Transcript Slides - Clinical Trial Results

Proton Pump Inhibitor (PPI) Studies
Study Design: Clopidogrel + Omeprazole Interaction Studies*
Sequence: Clopidogrel or Placebo + Omeprazole → Clopidogrel or Placebo
Screening
Day –28 to
Day –7
≤21 days
Omeprazole
Day –5 to Day 5
Wash-out
period†
Clopidogrel or
Placebo
Day 1 to Day 5
Day 6
Admission
Inclusion
Procedures
Day –5
Inclusion
Randomization
Omeprazole
Administration
Day –1
Clopidogrel
or Placebo
Administration
Day 6
Discharge
Clopidogrel or
Placebo
Day 1 to Day 5
Day –1
Admission
Inclusion
Procedures
Day 6
Discharge
Follow-up at least
7 to 10 days
post-dose
End-of-Study
Visit
Day 1
Clopidogrel
or Placebo
Administration
*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
Angiolillo DA, et al. Clin Pharmacol Ther. 2010 Sep 15. [Epub ahead of print]
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Standard-Dose Clopidogrel + Omeprazole
Administered Together: Pharmacodynamic Data
Mean ± SEM of Maximum Platelet Aggregation (%) Induced by ADP 5 µM
Estimated Treatment Difference in MPA (%) Induced by ADP 5 µM at Day 5
Parameter
Comparison
MPA (%), ADP 5 µM
Clopidogrel + Omeprazole minus Clopidogrel Alone at D5
Estimate
90% CI
P-value
8.0
4.7 to 11.3
<0.0001
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]
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Standard-Dose Clopidogrel + Omeprazole Administered
Together: Effect on Clopidogrel Active Metabolite H4
60
Day 1 – 300 mg
50
Clopidogrel alone
Clopidogrel + omeprazole
LOQ = 0.500 ng/mL
40
30
20
10
0
0.0
0.5
1.0
1.5
Nominal Time (h)
2.0
2.5
3.0
Mean (SD) Active Metabolite H4 Concentration (ng/mL)
Mean (SD) Active Metabolite H4 Concentration (ng/mL)
Mean (SD) Plasma Concentration of Clopidogrel Active Metabolite H4 After a 300-mg
Loading Dose (Left) and 75-mg Maintenance Dose (Right)
25
Day 5 – 75 mg
20
Clopidogrel alone
Clopidogrel + omeprazole
LOQ = 0.500 ng/mL*
15
10
5
0
0.0
0.5
1.0
1.5
2.0
Nominal Time (h)
• 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).
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]
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Standard-Dose Clopidogrel + Omeprazole Administered
12 Hours Apart: Pharmacodynamic Data
Mean ± SEM of Maximum Platelet Aggregation (%) Induced by ADP 5 µM
Estimated Treatment Difference in MPA (%) Induced by ADP 5 µM at Day 5
Parameter
Comparison
MPA (%), ADP 5 µM
Clopidogrel + Omeprazole minus Clopidogrel Alone at D5
Estimate
90% CI
P-value
5.6
2.8 to 8.5
0.0014
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]
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Standard-Dose Clopidogrel + Omeprazole Administered 12
Hours Apart: Effect on Clopidogrel Active Metabolite H4
50
Day 1 - 300 mg
40
Clopidogrel alone
Clopidogrel + omeprazole
LOQ = 0.500 ng/mL
30
20
10
0
0.0
0.5
1.0
1.5
Nominal Time (h)
2.0
2.5
3.0
Mean (SD) Active Metabolite H4 Concentration (ng/mL)
Mean (SD) Active Metabolite H4 Concentration (ng/mL)
Mean (SD) Plasma Concentration of Clopidogrel Active Metabolite H4 After a 300-mg
Loading Dose (Left) and 75-mg Maintenance Dose (Right)
25
Day 5 - 75 mg
20
Clopidogrel alone
Clopidogrel + omeprazole
LOQ = 0.500 ng/mL
15
10
5
0
0.0
0.5
1.0
1.5
2.0
Nominal Time (h)
• 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:
– 55% on Day 1 (P<0.001) and 56% on Day 5 (P<0.001) for maximum plasma concentration (Cmax), and
– 53% on Day 1 (P<0.001) and 47% on Day 5 (P<0.001) for area under the concentration–time curve from time zero to
24 hours (AUC0-24).
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] 6
Double-Dose Clopidogrel + Omeprazole
Administered Together: Pharmacodynamic Data
Mean ± SEM of Maximum Platelet Aggregation (%) Induced by ADP 5 µM
Estimated Treatment Difference in MPA (%) Induced by ADP 5 µM at Day 5
Parameter
Comparison
MPA (%), ADP 5 µM
Clopidogrel + Omeprazole minus Clopidogrel Alone at D5
Estimate
90% CI
P-value
8.1
5.7 to 10.6
<0.0001
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]
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Double-Dose Clopidogrel + Omeprazole Administered
Together: Effect on Clopidogrel Active Metabolite H4
60
Day 1: 600 mg
50
Clopidogrel alone
Clopidogrel + omeprazole
LOQ = 0.500 ng/mL
40
30
20
10
0
0
1
2
Nominal time (h)
3
4
Plasma Active Metabolite Concentrations (ng/mL)
Plasma Active Metabolite Concentrations (ng/mL)
Mean (SD) Plasma Concentration of Clopidogrel Active Metabolite H4 After a 600-mg
Loading Dose (Left) and 150-mg Maintenance Dose (Right)
25
Day 5: 150 mg
20
Clopidogrel alone
Clopidogrel + omeprazole
LOQ = 0.500 ng/mL
15
10
5
0
0
1
2
3
4
Nominal time (h)
• After coadministering omeprazole with clopidogrel (600-mg LD/150-mg/day MD), the clopidogrel active metabolite H4
pharmacokinetic parameters were consistently decreased by:
– 46% on Day 1 (P<0.001) and 50% on Day 5 (P<0.001) for maximum plasma concentration (Cmax), and
– 48% on Day 1 (P<0.001) and 41% on Day 5 (P<0.001) for area under the concentration–time curve from time zero to
24 hours (AUC0-24).
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]
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Study Design: Pantoprazole + Clopidogrel Interaction Study
Sequence: Clopidogrel or Placebo → Clopidogrel or Placebo + Pantoprazole
Screening
Day –21 to
Day –2
≤21 days
Clopidogrel or
Placebo
Day 1 to Day 5
Day –1
Admission
Inclusion
Procedures
Day 1
Inclusion
Randomization
Clopidogrel or
Placebo
Administration
Day 6
Discharge
Wash-out
period*
Pantoprazole
Day –7 to Day 5
Follow-up at least
7 to 10 days
post-dose
Day –8
Admission
Inclusion
Procedures
Day –7
Pantoprazole
Administration
Clopidogrel or
Placebo
Day 1 to Day 5
Day 6
Discharge
End-of-Study
Visit
*At least 14 days
Angiolillo DA, et al. Clin Pharmacol Ther. 2010 Sep 15. [Epub ahead of print]
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Standard-Dose Clopidogrel + Pantoprazole Administered
Together: Pharmacodynamic Data
Mean ± SEM of Maximum Platelet Aggregation (%) Induced by ADP 5 µM
Estimated Treatment Difference in MPA (%) Induced by ADP 5 µM at Day 5
Parameter
Comparison
MPA (%), ADP 5 µM
Clopidogrel + Pantoprazole minus Clopidogrel Alone at D5
Estimate
90% CI
P-value
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.
Angiolillo DA, et al. Clin Pharmacol Ther. 2010 Sep 15. [Epub ahead of print]
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Standard-Dose Clopidogrel + Pantoprazole Administered
Together: Effect on Clopidogrel Active Metabolite H4
Day 1 – 300 mg
50
Clopidogrel alone
Clopidogrel + pantoprazole
40
LOQ = 0.5 (ng/mL)
30
20
10
0
0.0
0.5
1.0
1.5
Nominal Time (hr)
2.0
3.0
Mean (SD) Active Metabolite H4 Concentration (ng/mL)
Mean (SD) Active Metabolite H4 Concentration (ng/mL)
Mean (SD) Plasma Concentration of Clopidogrel Active Metabolite H4 After a 300-mg
Loading Dose (Left) and 75-mg Maintenance Dose (Right)
Day 5 – 75 mg
20
Clopidogrel alone
Clopidogrel + pantoprazole
LOQ = 0.5 (ng/mL)
15
10
5
0
0.0
0.5
1.0
1.5
2.0
Nominal Time (hr)
• After coadministering pantoprazole with clopidogrel (300-mg LD/75-mg/day MD), the clopidogrel active metabolite H4
pharmacokinetic parameters were decreased by:
– 24% on Day 1 (P<0.001) and 28% on Day 5 (P<0.001) for maximum plasma concentration (Cmax), and
– 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).
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]
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Standard-Dose Clopidogrel + Omeprazole versus StandardDose Clopidogrel + Pantoprazole: VASP-PRI Data
Mean ± SEM of Vasodilator-Stimulated Phosphoprotein Phosphorylation-Platelet Reactivity Index (%)
Clopidogrel ± Pantoprazole
Clopidogrel ± Omeprazole
• 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.
Angiolillo DA, et al. Clin Pharmacol Ther. 2010 Sep 15. [Epub ahead of print]
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.
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