Proton Pump Inhibitor (PPI) Studies. Day –5 Inclusion Randomization Omeprazole Administration Day...

Proton Pump Inhibitor (PPI) Studies

Day –5Inclusion

RandomizationOmeprazole

Administration

Day –5Inclusion

RandomizationOmeprazole

Administration Day 1Clopidogrelor Placebo

Administration

Day 1Clopidogrelor Placebo

Administration

Study Design: Clopidogrel + Omeprazole Interaction Studies*

*Design is similar for 3 different comparisons: • Standard-dose clopidogrel (300-mg loading dose/75-mg/day maintenance dose)+ omeprazole 80 mg/day given

concomitantly vs standard-dose clopidogrel alone• Standard-dose clopidogrel + omeprazole 80 mg/day given 12 hours apart vs standard-dose clopidogrel alone• Double-dose clopidogrel (600-mg loading dose/150-mg/day maintenance dose) + omeprazole 80 mg/day given

concomitantly vs double-dose clopidogrel alone †At least 14 days

Sequence: Clopidogrel or Placebo + Omeprazole → Clopidogrel or Placebo

ScreeningDay –28 to

Day –7≤21 days


Day –7≤21 days

OmeprazoleDay –5 to Day 5

OmeprazoleDay –5 to Day 5

Day 6AdmissionInclusion

Procedures

Day 6AdmissionInclusion

Procedures

Day –1Clopidogrelor Placebo

Administration

Day –1Clopidogrelor Placebo

Administration

Day 6Discharge

Day 6Discharge

Day 6Discharge

Day 6Discharge

End-of-Study Visit

End-of-Study Visit

Follow-up at least7 to 10 days

post-dose


post-dose

Day –1AdmissionInclusion

Procedures


Procedures

Wash-out period†

Wash-out period†

Clopidogrel or Placebo

Day 1 to Day 5


Day 1 to Day 5


Day 1 to Day 5


Day 1 to Day 5

2Angiolillo DA, et al. Clin Pharmacol Ther. 2010 Sep 15. [Epub ahead of print]

Standard-Dose Clopidogrel + Omeprazole Administered Together: Pharmacodynamic Data

Mean ± SEM of Maximum Platelet Aggregation (%) Induced by ADP 5 µM

ADP, adenosine diphosphate; CI, confidence interval; D, day; MPA, maximum platelet aggregation; SEM, standard error of the mean; T, sampling time.ADP, adenosine diphosphate; CI, confidence interval; D, day; MPA, maximum platelet aggregation; SEM, standard error of the mean; T, sampling time. 3Angiolillo DA, et al. Clin Pharmacol Ther. 2010 Sep 15. [Epub ahead of print]

Estimated Treatment Difference in MPA (%) Induced by ADP 5 µM at Day 5

Parameter Comparison Estimate 90% CI P-value

MPA (%), ADP 5 µM Clopidogrel + Omeprazole minus Clopidogrel Alone at D5 8.0 4.7 to 11.3 <0.0001

Standard-Dose Clopidogrel + Omeprazole Administered Together: Effect on Clopidogrel Active Metabolite H4

Nominal Time (h)

Day 1 – 300 mg

0.0 0.5 1.0 1.5 2.0 2.5 3.0Mea

n (

SD

) A

ctiv

e M

etab

olit

e H

4 C

on

cen

trat

ion

(n

g/m

L)

0

10

20

30

40

50

60

Clopidogrel aloneClopidogrel + omeprazoleLOQ = 0.500 ng/mL

• After coadministering omeprazole with clopidogrel (300-mg LD/75-mg/day MD), the clopidogrel active metabolite H4 pharmacokinetic parameters were consistently decreased by:

– 46% on Day 1 (P<0.001) and 42% on Day 5 (P<0.001) for maximum plasma concentration (Cmax), and

– 45% on Day 1 (P<0.001) and 40% on Day 5 (P<0.001) for area under the concentration–time curve from time zero to 24 hours (AUC0-24).

Mean (SD) Plasma Concentration of Clopidogrel Active Metabolite H4 After a 300-mg Loading Dose (Left) and 75-mg Maintenance Dose (Right)

LD, loading dose; LOQ, lower limit of quantification.; MD, maintenance dose; SD, standard deviation.LD, loading dose; LOQ, lower limit of quantification.; MD, maintenance dose; SD, standard deviation.4

Angiolillo DA, et al. Clin Pharmacol Ther. 2010 Sep 15. [Epub ahead of print]

Mea

n (

SD

) A

ctiv

e M

etab

olit

e H

4 C

on

cen

trat

ion

(n

g/m

L)

Day 5 – 75 mg

Nominal Time (h)

0.0 0.5 1.0 1.5 2.0

0

5

10

15

20

25

Clopidogrel aloneClopidogrel + omeprazoleLOQ = 0.500 ng/mL*

Standard-Dose Clopidogrel + Omeprazole Administered 12 Hours Apart: Pharmacodynamic Data


5ADP, adenosine diphosphate; CI, confidence interval; D, day; MPA, maximum platelet aggregation; SEM, standard error of the mean; T, sampling time.ADP, adenosine diphosphate; CI, confidence interval; D, day; MPA, maximum platelet aggregation; SEM, standard error of the mean; T, sampling time. Angiolillo DA, et al. Clin Pharmacol Ther. 2010 Sep 15. [Epub ahead of print]



MPA (%), ADP 5 µM Clopidogrel + Omeprazole minus Clopidogrel Alone at D5 5.6 2.8 to 8.5 0.0014

Standard-Dose Clopidogrel + Omeprazole Administered 12 Hours Apart: Effect on Clopidogrel Active Metabolite H4

Nominal Time (h)

Day 5 - 75 mg

0

5

10

15

20

25


Day 1 - 300 mg

Mea

n (

SD

) A

ctiv

e M

etab

olit

e H

4 C

on

cen

trat

ion

(n

g/m

L)

0


50

40

30

20

10

1.50.50.0 1.0 2.0 2.5 3.0 0.50.0 1.0 1.5 2.0


Nominal Time (h)

6

Mea

n (

SD

) A

ctiv

e M

etab

olit

e H

4 C

on

cen

trat

ion

(n

g/m

L)

• After separating the administration of omeprazole and clopidogrel (300-mg LD/75-mg/day MD) by 12 hours, the clopidogrel active metabolite H4 pharmacokinetic parameters were consistently decreased by:



LD, loading dose; LOQ, lower limit of quantification.; MD, maintenance dose; SD, standard deviation.LD, loading dose; LOQ, lower limit of quantification.; MD, maintenance dose; SD, standard deviation.Angiolillo DA, et al. Clin Pharmacol Ther. 2010 Sep 15. [Epub ahead of print]

Double-Dose Clopidogrel + Omeprazole Administered Together: Pharmacodynamic Data

7


ADP, adenosine diphosphate; CI, confidence interval; D, day; MPA, maximum platelet aggregation; SEM, standard error of the mean; T, sampling time.ADP, adenosine diphosphate; CI, confidence interval; D, day; MPA, maximum platelet aggregation; SEM, standard error of the mean; T, sampling time. Angiolillo DA, et al. Clin Pharmacol Ther. 2010 Sep 15. [Epub ahead of print]



MPA (%), ADP 5 µM Clopidogrel + Omeprazole minus Clopidogrel Alone at D5 8.1 5.7 to 10.6 <0.0001

Double-Dose Clopidogrel + Omeprazole Administered Together: Effect on Clopidogrel Active Metabolite H4



8

Pla

sma

Act

ive

Met

abo

lite

Co

nce

ntr

atio

ns

(ng

/mL

)

60

0 1 2 3 40 1 2 3 4

Nominal time (h)Nominal time (h)

Day 1: 600 mgDay 1: 600 mg

50

40

30

20

10

0

Nominal time (h)Nominal time (h)

Day 5: 150 mgDay 5: 150 mg

0 1 2 3 40 1 2 3 4

25

20

15

10

5

0

Pla

sma

Act

ive

Met

abo

lite

Co

nce

ntr

atio

ns

(ng

/mL

)


• After coadministering omeprazole with clopidogrel (600-mg LD/150-mg/day MD), the clopidogrel active metabolite H4 pharmacokinetic parameters were consistently decreased by:




Day 1Inclusion

RandomizationClopidogrel or

PlaceboAdministration

Day 1Inclusion

RandomizationClopidogrel or

PlaceboAdministration Day –7

PantoprazoleAdministration

Day –7Pantoprazole

Administration

Study Design: Pantoprazole + Clopidogrel Interaction Study

*At least 14 days

Sequence: Clopidogrel or Placebo → Clopidogrel or Placebo + Pantoprazole


Day –2≤21 days


Day –2≤21 days


Procedures


Procedures

Day 6Discharge

Day 6Discharge

Day 6Discharge

Day 6Discharge

End-of-Study Visit

End-of-Study Visit


post-dose


post-doseDay –8

AdmissionInclusion

Procedures


Procedures

Wash-out period*

Wash-out period*


Day 1 to Day 5


Day 1 to Day 5


Day 1 to Day 5


Day 1 to Day 5

9

PantoprazoleDay –7 to Day 5Pantoprazole

Day –7 to Day 5


Standard-Dose Clopidogrel + Pantoprazole Administered Together: Pharmacodynamic Data


10



MPA (%), ADP 5 µM Clopidogrel + Pantoprazole minus Clopidogrel Alone at D5

4.3 1.4 to 7.1 0.0136

ADP, adenosine diphosphate; CI, confidence interval; D, day; MPA, maximum platelet aggregation; SEM, standard error of the mean; T, sampling time.ADP, adenosine diphosphate; CI, confidence interval; D, day; MPA, maximum platelet aggregation; SEM, standard error of the mean; T, sampling time. Angiolillo DA, et al. Clin Pharmacol Ther. 2010 Sep 15. [Epub ahead of print]

Standard-Dose Clopidogrel + Pantoprazole Administered Together: Effect on Clopidogrel Active Metabolite H4

0.0 0.5 1.0 1.5 2.0 3.0

Mea

n (

SD

) A

ctiv

e M

etab

olit

e H

4 C

on

cen

trat

ion

(n

g/m

L)

0

10

20

30

40

50 Clopidogrel alone

Clopidogrel + pantoprazole

LOQ = 0.5 (ng/mL)

Day 1 – 300 mg

Nominal Time (hr)

11

Clopidogrel alone

Clopidogrel + pantoprazole

LOQ = 0.5 (ng/mL)

Day 5 – 75 mg

0.0 0.5 1.0 1.5 2.0

0

5

10

15

20

Nominal Time (hr)

Mea

n (

SD

) A

ctiv

e M

etab

olit

e H

4 C

on

cen

trat

ion

(n

g/m

L)

• After coadministering pantoprazole with clopidogrel (300-mg LD/75-mg/day MD), the clopidogrel active metabolite H4 pharmacokinetic parameters were decreased by:


– 20% on Day 1 (P<0.001) and 14% on Day 5 (P=0.001) for area under the concentration–time curve from time zero to 24 hours (AUC0-24).



Standard-Dose Clopidogrel + Omeprazole versus Standard-Dose Clopidogrel + Pantoprazole: VASP-PRI Data

12

Mean ± SEM of Vasodilator-Stimulated Phosphoprotein Phosphorylation-Platelet Reactivity Index (%)

D, day; LD, loading dose; LOQ, lower limit of quantification; MD, maintenance dose; SEM, standard error of the mean; T, sampling time; VASP-PRI, vasodilator-stimulated phosphoprotein phosphorylation-platelet reactivity index.D, day; LD, loading dose; LOQ, lower limit of quantification; MD, maintenance dose; SEM, standard error of the mean; T, sampling time; VASP-PRI, vasodilator-stimulated phosphoprotein phosphorylation-platelet reactivity index.

• After coadministering omeprazole (left panel) or pantoprazole (right panel) with clopidogrel (300-mg LD/75-mg/day MD), the estimated treatment differences (90% CIs) at Day 5 were:

– 20.7% (90% CI, 14.1% to 27.2%; P<0.0001) for omeprazole and

– 3.9% (–2.7% to 10.4%; P=0.3319) for pantoprazole.

Clopidogrel ± Omeprazole Clopidogrel ± Pantoprazole


Proton Pump Inhibitor (PPI) Studies. Day –5 Inclusion Randomization Omeprazole Administration Day...

Documents

Transcript of Proton Pump Inhibitor (PPI) Studies. Day –5 Inclusion Randomization Omeprazole Administration Day...