640.220.30443104450.0923760431

1.690.790.29189752770.2886751346

2.010.820.26481330590.2834206639

2.011.950.28774989140.4330127019

1.951.20.27315388240.3954849344

2.21.780.28782096710.3868246804

Placebo

20mg, (30/70, 6mg/14mg)

Hour

Average Rating


DEP P&20mgs

1.640.220.420.30443104450.09237604310.1897366596

1.690.790.510.29189752770.28867513460.1386952185

2.010.821.230.26481330590.28342066390.4099186911

2.011.951.850.28774989140.43301270190.534048999

1.951.21.10.27315388240.39548493440.1674315781

2.21.782.130.28782096710.38682468040.5022947342

Placebo

20mg, (30/70, 6mg/14mg)

20mg (40/60, 8mg/12mg)

Hour

Average Rating


DEP 40-60

1.640.420.30443104450.1897366596

1.690.510.29189752770.1386952185

2.011.230.26481330590.4099186911

2.011.850.28774989140.534048999

1.951.10.27315388240.1674315781

2.22.130.28782096710.5022947342

Placebo

20mg (40/60, 8mg/12mg)

Hour

Average Rating


DEP P&40mgs

1.640.510.260.30443104450.23216373530.1043551628

1.690.980.340.29189752770.33769270590.167600716

2.011.180.940.26481330590.47035769750.3604996533

2.011.251.680.28774989140.50955417230.4427188724

1.951.181.220.27315388240.48844837820.474341649

2.21.642.050.28782096710.40402520170.4522057054

Placebo

40mg (30/70, 12mg/28mg)

40mg (40/60, 16mg/24mg)

Hour

Average Rating


Sheet2

Sheet3

MPH OvercoatMembranePolymerMPH #2MPH #1HoleExtended Release (ER) MPHImmediate Release (IR) MPHEQXL

Chart1

0.320.330.66

2.391.031.44

3.311.31.54

3.541.511.71

3.711.791.79

4.5221.87

4.031.761.61

2.771.371.32

1.790.870.93

1.370.650.64

0.840.420.36

0.510.290.26

0.30.260.23

Intact capsule

Time (hrs)

Methylphenidate (ng/mL)

Sheet1

Intact capsulesdSprinkledsd

0.50.320.330.960.66

12.391.033.151.44

23.311.33.651.54

33.541.513.931.71

43.711.794.051.79

54.5224.691.87

64.031.764.021.61

82.771.372.731.32

101.790.871.820.93

121.370.651.370.64

160.840.420.80.36

200.510.290.470.26

240.30.260.30.23

Sheet1

0.320.960.330.660.660.66

2.393.151.031.441.441.44

3.313.651.31.541.541.54

3.543.931.511.711.711.71

3.714.051.791.791.791.79

4.524.6921.871.871.87

4.034.021.761.611.611.61

2.772.731.371.321.321.32

1.791.820.870.930.930.93

1.371.370.650.640.640.64

0.840.80.420.360.360.36

0.510.470.290.260.260.26

0.30.30.260.230.230.23

Intact capsule

Sprinkled

Time (hrs)

Methylphenidate (ng/mL)

Sheet2

Sheet3

Sheet4

Sheet5

Sheet6

Sheet7

Sheet8

Sheet9

Sheet10

Non-Equivalence StudyEquasym XL v ConcertaA 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 PLAMed Dose Group: EQXL 40 mg vs CON 36 mg vs PLAHigh Dose Group: EQXL 60 mg vs CON 54 mg vs PLA

Initial (IR) and Extended (ER) MPH Components(Swanson et al, 2002, J Attention Disorders, 6:s73s88)

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)00.20.40.60.8101.534.567.5910.51213.5Time (h) MPH ng/ml/mg/m2EQXL MEANCON MEAN

EQXL 20mg (6+14)CON 18mg (4+14)EQXL 40mg (12+28)CON 36mg (8+28)EQXL 60mg (18+42)CON 54mg (12+42)Time post-dose (h)Dose level 1Non-Equivalence Design for Comparison of 2 Active Conditions: Equasym XL vs Concerta (Swanson et al, Pediatrics, 2004)Dose level 2Dose level 31015EQXLCONPLA***481216[Mean +/- SEM]481216***0.01.53.04.56.07.59.010.512.0406080100120[Mean +/- SEM]0.01.53.04.56.07.59.010.512.0406080100120**SKAMP DeportmentSKAMP AttentionPERMP #Answered Correctly

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

A Comparison of Once-Daily Extended-Release Methylphenidate Formulations in Children With ADHD in the Laboratory School Pediatrics, 2004, 113: s206-216

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.

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

Volkow and Swanson, in press(Chapter 14, Rutters Child and Adolescent Psychiatry, 5th Edition)

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).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. 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.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.Schnippers notes:This is what the ALZA technology team come up withOROS technologyreliable/reproducibleused in products such as Padmixture rocardia XLOvercoatImmediate-release MPHSemipermeable membranePolymer layerwater absorbed and expands the polymer compartmentTwo concentrations of drugCompartment 1lower concentrationCompartment 2delivered later in the dayhigher concentrationAdmixture between 1 and 2mid-level concentration in middayDrug pushed out of a very precisely laser-drilled hole at the top of the tabletTechnologically vary advanced/complexNext steptest to make sure it produced target PK profile in vivoOROS extended-release technology has been in use nearly 20 years and is used inDitropan XLProcardia XLGlucotrol XLSudafed 24-hourVolmax (in patients aged 6 years and older)TegretolXR (in patients of all ages)

These are the equivalent doses of 3 formulations of methylphenidate that are now available in the US.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.

can we give “hyperactive” children 8 tests across the day?

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