1. Proton Pump Inhibitor (PPI) Studies
Speaker to refer to slide for presentation.

2. 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
Follow-up at least
7 to 10 days post-dose
Clopidogrel or Placebo
Day 1 to Day 5
Day 6
Admission
Inclusion
Procedures
Day –1 Admission Inclusion Procedures
Day 6
Discharge
Day 6
Discharge
End-of-Study Visit
Day –5 Inclusion
Randomization
Omeprazole
Administration
Day –1 Clopidogrel
or Placebo
Administration
All 3 studies were randomized, placebo-controlled, 2-period, 2-sequence, crossover, pharmacokinetic and pharmacodynamic interaction studies.
Primary objective: To assess the effects of clopidogrel, given either alone or concomitantly with omeprazole, on platelet aggregation induced by adenosine diphosphate (ADP).
Primary criteria: Maximum platelet aggregation intensity (MAI) as stimulated by ADP 5 µM, after 5 days of clopidogrel repeated dosing.
Subjects received a loading dose of clopidogrel for 1 day followed by 4 days of clopidogrel maintenance doses for both periods. Omeprazole was given once daily for 10 days in the period of clopidogrel or placebo + omeprazole administration; administration for 5 days prior to clopidogrel and then concomitantly with clopidogrel for 5 days.
Total duration per subject from screening: from 8 to 9 weeks.
Screening: 2 to 21 days before the first dosing (clopidogrel or omeprazole)
Period of clopidogrel or placebo: 5 days
Period of clopidogrel or placebo + omeprazole: 12 days
Wash-out period: at least 14 days with respect to clopidogrel treatment
End of study: at 7 to 10 days after the last dosing
Note that this slide presents only 1 treatment sequence. Patients could also be randomized to the sequence of Clopidogrel or Placebo followed by Clopidogrel or Placebo + Omeprazole.
Reference
1. Angiolillo DA, et al. Clin Pharmacol Ther 2010; in press.
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 Sep 15. [Epub ahead of print] 2

3. Standard-Dose Clopidogrel + Omeprazole Administered Together: Pharmacodynamic Data
Mean ± SEM of Maximum Platelet Aggregation (%) Induced by ADP 5 µM
This was a randomized, placebo-controlled, two-period, two-sequence, cross-over pharmacokinetic and pharmacodynamic interaction study after 5-day repeated oral doses of clopidogrel (300-mg loading dose followed by 75 mg/d for 4 days) administered alone or given concomitantly with omeprazole 80 mg/d in 72 healthy men and women.
The pharmacodynamic population included all 72 subjects.
The graph on the slide shows the mean values of maximum platelet aggregation (MPA) (%) induced by adenosine diphosphate (ADP) at each timepoint for up to 5 days after treatment with clopidogrel in the presence and absence of omeprazole.
In the presence of omeprazole, there was a decrease of the antiplatelet activity of clopidogrel after both the loading and maintenance doses. On Day 5, there was an absolute increase of 8.0% (90% confidence interval [CI], ; P<0.0001) in the MPA induced by ADP 5 µM under combined treatment, compared with the value observed under clopidogrel alone.
The decreased antiplatelet activity of clopidogrel when coadministered with omeprazole was also reflected in increases in vasodilator-stimulated phosphoprotein (VASP) phosphorylation and decreases in bleeding time.
Reference
1. Angiolillo DA, et al. Clin Pharmacol Ther 2010; in press.
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
ADP, adenosine diphosphate; CI, confidence interval; D, day; MPA, maximum platelet aggregation; SEM, standard error of the mean; T, sampling time. 3
Angiolillo DA, et al. Clin Pharmacol Ther Sep 15. [Epub ahead of print]

4. Standard-Dose Clopidogrel + Omeprazole Administered Together: Effect on Clopidogrel Active Metabolite H4
Mean (SD) Plasma Concentration of Clopidogrel Active Metabolite H4 After a 300-mg Loading Dose (Left) and 75-mg Maintenance Dose (Right) 60
Day 5 – 75 mg
Nominal Time (h)
0.0
0.5
1.0
1.5
2.0 5 10 15 20 25
Clopidogrel alone
Clopidogrel + omeprazole
LOQ = ng/mL*
Day 1 – 300 mg 50
Clopidogrel alone
Clopidogrel + omeprazole 40
LOQ = ng/mL
Mean (SD) Active Metabolite H4 Concentration (ng/mL) 30
Mean (SD) Active Metabolite H4 Concentration (ng/mL) 20 10
The pharmacokinetic population included 66 subjects.
Based on AUC(0-24) ratios (standard-dose clopidogrel + omeprazole vs standard-dose clopidogrel alone), the active metabolite H4 exposure was decreased by 45% following a 300-mg loading dose of clopidogrel given concomitantly with 80 mg omeprazole (AUC0-24 ratio of 0.55; 90% CI, ; P<0.001) and by 40% following an additional 4-day 75-mg maintenance dose of clopidogrel + omeprazole (AUC0-24 ratio of 0.60; 90% CI, ; P<0.001).
After a 300-mg clopidogrel loading dose given concomitantly with omeprazole, the Cmax ratio was 0.54 (90% CI, ; P<0.001); after an additional 4 days of clopidogrel 75 mg/day given concomitantly with omeprazole, the Cmax ratio was 0.58 (90% CI, ; P<0.001).
Simultaneous administration of a 300-mg clopidogrel loading dose with omeprazole increased exposure of unchanged clopidogrel (AUC0-24 ratio, 1.19; 90% CI, ; P=0.012), and after 4 days of clopidogrel 75 mg/day, unchanged clopidogrel exposure increased by 51% (AUC0-24 ratio, 1.51; 90% CI, ; P<0.001).
Reference
1. Angiolillo DA, et al. Clin Pharmacol Ther 2010; in press.
0.0
0.5
1.0
1.5
2.0
2.5
3.0
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 Sep 15. [Epub ahead of print] 4

5. Standard-Dose Clopidogrel + Omeprazole Administered 12 Hours Apart: Pharmacodynamic Data
Mean ± SEM of Maximum Platelet Aggregation (%) Induced by ADP 5 µM
This was a randomized, placebo-controlled, two-period, two-treatment, two-sequence, cross-over pharmacodynamic and pharmacokinetic interaction study after 5-day repeated oral doses of clopidogrel (300-mg loading dose followed by 75 mg/d) administered alone or given with omeprazole 80 mg/d (12 hours apart on the same days) in 72 healthy men and women.
The pharmacodynamic population included all 72 subjects.
The graph shows mean values of MPA (%) induced by ADP 5 µM at each time point for up to 5 days after treatment with clopidogrel (300-mg loading dose followed by 4 additional days of 75 mg/d) administered alone or given with omeprazole 80 mg/d at a 12-hour interval.
In the presence of omeprazole, given 12 hours apart from clopidogrel, there was a decrease of clopidogrel antiplatelet activity after both the loading and maintenance doses. On Day 5, there was an absolute increase of 5.6% (90% CI, 2.8 to 8.5; P=0.0014) in the MPA induced by ADP 5 µM under combined treatment, compared with the value observed under clopidogrel alone.
The decreased antiplatelet activity of clopidogrel when administered 12 hours apart from omeprazole was also reflected in increases in vasodilator-stimulated phosphoprotein (VASP) phosphorylation and decreases in bleeding time.
Reference
1. Angiolillo DA, et al. Clin Pharmacol Ther 2010; in press.
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
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. 5
Angiolillo DA, et al. Clin Pharmacol Ther Sep 15. [Epub ahead of print]

6. Standard-Dose Clopidogrel + Omeprazole Administered 12 Hours Apart: Effect on Clopidogrel Active Metabolite H4
Mean (SD) Plasma Concentration of Clopidogrel Active Metabolite H4 After a 300-mg Loading Dose (Left) and 75-mg Maintenance Dose (Right) 50 25
Day mg
Day mg 40 20
Clopidogrel alone
Clopidogrel alone
Clopidogrel + omeprazole
Clopidogrel + omeprazole 30
LOQ = ng/mL
LOQ = ng/mL 15
Mean (SD) Active Metabolite H4 Concentration (ng/mL)
Mean (SD) Active Metabolite H4 Concentration (ng/mL) 20 10 10 5
The pharmacokinetic population included 65 subjects.
Based on AUC(0-24) ratios (standard-dose clopidogrel + omeprazole vs standard-dose clopidogrel alone), the active metabolite H4 exposure was decreased by 53% following a 300-mg loading dose of clopidogrel given 12 hours before 80 mg omeprazole (AUC0-24 ratio of 0.47; 90% CI, ; P<0.001) and by 47% following an additional 4-day 75-mg maintenance dose of clopidogrel + omeprazole (AUC0-24 ratio of 0.53; 90% CI, ; P<0.001).
After a 300-mg clopidogrel loading dose given 12 hours before omeprazole, the Cmax ratio was 0.45 (90% CI, ; P<0.001); after an additional 4 days of clopidogrel 75 mg/day given 12 hours before omeprazole, the Cmax ratio was 0.44 (90% CI, ; P<0.001).
Administration of a 300-mg clopidogrel loading dose 12 hours before omeprazole increased exposure of unchanged clopidogrel (AUC0-24 ratio, 1.19; 90% CI, ; P=0.001), and after 4 days of clopidogrel 75 mg/day, unchanged clopidogrel exposure increased by 37% (AUC0-24 ratio, 1.37; 90% CI, ; P<0.001).
Reference
1. Angiolillo DA, et al. Clin Pharmacol Ther 2010; in press.
0.0
0.5
1.0
1.5
2.0
2.5
3.0
0.0
0.5
1.0
1.5
2.0
Nominal Time (h)
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. 6
Angiolillo DA, et al. Clin Pharmacol Ther Sep 15. [Epub ahead of print]

7. Double-Dose Clopidogrel + Omeprazole Administered Together: Pharmacodynamic Data
Mean ± SEM of Maximum Platelet Aggregation (%) Induced by ADP 5 µM
This was a randomized, double-blind, placebo-controlled, two-period, two-treatment, two-sequence, cross-over pharmacodynamic and pharmacokinetic interaction study after 5-day repeated oral doses of clopidogrel (600-mg loading dose followed by 150 mg/d) administered alone or given concomitantly with omeprazole 80 mg/d in 72 healthy men and women.
The pharmacodynamic population included 71 subjects.
The graph shows the mean values of maximum platelet aggregation (MPA) (%) induced by adenosine diphosphate (ADP) 5 µM at each time point for up to 5 days after treatment with clopidogrel in the presence or absence of omeprazole.
In the presence of omeprazole, there was a decrease of the antiplatelet activity of clopidogrel after both the loading and maintenance doses. On Day 5, there was an absolute increase of 8.1% (90% CI, 5.7% to 10.6%; P<0.0001) in the MPA induced by ADP 5 µM under combined treatment, compared with the value observed under clopidogrel alone.
The decreased antiplatelet activity of clopidogrel when coadministered with omeprazole was also reflected in increases in vasodilator-stimulated phosphoprotein (VASP) phosphorylation and decreases in bleeding time.
Reference
1. Angiolillo DA, et al. Clin Pharmacol Ther 2010; in press.
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
8.1
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. 7
Angiolillo DA, et al. Clin Pharmacol Ther Sep 15. [Epub ahead of print]

8. Double-Dose Clopidogrel + Omeprazole Administered Together: Effect on Clopidogrel Active Metabolite H4
Mean (SD) Plasma Concentration of Clopidogrel Active Metabolite H4 After a 600-mg Loading Dose (Left) and 150-mg Maintenance Dose (Right)
Plasma Active Metabolite Concentrations (ng/mL) 60
Nominal time (h)
Day 1: 600 mg 50 40 30 20 10
Nominal time (h)
Day 5: 150 mg 25 20 15 10 5
Plasma Active Metabolite Concentrations (ng/mL)
Clopidogrel alone
Clopidogrel + omeprazole
LOQ = ng/mL
Clopidogrel alone
Clopidogrel + omeprazole
LOQ = ng/mL
The pharmacokinetic population included 65 subjects.
Based on AUC(0-24) ratios (double-dose clopidogrel + omeprazole vs double-dose clopidogrel alone), the active metabolite H4 exposure was decreased by 48% following a 600-mg loading dose of clopidogrel given concomitantly with 80 mg omeprazole (AUC0-24 ratio of 0.52; 90% CI, ; P<0.001) and by 41% following an additional 4-day 150-mg maintenance dose of clopidogrel + omeprazole (AUC0-24 ratio of 0.59; 90% CI, ; P<0.001).
After a 600-mg clopidogrel loading dose given concomitantly with omeprazole, the Cmax ratio was 0.54 (90% CI, ; P<0.001); after an additional 4 days of clopidogrel 150 mg/day given concomitantly with omeprazole, the Cmax ratio was 0.50 (90% CI, ; P<0.001).
Simultaneous administration of a 600-mg clopidogrel loading dose with omeprazole increased exposure of unchanged clopidogrel (AUC0-24 ratio, 1.19; 90% CI, ; P=0.002), and after 4 days of clopidogrel 150 mg/day, unchanged clopidogrel exposure increased by 44% (AUC0-24 ratio, 1.44; 90% CI, ; P<0.001).
Reference
1. Angiolillo DA, et al. Clin Pharmacol Ther 2010; in press.
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. 8
Angiolillo DA, et al. Clin Pharmacol Ther Sep 15. [Epub ahead of print]

9. Study Design: Pantoprazole + Clopidogrel Interaction Study
Omeprazole Interaction Studies
Sequence: Clopidogrel or Placebo → Clopidogrel or Placebo + Pantoprazole
Screening
Day –21 to Day –2
≤21 days
Clopidogrel or Placebo
Day 1 to Day 5
Wash-out period*
Pantoprazole
Day –7 to Day 5
Follow-up at least
7 to 10 days post-dose
Day –1
Admission
Inclusion
Procedures
Day 6
Discharge
Day –8 Admission Inclusion Procedures
Clopidogrel or Placebo
Day 1 to Day 5
Day 1 Inclusion
Randomization
Clopidogrel or Placebo
Administration
Speaker to refer to slide for presentation.
Note that this slide presents only 1 sequence. Patients could also be randomized to the sequence of Clopidogrel or Placebo + Pantoprazole followed by Clopidogrel or Placebo Alone.
Reference
1. Angiolillo DA, et al. Clin Pharmacol Ther 2010; in press.
Day 6
Discharge
End-of-Study Visit
Day –7 Pantoprazole
Administration
*At least 14 days
Angiolillo DA, et al. Clin Pharmacol Ther Sep 15. [Epub ahead of print] 9

10. Standard-Dose Clopidogrel + Pantoprazole Administered Together: Pharmacodynamic Data
Mean ± SEM of Maximum Platelet Aggregation (%) Induced by ADP 5 µM
This was a randomized, placebo-controlled, 2-period, 2-sequence, cross-over pharmacodynamic and pharmacokinetic interaction study after 5 days repeated oral doses of clopidogrel (300-mg loading dose followed by 75 mg/day) alone or given concomitantly with pantoprazole 80 mg/day in 66 healthy men.
The pharmacodynamic population included 64 men.
The graph on the slide shows the mean values of maximum platelet aggregation (MPA) (%) induced by adenosine diphosphate (ADP) 5 µM at each timepoint for up to 5 days after treatment with clopidogrel in the presence or absence of pantoprazole.
In the presence of pantoprazole, there was a slight decrease of the antiplatelet activity of clopidogrel. On Day 5, there was an absolute increase of 4.3% (90% CI, 1.4% to 7.1%; P=0.0136) in the MPA induced by ADP 5 µM under combined treatment, compared with the value observed under clopidogrel alone.
The decreased antiplatelet activity of clopidogrel when coadministered with pantoprazole was not reflected in a significant increase in vasodilator-stimulated phosphoprotein (VASP) phosphorylation at Day 5.
These small pharmacodynamic effects are consistent with a 14% reduction in AUC0-24 of the clopidogrel active metabolite H4 after 5 days of coadministration of clopidogrel and pantoprazole.
Reference
1. Angiolillo DA, et al. Clin Pharmacol Ther 2010; in press.
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 + 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. 10
Angiolillo DA, et al. Clin Pharmacol Ther Sep 15. [Epub ahead of print]

11. Standard-Dose Clopidogrel + Pantoprazole Administered Together: Effect on Clopidogrel Active Metabolite H4
Mean (SD) Plasma Concentration of Clopidogrel Active Metabolite H4 After a 300-mg Loading Dose (Left) and 75-mg Maintenance Dose (Right)
0.0
0.5
1.0
1.5
2.0
3.0
Mean (SD) Active Metabolite H4 Concentration (ng/mL) 10 20 30 40 50
Clopidogrel alone
Clopidogrel + pantoprazole
LOQ = 0.5 (ng/mL)
Day 1 – 300 mg
Nominal Time (hr)
Clopidogrel alone
Clopidogrel + pantoprazole
LOQ = 0.5 (ng/mL)
Day 5 – 75 mg
0.0
0.5
1.0
1.5
2.0 5 10 15 20
Nominal Time (hr)
Mean (SD) Active Metabolite H4 Concentration (ng/mL)
The pharmacokinetic population included 58 men.
Based on AUC(0-24) ratios (standard-dose clopidogrel + pantoprazole vs standard-dose clopidogrel alone), the active metabolite H4 exposure was decreased by 20% following a 300-mg loading dose of clopidogrel given concomitantly 80 mg pantoprazole (AUC0-24 ratio of 0.80; 90% CI, ; P<0.001) and by 14% following an additional 4-day 75-mg maintenance dose of clopidogrel + pantoprazole (AUC0-24 ratio of 0.86; 90% CI, ; P=0.002).
After a 300-mg clopidogrel loading dose given concomitantly with pantoprazole, the Cmax ratio was 0.76 (90% CI, ; P<0.001); after an additional 4 days of clopidogrel 75 mg/day given concomitantly with pantoprazole, the Cmax ratio was 0.72 (90% CI, ; P<0.001).
Simultaneous administration of a 300-mg clopidogrel loading dose with pantoprazole did not affect exposure of unchanged clopidogrel (AUC0-24 ratio, 1.00; 90% CI, ; P=0.942), but after 4 days of clopidogrel 75 mg/day, unchanged clopidogrel exposure increased by 19% (AUC0-24 ratio, 1.19; 90% CI, ; P=0.011).
Reference
1. Angiolillo DA, et al. Clin Pharmacol Ther 2010; in press.
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. 11
Angiolillo DA, et al. Clin Pharmacol Ther Sep 15. [Epub ahead of print]

12. Standard-Dose Clopidogrel + Omeprazole versus Standard-Dose Clopidogrel + Pantoprazole: VASP-PRI Data
Mean ± SEM of Vasodilator-Stimulated Phosphoprotein Phosphorylation-Platelet Reactivity Index (%)
Clopidogrel ± Omeprazole
Clopidogrel ± Pantoprazole
VASP-PRI (%) was higher in the clopidogrel + omeprazole group (left panel): omeprazole decreased the effect of clopidogrel on platelet reactivity at Day 5.
There was a numerically small, statistically insignificant increase in VASP-PRI when clopidogrel was coadministered with pantoprazole, with the CI for the effect including zero (increase of 3.86% with 90% CI, to 10.44) (P=0.3319).
Reference
1. Angiolillo DA, et al. Clin Pharmacol Ther 2010; in press.
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 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. 12