Factores genéticos y ambientales asociados con la respuesta a warfarina en pacientes colombianos
Palabras clave:
warfarina/farmacología, farmacogenética, anticoagulantes, coagulación sanguínea, polimorfismo genético, tiempo de protrombina, vitamina K
Resumen
Introducción. La warfarina es un anticoagulante de difícil manejo por su estrecho margen terapéutico y los numerosos factores que influyen en la respuesta.
Objetivo. Determinar la contribución de variables demográficas, clínicas y genéticas sobre las dosis de mantenimiento de warfarina en pacientes colombianos.
Materiales y métodos. Se incluyeron 145 adultos de ambos sexos, en anticoagulación estable con International Normalized Ratio (INR) entre 2 y 3, al menos, durante dos meses, sin cambio en las dosis de warfarina ni en el preparado comercial. Previa firma del consentimiento informado de cada voluntario, se registró su edad, sexo, peso, talla, tabaquismo, enfermedades concomitantes, medicación simultánea, INR, dosis de warfarina, su indicación y nombre comercial.
Cada paciente se tipificó para los genes CYP2C9, VKORC1, CYP4F2 y PROC, y en 59 de ellos, se cuantificaron las concentraciones séricas de warfarina. La genotipificación y la cuantificación sanguínea se hicieron mediante minisecuenciación y HPLC, respectivamente.
Resultados. Los factores de edad, medicación simultánea con inhibidores (amiodarona, sertralina, fluoxetina) o inductores enzimáticos (fenitoína, carbamacepina), los alelos rs1799853 (*2) y rs1057910 (*3) del gen CYP2C9, así como rs9923231 del gen VKORC1, se asociaron con las dosis de warfarina requeridas para conseguir anticoagulación con INR de 2 a 3.
Dichas variables se incluyeron en un modelo de regresión lineal múltiple que permitiera predecir la dosis semanal de warfarina, y se obtuvo un algoritmo que explica el 47,4% de la variabilidad en las dosis.
Conclusión. La consideración de las variables clínicas y las farmacogenéticas puede mejorar la relación entre seguridad y eficacia de la warfarina, aunque la adopción de un algoritmo de dosificación farmacogenético requiere información obtenida con ensayos clínicos.
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Referencias bibliográficas
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16. Loebstein R, Dvoskin I, Halkin H, Vecsler M, Lubetsky A, Rechavi G, et al. A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin resistance. Blood. 2007;109:2477-80.
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19. Osman A, Arbring K, Lindahl TL. A new high-performance liquid chromatographic method for determination of warfarin enantiomers. J Chromatogr B Analyt Technol Biomed Life Sci. 2005;826:75-80.
20. Perini JA, Struchiner CJ, Silva-Assunção E, Santana IS, Rangel F, Ojopi EB, et al. Pharmacogenetics of warfarin: development of a dosing algorithm for brazilian patients. Clin Pharmacol Ther. 2008;84:722-8.
21. Gage BF, Eby C, Johnson JA, Deych E, Rieder MJ, Ridker PM, et al. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Ther. 2008;84:326-31.
22. Ohno M, Yamamoto A, Ono A, Miura G, Funamoto M, Takemoto Y, et al. Influence of clinical and genetic factors on warfarin dose requirements among Japanese patients. Eur J Clin Pharmacol. 2009;65:1097-103.
23. Sandanaraj E, Lal S, Cheung YB, Xiang X, Kong MC, Lee LH, et al. VKORC1 diplotype-derived dosing model to explain variability in warfarin dose requirements in Asian patients. Drug Metab Pharmacokinet. 2009;24:365-75.
24. Majerus PW, Tollefsen DM. Blood coagulation and anticoagulant, thrombolytic, and antiplatelet drugs. In: Brunton LL, Lazo JS, Parker KL, editors. The pharmacological basis of therapeutics. 11 ed. Mexico D.F.: Mc Graw-Hill; 2006. p. 1475-80.
25. Schein JR. Cigarette smoking and clinically significant drug interactions. Ann Pharmacother. 1995;29:1139-48.
26. Holbrook AM, Pereira JA, Labiris R, McDonald H, Douketis JD, Crowther M, et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med. 2005;165:1095-106.
27. Vázquez SR, Rondina MT, Pendleton RC. Azathioprine-induced warfarin resistance. Ann Pharmacother. 2008; 42:1118-23.
28. Sconce EA, Khan TI, Daly AK, Wynne HA, Kamali F. The impact of simvastatin on warfarin disposition and dose requirements. J Thromb Haemost. 2006;4:1422-4.
29. Einarson TR, Metge CJ, Iskedjian M, Mukherjee J. An examination of the effect of cytochrome P450 drug interactions of hydroxymethylglutaryl-coenzyme A reductase inhibitors on health care utilization: a Canadian population-based study. Clin Ther. 2002;24:2126-36.
30. Meeks ML, Mahaffey KW, Katz MD. Danazol increases the anticoagulant effect of warfarin. Ann Pharmacother. 1992;26:641-2.
31. Santamaría MG, Agnelli G, Taliani MR, Prandoni P, Moia M, Bazzan M, et al. Thrombophilic abnormalities and recurrence of venous thromboembolism in patients treated with standardized anticoagulant treatment. Thromb Res. 2005;116:301-6.
32. Kesselheim AS, Misono AS, Lee JL, Stedman MR, Brookhart MA, Choudhry NK, et al. Clinical equivalence of generic and brand-name drugs used in cardiovascular disease: a systematic review and meta-analysis. JAMA. 2008;300:2514-26.
33. Llerena A, Dorado P, O'Kirwan F, Jepson R, Licinio J, Wong ML. Lower frequency of CYP2C9*2 in Mexican-Americans compared to Spaniards. Pharmacogenomics J. 2004;4:403-6.
34. Aklillu E, Leong C, Loebstein R, Halkin H, Gak E. VKORC1 Asp36Tyr warfarin resistance marker is common in Ethiopian individuals. Blood. 2008;111:3903-4.
35. Sinxadi P, Blockman M. Warfarin resistance. Cardiovasc J Afr. 2008;19:215-7.
36. Kim MJ, Huang SM, Meyer UA, Rahman A, Lesko LJ. A regulatory science perspective on warfarin therapy: a pharmacogenetic opportunity. J Clin Pharmacol. 2009;49:138-46.
37. Hynicka LM, Cahoon WD Jr, Bukaveckas BL. Genetic testing for warfarin therapy initiation. Ann Pharmacother. 2008;42:1298-303.
38. Kangelaris KN, Bent S, Nussbaum RL, Garcia DA, Tice JA. Genetic testing before anticoagulation? A systematic review of pharmacogenetic dosing of warfarin. J Gen Intern Med. 2009;24:656-64.
39. Huang SW, Chen HS, Wang XQ, Huang L, Xu DL, Hu XJ, et al. Validation of VKORC1 and CYP2C9 genotypes on interindividual warfarin maintenance dose: a prospective study in Chinese patients. Pharmacogenet Genomics. 2009;19:226-34.
40. You JH, Tsui KK, Wong RS, Cheng G. Potential clinical and economic outcomes of CYP2C9 and VKORC1 genotype-guided dosing in patients starting warfarin therapy. Clin Pharmacol Ther. 2009:86:540-7.
41. Scott SA, Jaremko M, Lubitz SA, Kornreich R, Halperin JL, Desnick RJ. CYP2C9*8 is prevalent among African-Americans: implications for pharmacogenetic dosing. Pharmacogenomics. 2009;10:1243-55.
42. Limdi NA, Wiener H, Goldstein JA, Acton RT, Beasley TM. Influence of CYP2C9 and VKORC1 on warfarin response during initiation of therapy. Blood Cells Mol Dis. 2009;43:119-28.
43. Caldwell MD, Awad T, Johnson JA, Gage BF, Falkowski M, Gardina P, et al. CYP4F2 genetic variant alters required warfarin dose. Blood. 2008;111:4106-12.
2. Sconce EA, Kamali F. Appraisal of current vitamin K dosing algorithms for the reversal of over-anticoagulation with warfarin: the need for a more tailored dosing regimen. Eur J Haematol. 2006;77:457-62.
3. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133:160S-98S.
4. Greenblatt DJ, von Moltke LL. Interaction of warfarin with drugs, natural substances, and foods. J Clin Pharmacol. 2005;45:127-32.
5. Rettie AE, Jones JP. Clinical and toxicological relevance of CYP2C9: drug-drug interactions and pharmacogenetics. Annu Rev Pharmacol Toxicol. 2005;45:477-94.
6. Sconce EA, Khan TI, Wynne HA, Avery P, Monkhouse L, King BP, et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood. 2005;106:2329-33.
7. Wadelius M, Chen LY, Eriksson N, Bumpstead S, Ghori J, Wadelius C, et al. Association of warfarin dose with genes involved in its action and metabolism. Hum Genet. 2007;121:23-34.
8. Lindh JD, Holm L, Andersson ML, Rane A. Influence of CYP2C9 genotype on warfarin dose requirements-a systematic review and meta-analysis. Eur J Clin Pharmacol. 2008;65:365-75.
9. Takeuchi F, McGinnis R, Bourgeois S, Barnes C, Eriksson N, Soranzo N, et al. A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. PLoS Genet. 2009;5:e1000433.
10. Kimura R, Miyashita K, Kokubo Y, Akaiwa Y, Otsubo R, Nagatsuka K, et al. Genotypes of vitamin K epoxide reductase, gamma-glutamyl carboxylase, and cytochrome P450 2C9 as determinants of daily warfarin dose in Japanese patients. Thromb Res. 2007;120:181-6.
11. Fuchshuber-Moraes M, Perini JA, Rosskopf D, Suarez-Kurtz G. Exploring warfarin pharmacogenomics with the extreme-discordant-phenotype methodology: impact of FVII polymorphisms on stable anticoagulation with warfarin. Eur J Clin Pharmacol 2009;65:789-93.
12. Wadelius M, Chen LY, Lindh JD, Eriksson N, Ghori MJ, Bumpstead S, et al. The largest prospective warfarin-treated cohort supports genetic forecasting. Blood. 2009;113:784-92.
13. Palacio L, Falla D, Tobón I, Mejía F, Lewis J, Martínez A, et al. Pharmacogenetic impact of VKORC1 and CYP2C9 allelic variants on warfarin dose requirements in a Hispanic population isolate. Clin Appl Thromb Hemost. 2009;16:83-90.
14. International Warfarin Pharmacogenetics Consortium, Klein TE, Altman RB, Eriksson N, Gage BF, Kimmel SE, et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med. 2009;360:753-64.
15. Limdi NA, Beasley TM, Crowley MR, Goldstein JA, Rieder MJ, Flockhart DA, et al. VKORC1 polymorphisms, haplotypes and haplotype groups on warfarin dose among African-Americans and European-Americans. Pharmacogenomics. 2008;9:1445-58.
16. Loebstein R, Dvoskin I, Halkin H, Vecsler M, Lubetsky A, Rechavi G, et al. A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin resistance. Blood. 2007;109:2477-80.
17. Garcia DA, Hylek E. Warfarin pharmacogenetics. N Engl J Med. 2009;360:2474.
18. Gulseth MP, Grice GR, Dager WE. Pharmacogenomics of warfarin: uncovering a piece of the warfarin mystery. Am J Health Syst Pharm. 2009;66:123-33.
19. Osman A, Arbring K, Lindahl TL. A new high-performance liquid chromatographic method for determination of warfarin enantiomers. J Chromatogr B Analyt Technol Biomed Life Sci. 2005;826:75-80.
20. Perini JA, Struchiner CJ, Silva-Assunção E, Santana IS, Rangel F, Ojopi EB, et al. Pharmacogenetics of warfarin: development of a dosing algorithm for brazilian patients. Clin Pharmacol Ther. 2008;84:722-8.
21. Gage BF, Eby C, Johnson JA, Deych E, Rieder MJ, Ridker PM, et al. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Ther. 2008;84:326-31.
22. Ohno M, Yamamoto A, Ono A, Miura G, Funamoto M, Takemoto Y, et al. Influence of clinical and genetic factors on warfarin dose requirements among Japanese patients. Eur J Clin Pharmacol. 2009;65:1097-103.
23. Sandanaraj E, Lal S, Cheung YB, Xiang X, Kong MC, Lee LH, et al. VKORC1 diplotype-derived dosing model to explain variability in warfarin dose requirements in Asian patients. Drug Metab Pharmacokinet. 2009;24:365-75.
24. Majerus PW, Tollefsen DM. Blood coagulation and anticoagulant, thrombolytic, and antiplatelet drugs. In: Brunton LL, Lazo JS, Parker KL, editors. The pharmacological basis of therapeutics. 11 ed. Mexico D.F.: Mc Graw-Hill; 2006. p. 1475-80.
25. Schein JR. Cigarette smoking and clinically significant drug interactions. Ann Pharmacother. 1995;29:1139-48.
26. Holbrook AM, Pereira JA, Labiris R, McDonald H, Douketis JD, Crowther M, et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med. 2005;165:1095-106.
27. Vázquez SR, Rondina MT, Pendleton RC. Azathioprine-induced warfarin resistance. Ann Pharmacother. 2008; 42:1118-23.
28. Sconce EA, Khan TI, Daly AK, Wynne HA, Kamali F. The impact of simvastatin on warfarin disposition and dose requirements. J Thromb Haemost. 2006;4:1422-4.
29. Einarson TR, Metge CJ, Iskedjian M, Mukherjee J. An examination of the effect of cytochrome P450 drug interactions of hydroxymethylglutaryl-coenzyme A reductase inhibitors on health care utilization: a Canadian population-based study. Clin Ther. 2002;24:2126-36.
30. Meeks ML, Mahaffey KW, Katz MD. Danazol increases the anticoagulant effect of warfarin. Ann Pharmacother. 1992;26:641-2.
31. Santamaría MG, Agnelli G, Taliani MR, Prandoni P, Moia M, Bazzan M, et al. Thrombophilic abnormalities and recurrence of venous thromboembolism in patients treated with standardized anticoagulant treatment. Thromb Res. 2005;116:301-6.
32. Kesselheim AS, Misono AS, Lee JL, Stedman MR, Brookhart MA, Choudhry NK, et al. Clinical equivalence of generic and brand-name drugs used in cardiovascular disease: a systematic review and meta-analysis. JAMA. 2008;300:2514-26.
33. Llerena A, Dorado P, O'Kirwan F, Jepson R, Licinio J, Wong ML. Lower frequency of CYP2C9*2 in Mexican-Americans compared to Spaniards. Pharmacogenomics J. 2004;4:403-6.
34. Aklillu E, Leong C, Loebstein R, Halkin H, Gak E. VKORC1 Asp36Tyr warfarin resistance marker is common in Ethiopian individuals. Blood. 2008;111:3903-4.
35. Sinxadi P, Blockman M. Warfarin resistance. Cardiovasc J Afr. 2008;19:215-7.
36. Kim MJ, Huang SM, Meyer UA, Rahman A, Lesko LJ. A regulatory science perspective on warfarin therapy: a pharmacogenetic opportunity. J Clin Pharmacol. 2009;49:138-46.
37. Hynicka LM, Cahoon WD Jr, Bukaveckas BL. Genetic testing for warfarin therapy initiation. Ann Pharmacother. 2008;42:1298-303.
38. Kangelaris KN, Bent S, Nussbaum RL, Garcia DA, Tice JA. Genetic testing before anticoagulation? A systematic review of pharmacogenetic dosing of warfarin. J Gen Intern Med. 2009;24:656-64.
39. Huang SW, Chen HS, Wang XQ, Huang L, Xu DL, Hu XJ, et al. Validation of VKORC1 and CYP2C9 genotypes on interindividual warfarin maintenance dose: a prospective study in Chinese patients. Pharmacogenet Genomics. 2009;19:226-34.
40. You JH, Tsui KK, Wong RS, Cheng G. Potential clinical and economic outcomes of CYP2C9 and VKORC1 genotype-guided dosing in patients starting warfarin therapy. Clin Pharmacol Ther. 2009:86:540-7.
41. Scott SA, Jaremko M, Lubitz SA, Kornreich R, Halperin JL, Desnick RJ. CYP2C9*8 is prevalent among African-Americans: implications for pharmacogenetic dosing. Pharmacogenomics. 2009;10:1243-55.
42. Limdi NA, Wiener H, Goldstein JA, Acton RT, Beasley TM. Influence of CYP2C9 and VKORC1 on warfarin response during initiation of therapy. Blood Cells Mol Dis. 2009;43:119-28.
43. Caldwell MD, Awad T, Johnson JA, Gage BF, Falkowski M, Gardina P, et al. CYP4F2 genetic variant alters required warfarin dose. Blood. 2008;111:4106-12.
Cómo citar
1.
Isaza C, Beltrán L, Henao J, Porras G, Pinzón A, Vallejos Álvaro, et al. Factores genéticos y ambientales asociados con la respuesta a warfarina en pacientes colombianos. biomedica [Internet]. 30 de septiembre de 2010 [citado 24 de abril de 2024];30(3):410-20. Disponible en: https://revistabiomedica.org/index.php/biomedica/article/view/275
Publicado
2010-09-30
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