European Journal of Clinical Pharmacology

, Volume 70, Issue 9, pp 1049–1057 | Cite as

Prasugrel but not high dose clopidogrel overcomes the lansoprazole neutralizing effect of P2Y12 inhibition: Results of the randomized DOSAPI study

  • Jean-Philippe Collet
  • Jean-Sébastien Hulot
  • Jérémie Abtan
  • Ghalia Anzaha
  • Mathieu Kerneis
  • Johanne Silvain
  • Guillaume Cayla
  • Stephen A. O’Connor
  • Olivier Barthélémy
  • Farzin Beygui
  • Sophie Galier
  • Delphine Brugier
  • Eric J. Stanek
  • Scott L. Charland
  • Vanessa Gallois
  • Gilles Montalescot
  • for the DOSAPI investigators.
Clinical Trial



The potential negative metabolic interaction between proton pump inhibitors and clopidogrel is an unsolved issue. We hypothesized that doubling the clopidogrel maintenance dose (150 mg) would be less effective than switching to prasugrel 10 mg maintenance dose (MD) to overcome this negative interaction.

Method and results

In a randomized study with a factorial design, 82 stable coronary artery disease patients treated with 75 mg clopidogrel MD and aspirin were assigned to receive in a double blind fashion lansoprazole (30 mg/day) or placebo and to receive in an open fashion 150 mg clopidogrel MD or 10 mg prasugrel MD. The primary endpoint was the relative change in residual platelet reactivity over the 14-day study period [(RPA14day-RPAbaseline)/RPAbaseline].

The effect of doubling the clopidogrel MD on relative change in RPA was neutralized by lansoprazole (−53.6±48.4 % versus +0.8±53.7 % without and with lansoprazole, respectively, p = 0.02) whereas 10 mg of prasugrel MD dramatically reduced RPA irrespective of lansoprazole co-administration (−81.8 %±24.8 % vs. −72.9 %±32.9 % without and with lansoprazole, respectively, p = NS). Lansoprazole exposure was the only parameter with a significant interaction with RPA among subgroups.


The higher platelet inhibitory effect obtained by doubling the clopidogrel MD was totally neutralized by the co-administration of lansoprazole. This drug interaction was not observed with prasugrel 10 mg.


Thienopyridine Proton pump inhibitor Platelet reactivity Coronary artery disease 


Financial support

ACTION study group, France ( and Medco Health Solutions, Inc. (Franklin Lakes, NJ USA).

Supplementary material

228_2014_1710_MOESM1_ESM.odt (8 kb)
ESM 1(ODT 7 kb)


  1. 1.
    Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, Ikeda T, Kurihara A (2009) Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos 38(1):92–9CrossRefGoogle Scholar
  2. 2.
    Hagihara K, Nishiya Y, Kurihara A, Kazui M, Farid NA, Ikeda T (2008) Comparison of human cytochrome P450 inhibition by the thienopyridines prasugrel, clopidogrel, and ticlopidine. Drug Metab Pharmacokinet 23:412–420PubMedCrossRefGoogle Scholar
  3. 3.
    Savi P, Zachayus JL, Delesque-Touchard N, Labouret C, Hervé C, Uzabiaga MF, Pereillo JM, Culouscou JM, Bono F, Ferrara P, Herbert JM (2006) The active metabolite of Clopidogrel disrupts P2Y12 receptor oligomers and partitions them out of lipid rafts. Proc Natl Acad Sci U S A 103:11069–74PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Collet JP, Hulot JS, Anzaha G, Pena A, Chastre T, Caron C, Silvain J, Cayla G, Bellemain-Appaix A, Vignlalou JB, Gallier S, Barthélémy O, Beygui F, Gallois V, Montalescot G (2011) High Doses of Clopidogrel to Overcome Genetic Resistance (The CLOVIS-2 study). J Am Coll Cardiol Intv 4:392–402Google Scholar
  5. 5.
    Parodi G, Marcucci R, Valenti R, Gori AM, Migliorini A, Giusti B, Buonamici P, Gensini GF, Abbate R, Antoniucci D (2011) High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI. JAMA 306(11):1215–23PubMedCrossRefGoogle Scholar
  6. 6.
    Cayla G, Hulot JS, O’Connor S, Pathak A, Scott SA, Gruel Y, Sillvain J, Vignalou JB, Huerre Y, De la Briolle A, Allanic F, Beygui F, Barthélémy O, Montalescot G, Collet JP (2011) Clinical, angiographic, and genetic factors associated with early coronary stent thrombosis. JAMA 306(16):1765–1774PubMedCrossRefGoogle Scholar
  7. 7.
    Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS (2009) Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 360:354–62PubMedCrossRefGoogle Scholar
  8. 8.
    Mega JL, Simon T, Anderson JL, Bliden K, Collet J-P, Danchin N, Giusti B, Gurbel P, Horne BD, Kastrati A, Montalescot G, Neumann F-J, Shen L, Sibbing D, Steg PG, Trenk D, Wiviott SD, Sabatine MS (2009) CYP2C19 Genetic Variants and Clinical Outcomes With Clopidogrel: A Collaborative Meta-Analysis. Circulation 120:S598–b–91Google Scholar
  9. 9.
    Shuldiner AR, O’Connell JR, Gurbel PA, Bliden KP, Ghandi A, Ryan K, Horenstein RB, Damcott CM, Pakyz R, Gibson Q, Tantry US, Pollin T, Post W, Parsa A, Mitchell BD, Faraday N, Herzog W, Antonino MJ (2009) Influence of CYP2C19 polymorphism on antiplatelet effects of clopidogrel and long-term recurrent ischemic event occurrence. JAMA 302(8):849–858PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Farid NA, Kurihara A, Wrighton SA (2010) Metabolism and disposition of the thienopyridine antiplatelet drugs ticlopidine, clopidogrel, and prasugrel in humans. J Clin Pharmacol 50:126–142PubMedCrossRefGoogle Scholar
  11. 11.
    Li X-Q, Andersson TB, Ahlström M, Weidolf L (2004) Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug Metab Dispos 32:821–827PubMedCrossRefGoogle Scholar
  12. 12.
    Hamm CW, Bassand J-P, Agewall S, Bax J, Boersma E, Bueno H, Caso P, Dudek D, Gielen S, Huber K, Ohman M, Petrie MC, Sonntag F, Uva MS, Storey RF, Wijns W, Zahger D, Bax JJ, Auricchio A, Baumgartner H, Ceconi C, Dean V, Deaton C, Fagard R, Funck-Brentano C, Hasdai D, Hoes A, Knuuti J, Kolh P, McDonagh T, Moulin C, Poldermans D, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Torbicki A, Vahanian A, Windecker S, Windecker S, Achenbach S, Badimon L, Bertrand M, Bøtker HE, Collet J-P, Crea F, Danchin N, Falk E, Goudevenos J, Gulba D, Hambrecht R, Herrmann J, Kastrati A, Kjeldsen K, Kristensen SD, Lancellotti P, Mehilli J, Merkely B, Montalescot G, Neumann F-J, Neyses L, Perk J, Roffi M, Romeo F, Ruda M, Swahn E, Valgimigli M, Vrints CJ, Widimsky P (2011) ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: the Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 32:2999–3054PubMedCrossRefGoogle Scholar
  13. 13.
    Abraham NS, Hlatky MA, Antman EM, Bhatt DL, Bjorkman DJ, Clark CB, Furberg CD, Johnson DA, Kahi CJ, Laine L, Mahaffey KW, Quigley EM, Scheiman J, Sperling LS, Tomaselli GF (2010) ACCF/ACG/AHA 2010 Expert Consensus Document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents. Circulation 122:2619–2633PubMedCrossRefGoogle Scholar
  14. 14.
    Bhatt DL, Cryer BL, Contant CF, Cohen M, Lanas A, Schnitzer TJ, Shook TL, Lapuerta P, Goldsmith MA, Laine L, Scirica BM, Murphy SA, Cannon CP, COGENT Investigators (2010) Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 363(20):1909–17PubMedCrossRefGoogle Scholar
  15. 15.
    Lai KC, Lam SK, Chu KM, Wong BCY, Hui WM, Hu WHC, Lau GKK, Wong WM, Yuen MF, Chan AOO, Lai CL, Wong J (2002) Lansoprazole for the prevention of recurrences of ulcer complications from long-term low-dose aspirin use. N Engl J Med 346:2033–2038PubMedCrossRefGoogle Scholar
  16. 16.
    Hulot JS, Collet JP, Silvain J, Pena A, Bellemain A, Barthélémy O, Cayla G, Beygui F, Montalescot G (2010) Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-funtion allele or proton pump inhibitor co-administration: a systematic meta-analysis. J Am Coll Cardiol 56(2):134–143PubMedCrossRefGoogle Scholar
  17. 17.
    Agewall S, Cattaneo M, Collet JP, Andreotti F, Lip GYH, Verheugt FWA, Huber K, Grove EL, Morais J, Husted S, Wassmann S, Rosano G, Atar D, Pathak A, Kjeldsen K, Storey RF, On behalf of ESC Working Group on Cardiovascular Pharmacology and Drug Therapy and ESC Working Group on Thrombosis (2013) Expert position paper on the use of proton pump inhibitors in patients with cardiovascular disease and antithrombotic therapy. Eur Heart J. doi:10.1093/eurheartj/eht042 Google Scholar
  18. 18.
    Aradi D, Kuliczkowski W, Atar D, Serebruany VL (2012) Inter-patient variability and impact of proton pump inhibitors on platelet reactivity after prasugrel. Thromb Haemost 107:338–345PubMedCrossRefGoogle Scholar
  19. 19.
    Collet J-P, Hulot J-S, Pena A, Villard E, Esteve J-B, Silvain J, Payot L, Brugier D, Cayla G, Beygui F, Bensimon G, Funck-Brentano C, Montalescot G (2009) Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet 373:309–317PubMedCrossRefGoogle Scholar
  20. 20.
    Collet J-P, Silvain J, Landivier A, Tanguy M-L, Cayla G, Bellemain A, Vignolles N, Gallier S, Beygui F, Pena A, Montalescot G (2008) Dose effect of clopidogrel reloading in patients already on 75-mg maintenance dose: the reload with clopidogrel before coronary angioplasty in subjects treated long term with dual antiplatelet therapy (RELOAD) study. Circulation 118:1225–1233PubMedCrossRefGoogle Scholar
  21. 21.
    Campo G, Parrinello G, Ferraresi P, Lunghi B, Tebaldi M, Miccoli M, Marchesini J, Bernardi F, Ferrari R, Valgimigli M (2011) Prospective evaluation of on-clopidogrel platelet reactivity over time in patients treated with percutaneous coronary intervention. J Am Coll Cardiol 57:2474–83PubMedCrossRefGoogle Scholar
  22. 22.
    Gilard M, Arnaud B, Cornily JC, Le Gal G, Lacut K, Le Calvez G, Mansourati J, Mottier D, Abgrall JF, Boschat J (2008) Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol 51:256–60PubMedCrossRefGoogle Scholar
  23. 23.
    Hulot JS, Wuerzner G, Bachelot-Loza C, Azizi M, Blanchard A, Peyrard S, Funck-Brentano C, Gaussem P (2010) Effect of an increased clopidogrel maintenance dose or lansoprazole co-administration on the antiplatelet response to clopidogrel in CYP2C19-genotyped healthy subjects. J Thromb Haemost 8(3):610–3PubMedCrossRefGoogle Scholar
  24. 24.
    Angiolillo DJ, Gibson CM, Cheng S, Ollier C, Nicolas O, Bergougnan L, Perrin L, Lacreta FP, Hurbin F, Dubar M (2011) Differential effects of omeprazole and pantoprazole on the pharmacodynamics and pharmacokinetics of clopidogrel in healthy subjects: Randomized, placebo-controlled, crossover comparison studies. Clin Pharmacol Ther 89(1):65–74PubMedCrossRefGoogle Scholar
  25. 25.
    Frelinger AL 3rd, Lee RD, Mulford DJ, Wu J, Nudurupati S, Nigam A, Brooks JK, Bhatt DL, Michelson AD (2012) A randomized, 2-period, crossover design study to assess the effects of dexlansoprazole, lansoprazole, esomeprazole, and omeprazole on the steady-state pharmacokinetics and pharmacodynamics of clopidogrel in healthy volunteers. J Am Coll Cardiol 59:1304–1311PubMedCrossRefGoogle Scholar
  26. 26.
    Montalescot G, Sideris G, Cohen R, Meuleman C, Bal dit Sollier C, Barthélémy O, Henry P, Lim P, Beygui F, Collet JP, Marshall D, Luo J, Petitjean H, Drouet L (2010) Prasugrel compared with high-dose clopidogrel in acute coronary syndrome. The randomised, double-blind ACAPULCO study. Thromb Haemost 103:213–23PubMedCrossRefGoogle Scholar
  27. 27.
    Wiviott SD, Trenk D, Frelinger AL, O’Donoghue M, Neumann FJ, Michelson AD, Angiolillo DJ, Hod H, Montalescot G, Miller DL, Jakubowski JA, Cairns R, Murphy SA, McCabe CH, Antman EM, Braunwald E, for The PRINCIPLE-TIMI 44 Investigators (2007) Prasugrel compared to high loading and maintenance dose clopidogrel in patients with planned percutaneous coronary intervention: The PRINCIPLE-TIMI 44 Trial. Circulation 116(25):2923–32PubMedCrossRefGoogle Scholar
  28. 28.
    Brandt JT, Close SL, Iturria SJ, Payne CD, Farid NA, Ernest CS 2nd, Lachno DR, Salazar D, Winters KJ (2007) Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost 5:2429–36PubMedCrossRefGoogle Scholar
  29. 29.
    Wiviott SD, Braunwald E, McCabe CH, Horvath I, Keltai M, Herrman JP, Van de Werf F, Downey WE, Scirica BM, Murphy SA, Antman EM, TRITON-TIMI 38 Investigators (2008) Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial. Lancet 371(9621):1353–63PubMedCrossRefGoogle Scholar
  30. 30.
    The CURRENT-OASIS 7 Investigators (2010) Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med 363:930–42CrossRefGoogle Scholar
  31. 31.
    Pham J-P, Ueno M, Tello-Montoliu A, Ferreiro JL, Tomasello SD, Dharmashankar K, Kodali M, Seecheran N, Capodanno D, Desai B, Bass TA, Angiolillo DJ (2011) Impact of gastric acid-suppressing therapies on platelet reactivity in patients with coronary artery disease treated with clopidogrel: results of a pharmacodynamic study. J Am Coll Cardiol 58:1396–1398PubMedCrossRefGoogle Scholar
  32. 32.
    Small DS, Farid NA, Payne CD, Weerakkody GJ, Li YG, Brandt JT, Salazar DE, Winters KJ (2008) Effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. J Clin Pharmacol 48:475–484PubMedCrossRefGoogle Scholar
  33. 33.
    Moceri P, Doyen D, Cerboni P, Ferrari E (2011) Doubling the dose of clopidogrel restores the loss of antiplatelet effect induced by esomeprazole. Thromb Res 128:458–462PubMedCrossRefGoogle Scholar
  34. 34.
    Mega JL, Hochholzer W, Frelinger AL 3rd, Kluk MJ, Angiolillo DJ, Kereiakes DJ, Isserman S, Rogers WJ, Ruff CT, Contant C, Pencina MJ, Scirica BM, Longtine JA, Michelson AD, Sabatine MS (2011) Dosing clopidogrel based on CYP2C19 genotype and the effect on platelet reactivity in patients with stable cardiovascular disease. JAMA 306(20):2221–8PubMedCrossRefGoogle Scholar
  35. 35.
    Simon T, Steg PG, Gilard M, Blanchard D, Bonello L, Hanssen M, Lardoux H, Coste P, Lefèvre T, Drouet E, Mulak G, Bataille V, Ferrières J, Verstuyft C, Danchin N (2011) Clinical events as a function of proton pump inhibitor use, clopidogrel use, and cytochrome P450 2C19 genotype in a large nationwide cohort of acute myocardial infarction: Results from the French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) registry. Circulation 123:474–482PubMedCrossRefGoogle Scholar
  36. 36.
    Frelinger AL 3rd, Bhatt DL, Lee RD, Mulford DJ, Wu J, Nudurupati S, Nigam A, Lampa M, Brooks JK, Barnard MR, Michelson AD (2013) Clopidogrel Pharmacokinetics and Pharmacodynamics Vary Widely Despite Exclusion or Control of Polymorphisms (CYP2C19, ABCB1, PON1), Noncompliance, Diet, Smoking, Co-medications (Including Proton Pump Inhibitors), and Pre-existent Variability in Platelet Function. J Am Coll Cardiol 61(8):872–879Google Scholar
  37. 37.
    Steg PG, James SK, Atar D, Badano LP, Blömstrom-Lundqvist C, Borger MA, Di Mario C, Dickstein K, Ducrocq G, Fernandez-Aviles F, Gershlick AH, Giannuzzi P, Halvorsen S, Huber K, Juni P, Kastrati A, Knuuti J, Lenzen MJ, Mahaffey KW, Valgimigli M, van’t Hof A, Widimsky P, Zahger D (2012) ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 33:2569–2619PubMedCrossRefGoogle Scholar
  38. 38.
    O’Donoghue ML, Braunwald E, Antman EM, Murphy SA, Bates ER, Rozenman Y, Michelson AD, Hautvast RW, Ver Lee PN, Close SL, Shen L, Mega JL, Sabatine MS, Wiviott SD (2009) Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials. Lancet 374(9694):989–97PubMedCrossRefGoogle Scholar
  39. 39.
    Goodman SG, Clare R, Pieper KS, Nicolau JC, Storey RF, Cantor WJ, Mahaffey KW, Angiolillo DJ, Husted S, Cannon CP, James SK, Kilhamn J, Steg PG, Harrington RA, Wallentin L (2012) Association of proton pump inhibitor use on cardiovascular outcomes with clopidogrel and ticagrelor: Insights from the platelet inhibition and patient outcomes trial. Circulation 125:978–986PubMedCrossRefGoogle Scholar
  40. 40.
    Roe MT, Armstrong PW, Fox KAA, White HD, Prabhakaran D, Goodman SG, Cornel JH, Bhatt DL, Clemmensen P, Martinez F, Ardissino D, Nicolau JC, Boden WE, Gurbel PA, Ruzyllo W, Dalby AJ, McGuire DK, Leiva-Pons JL, Parkhomenko A, Gottlieb S, Topacio GO, Hamm C, Pavlides G, Goudev AR, Oto A, Tseng C-D, Merkely B, Gasparovic V, Corbalan R, Cinteză M, McLendon RC, Winters KJ, Brown EB, Lokhnygina Y, Aylward PE, Huber K, Hochman JS, Ohman EM (2012) Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med 367:1297–1309PubMedCrossRefGoogle Scholar
  41. 41.
    Collet J-P, Cuisset T, Rangé G, Cayla G, Elhadad S, Pouillot C, Henry P, Motreff P, Carrié D, Boueri Z, Belle L, Van Belle E, Rousseau H, Aubry P, Monségu J, Sabouret P, O’Connor SA, Abtan J, Kerneis M, Saint-Etienne C, Barthélémy O, Beygui F, Silvain J, M D EV, Montalescot G (2012) Bedside Monitoring to Adjust Antiplatelet Therapy for Coronary Stenting. N Engl J Med 367:2100–2109Google Scholar
  42. 42.
    Gurbel PA, Erlinge D, Ohman EM, Neely B, Neely M, Goodman SG, Huber K, Chan MY, Cornel JH, Brown E, Zhou C, Jakubowski JA, White HD, Fox KAA, Prabhakaran D, Armstrong PW, Tantry US, Roe MT (2012) Platelet function during extended prasugrel and clopidogrel therapy for patients with ACS treated without revascularization: the TRILOGY ACS platelet function substudy. JAMA 308:1785–1794PubMedCrossRefGoogle Scholar
  43. 43. FDSC reduced effectiveness of P (clopidogrel) in patients who are poor metabolizers of the drug. A at:, DrugSafetyInformationforPatientsandProviders/ucm203888.htm. Accessed April 28 2010
  44. 44.
    Chen C-H, Yang J-C, Uang Y-S, Lin C-J (2012) Differential inhibitory effects of proton pump inhibitors on the metabolism and antiplatelet activities of clopidogrel and prasugrel. Biopharm Drug Dispos 33:278–283PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Jean-Philippe Collet
    • 1
  • Jean-Sébastien Hulot
    • 2
    • 3
  • Jérémie Abtan
    • 1
  • Ghalia Anzaha
    • 1
  • Mathieu Kerneis
    • 1
  • Johanne Silvain
    • 1
  • Guillaume Cayla
    • 1
  • Stephen A. O’Connor
    • 1
  • Olivier Barthélémy
    • 1
  • Farzin Beygui
    • 1
  • Sophie Galier
    • 1
  • Delphine Brugier
    • 1
  • Eric J. Stanek
    • 4
  • Scott L. Charland
    • 4
  • Vanessa Gallois
    • 1
  • Gilles Montalescot
    • 1
    • 5
  • for the DOSAPI investigators.
  1. 1.ACTION Study Group, Hôpital Pitié-Salpêtrière (APHP), Institut de Cardiologie, INSERM, UMR_S 1166, Pitié-Salpêtrière Hospital (AP-HP)Université Pierre et Marie Curie (UPMC Paris 6)ParisFrance
  2. 2.UPMC Univ Paris 06, UMR_S 1166, ICANSorbonne UniversitésParisFrance
  3. 3.Department of Pharmacology & Institute of CardioMetabolism and NutritionAP-HP, Hôpital Pitié-SalpêtrièreParisFrance
  4. 4.Medco Research InstituteMedco Health Solutions, Inc.Franklin LakesUSA
  5. 5.Institut de Cardiologie, Bureau 2-236Pitié-Salpêtrière University HospitalParisFrance

Personalised recommendations