T. Andersson 1, P. Nagy 1, M. Niazi 1, S. Nylander 1, L. Wallentin 2. ESC 2012, Munich, Germany. (1) AstraZeneca R&D, Mölndal, Sweden

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1 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

2 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

3 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

4 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 NCT ADP = adenosine disphosphate; ESO = esomeprazole; OME = omeprazole; LANSO = lansoprazole; PD = pharmacodynamics; PK = pharmacokinetics; PPIs = proton pump inhibitors

5 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)

6 Mean (SD) Plasma Concentrations of AMC vs Time Clopidogrel Active Metabolite Plasma Concentration (ng/ml) Day 1 Day 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) 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) Day 14 Day 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) 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

7 Mean (SD) mipa (%) Induced by 2 µm ADP 8 8 Mean mipa (%) Induced by 2 M ADP Treatment A [n=63 (Day 2), n=6 (Day 3)] Treatment D [n=1 (Day 2); n=97 (Day 3)] Treatment duration (days) Mean mipa (%) Induced by 2 M ADP Treatment B [n=6 (Day 2); n=6 (Day 3)] Treatment D [n=1 (Day 2); n=97 (Day 3)] Treatment duration (days) 8 Mean mipa (%) Induced by 2 M ADP Treatment C [n=62 (Day 2); n=6 (Day 3)] Treatment D [n=1 (Day 2); n=97 (Day 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

8 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 NCT ASA = acetylsalicylic acid; ADP = adenosine disphosphate; ESO = esomeprazole; PD = pharmacodynamics; PK = pharmacokinetics

9 Mean Plasma Concentrations of AMC vs Time 11 1 Linear Scale Clopidogrel n=56 Clopidogrel + Esomeprazole/ASA n=58 Mean Concentration (ng/ml) Time (h) Systemic exposure (AUC and C max ) of AMC decreased by ~4% AMC = active metabolite of clopidogrel; ASA = acetylsalicylic acid

10 mipa (%) Individual mipa (%) vs AUC t of AMC No change in effect; ΔmIPA =.1, 9% CI = -3.78, Clopidogrel Clopidogrel+FDC + Esomeprazole / ASA Log. (Clopidogrel) Log (Clopidogrel + Esomeprazole / ASA) Log. (Clopidogrel+FDC) AUC -t (ng*h/ml) AMC = active metabolite of clopidogrel; ASA = acetylsalicylic acid; mipa = maximal inhibition of platelet aggregation

11 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

12 Back-up slides

13 Fraction Fraction subjects with mpa>5% MPA >5% Fraction of Subjects with MPA >5% (~PRU >23) 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

14 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

15 Fraction Fraction subjects subjects with with PRI>65% PRI >65% Fraction of Subjects with PRI >65% (~PRU >23) 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

16 % 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= % ASA-treated PRP ASA contribution Untreated PRP µm Clopidogrel active metabolite In-house data ADP = adenosine diphosphate; ASA = acetylsalicylic acid; mipa = maximal inhibition of platelet aggregation; PRP = platelet-rich plasma