Impact of omeprazole, esomeprazole +/- acetylsalicylic acid and lansoprazole on the pharmacodynamics and pharmacokinetics of clopidogrel in healthy volunteers T. Andersson 1, P. Nagy 1, M. Niazi 1, S. Nylander 1, L. Wallentin 2 (1) AstraZeneca R&D, Mölndal, Sweden (2) Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden ESC 212, Munich, Germany
Author Disclosures T. Andersson, P. Nagy, M. Niazi and S. Nylander: employees, AstraZeneca L. Wallentin: research grants, AstraZeneca This study was supported by AstraZeneca R&D, Mölndal, Sweden Medical writing support was provided by Steve Winter (inscience Communications, Springer Healthcare) and was funded by AstraZeneca
Metabolism of Clopidogrel 2B6, 3A4 1A2, 2C9 Clopidogrel CYP2C19 Active Metabolite of Clopidogrel (AMC) PPIs Metabolites Note: Impaired or no CYP2C19 function PMs: AMC 4 6% lower PMs+IMs: AMC 32% lower; ΔMPA 9% lower ΔMPA = absolute difference of the reduction in maximal platelet aggregation Mega et al. NEJM 29 Brandt et al. J Thromb Haemost 27 Umemura et al. J Thromb Haemost 28
Study 34: Clopidogrel + Omeprazole / Esomeprazole / Lansoprazole Objectives: To investigate the impact of 3 PPIs OME 8 mg/day, ESO 4 mg/day or LANSO 6 mg/day on the PD and PK of clopidogrel during 29 days concomitant treatment in healthy volunteers Methods: PD of clopidogrel was assessed by maximum inhibition of platelet aggregation induced by 2 M ADP on days 2, 6, 15 and 3 relative to baseline PK of clopidogrel was assessed by means of systemic exposure of the active metabolite after a loading dose (3 mg; Day 1) and during maintenance dosing (75 mg/day) on days 5, 14 and 29 Design: Incomplete randomized crossover study, with ~6 subjects/arm NCT1147588 ADP = adenosine disphosphate; ESO = esomeprazole; OME = omeprazole; LANSO = lansoprazole; PD = pharmacodynamics; PK = pharmacokinetics; PPIs = proton pump inhibitors
Study 34: Clopidogrel + Omeprazole / Esomeprazole / Lansoprazole Treatment A/B/C/D Treatment A/B/C/D Treatment A/B/C/D Washout (14 days) Washout (14 days) Period 1 (3 days) Period 2 (3 days) Period 3 (3 days) Treatment A: Lansoprazole 6 mg/day + clopidogrel 3 mg/75 mg B: Omeprazole 8 mg/day + clopidogrel 3 mg/75 mg C: Esomeprazole 4 mg/day + clopidogrel 3 mg/75 mg D: Clopidogrel 3 mg/75 mg (all subjects)
Mean (SD) Plasma Concentrations of AMC vs Time Clopidogrel Active Metabolite Plasma Concentration (ng/ml) 7 6 5 4 3 2 1 Day 1 Day 5 1 2 3 4 5 6 Time (h) Treatment A (n=65) Treatment B (n=64) Treatment C (n=65) Treatment D (n=11) Clopidogrel Active Metabolite Plasma Concentration (ng/ml) 25 2 15 1 5 1 2 3 4 Time (h) Treatment A (n=64) Treatment B (n=64) Treatment C (n=64) Treatment D (n=11) Clopidogrel Active Metabolite Plasma Concentration (ng/ml) 25 2 15 1 5 Day 14 Day 29 1 2 3 4 Time (h) Treatment A (n=62) Treatment B (n=63) Treatment C (n=64) Treatment D (n=99) Clopidogrel Active Metabolite Plasma Concentration (ng/ml) 25 2 15 1 5 1 2 3 4 Time (h) Treatment A (n=6) Treatment B (n=63) Treatment C (n=62) Treatment D (n=97) A: lansoprazole 6 mg/day; B: omeprazole 8 mg/day; C: esomeprazole 4 mg/day; D: clopidogrel alone AMC = active metabolite of clopidogrel; SD = standard deviation
Mean (SD) mipa (%) Induced by 2 µm ADP 8 8 Mean mipa (%) Induced by 2 M ADP 7 6 5 4 3 2 1 Treatment A [n=63 (Day 2), n=6 (Day 3)] Treatment D [n=1 (Day 2); n=97 (Day 3)] 5 1 15 2 25 3 Treatment duration (days) Mean mipa (%) Induced by 2 M ADP 7 6 5 4 3 2 1 Treatment B [n=6 (Day 2); n=6 (Day 3)] Treatment D [n=1 (Day 2); n=97 (Day 3)] 5 1 15 2 25 3 Treatment duration (days) 8 Mean mipa (%) Induced by 2 M ADP 7 6 5 4 3 2 1 Treatment C [n=62 (Day 2); n=6 (Day 3)] Treatment D [n=1 (Day 2); n=97 (Day 3)] 5 1 15 2 25 3 Treatment duration (days) A: lansoprazole 6 mg/day; B: omeprazole 8 mg/day; C: esomeprazole 4 mg/day; D: clopidogrel alone ADP = adenosine diphosphate; mipa = maximal inhibition of platelet aggregation; SD = standard deviation
Study 1: Clopidogrel + Esomeprazole / ASA Objectives: To investigate the impact of ESO 2 mg/day + ASA 81 mg/day (fixed combination) on the PD and PK of clopidogrel after 9 days concomitant treatment in healthy volunteers Methods: PD of clopidogrel was assessed by maximum inhibition of platelet aggregation induced by 2 M ADP PK of clopidogrel was assessed by means of systemic exposure of the active metabolite on day 9 Design: Randomized 2-way crossover study, with ~6 subjects/arm NCT121339 ASA = acetylsalicylic acid; ADP = adenosine disphosphate; ESO = esomeprazole; PD = pharmacodynamics; PK = pharmacokinetics
Mean Plasma Concentrations of AMC vs Time 11 1 Linear Scale Clopidogrel n=56 Clopidogrel + Esomeprazole/ASA n=58 Mean Concentration (ng/ml) 9 8 7 6 5 4 3 2 1 1 2 3 4 Time (h) Systemic exposure (AUC and C max ) of AMC decreased by ~4% AMC = active metabolite of clopidogrel; ASA = acetylsalicylic acid
mipa (%) Individual mipa (%) vs AUC t of AMC No change in effect; ΔmIPA =.1, 9% CI = -3.78, 3.99 1 75 5 Clopidogrel Clopidogrel+FDC + Esomeprazole / ASA Log. (Clopidogrel) Log (Clopidogrel + Esomeprazole / ASA) Log. (Clopidogrel+FDC) 25-25 1 2 3 4 5 AUC -t (ng*h/ml) AMC = active metabolite of clopidogrel; ASA = acetylsalicylic acid; mipa = maximal inhibition of platelet aggregation
Summary Results / Conclusions All PPIs decreased systemic exposure of AMC Omeprazole 8 mg (45 5%) Esomeprazole 4 mg (35 4%) Lansoprazole 6 mg (18 3%) All PPIs decreased clopidogrel-induced inhibition of platelet aggregation Omeprazole 8 mg (16 17%) Esomeprazole 4 mg (11 17%) Lansoprazole 6 mg (6 11%) Esomeprazole given together with low-dose ASA (fixed-dose combination; 2 mg + 81 mg) decreased systemic exposure of AMC (4%) but had no apparent effect on clopidogrel-induced inhibition of platelet aggregation No new safety signals were identified in the studies AMC = active metabolite of clopidogrel; ASA = acetylsalicylic acid; PPIs = proton pump inhibitors
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Fraction Fraction subjects with mpa>5% MPA >5% Fraction of Subjects with MPA >5% (~PRU >23) 1 8 6 4 2 Lanso 6mg+Clo 3/75mg Ome 8mg+Clo 3/75mg Eso 4mg+Clo 3/75mg Clo 3/75mg 15 3 Treatment duration Day (days) MPA = maximal platelet aggregation; PRU = P2Y12 reaction units Brar et al. J Am Coll Cardiol 211
2 µm ADP induced mpa(%) Individual Data and Fraction of Subjects with MPA >5% (~PRU >23) 1 5 Baseline Clopidogrel (26%) Baseline Clopidogrel + Esomeprazole / ASA (19%) ASA = acetylsalicylic acid; MPA = maximal platelet aggregation; PRU = P2Y12 reaction units Brar et al. J Am Coll Cardiol 211
Fraction Fraction subjects subjects with with PRI>65% PRI >65% Fraction of Subjects with PRI >65% (~PRU >23) 1 8 6 4 2 Lanso 6mg+Clo 3/75mg Ome 8mg+Clo 3/75mg Eso 4mg+Clo 3/75mg Clo 3/75mg 15 3 Day Treatment duration (days) PRI = platelet reactivity index; PRU = P2Y12 reaction units Brar et al. J Am Coll Cardiol 211
% mipa ASA has an Additive Effect on Top of P2Y12 inhibition on ADP-induced Platelet Aggregation in vitro 75 2 µm ADP maximal aggregation, n=6 65 55 45 35-15 % 25 15 5-5 ASA-treated PRP ASA contribution Untreated PRP.1.1 1 1 µm Clopidogrel active metabolite In-house data ADP = adenosine diphosphate; ASA = acetylsalicylic acid; mipa = maximal inhibition of platelet aggregation; PRP = platelet-rich plasma