proton pump inhibitor (ppi) studies. day –5 inclusion randomization omeprazole administration day...
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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
ScreeningDay –28 to
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
Follow-up at least7 to 10 days
post-dose
Day –1AdmissionInclusion
Procedures
Day –1AdmissionInclusion
Procedures
Wash-out period†
Wash-out period†
Clopidogrel or Placebo
Day 1 to Day 5
Clopidogrel or Placebo
Day 1 to Day 5
Clopidogrel or Placebo
Day 1 to Day 5
Clopidogrel or Placebo
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
Mean ± SEM of Maximum Platelet Aggregation (%) Induced by ADP 5 µM
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]
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
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
Clopidogrel aloneClopidogrel + omeprazoleLOQ = 0.500 ng/mL
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
Clopidogrel aloneClopidogrel + omeprazoleLOQ = 0.500 ng/mL
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
Mean (SD) Plasma Concentration of Clopidogrel Active Metabolite H4 After a 300-mg Loading Dose (Left) and 75-mg Maintenance Dose (Right)
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:
– 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.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
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. Angiolillo 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 8.1 5.7 to 10.6 <0.0001
Double-Dose Clopidogrel + Omeprazole Administered Together: Effect on Clopidogrel Active Metabolite H4
Clopidogrel aloneClopidogrel + omeprazoleLOQ = 0.500 ng/mL
Mean (SD) Plasma Concentration of Clopidogrel Active Metabolite H4 After a 600-mg Loading Dose (Left) and 150-mg Maintenance Dose (Right)
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
)
Clopidogrel aloneClopidogrel + omeprazoleLOQ = 0.500 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:
– 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.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]
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
ScreeningDay –21 to
Day –2≤21 days
ScreeningDay –21 to
Day –2≤21 days
Day –1AdmissionInclusion
Procedures
Day –1AdmissionInclusion
Procedures
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
Follow-up at least7 to 10 days
post-doseDay –8
AdmissionInclusion
Procedures
Day –8AdmissionInclusion
Procedures
Wash-out period*
Wash-out period*
Clopidogrel or Placebo
Day 1 to Day 5
Clopidogrel or Placebo
Day 1 to Day 5
Clopidogrel or Placebo
Day 1 to Day 5
Clopidogrel or Placebo
Day 1 to Day 5
9
PantoprazoleDay –7 to Day 5Pantoprazole
Day –7 to Day 5
Angiolillo DA, et al. Clin Pharmacol Ther. 2010 Sep 15. [Epub ahead of print]
Standard-Dose Clopidogrel + Pantoprazole Administered Together: Pharmacodynamic Data
Mean ± SEM of Maximum Platelet Aggregation (%) Induced by ADP 5 µM
10
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.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:
– 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).
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.Angiolillo DA, et al. Clin Pharmacol Ther. 2010 Sep 15. [Epub ahead of print]
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
Angiolillo DA, et al. Clin Pharmacol Ther. 2010 Sep 15. [Epub ahead of print]