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International Journal of Clinical Pharmacy

, Volume 37, Issue 5, pp 925–930 | Cite as

Correlation of CYP2C19 genotype with plasma voriconazole levels: a preliminary retrospective study in Indians

  • Prerna K. Chawla
  • Shweta R. Nanday
  • Alpa J. Dherai
  • Rajeev Soman
  • Rohan V. Lokhande
  • Prasad R. Naik
  • Tester F. AshavaidEmail author
Research Article

Abstract

Background Voriconazole is an antifungal drug essentially metabolized by cytochrome P450 (CYP2C19) isozyme. Plasma voriconazole levels exhibit wide inter-individual variability due to several factors like age, weight, food or drug interactions or CYP2C19 polymorphisms. Objective In the present study, we assessed the correlation of voriconazole levels with CYP2C19 genotype in patients on voriconazole therapy. Setting Biochemistry Department of a 480 inpatient bed tertiary care hospital in India. Methods Plasma voriconazole estimation was done in seventy-two patients on standard weight based voriconazole therapy by High Performance Liquid Chromatography (HPLC) while genotype assessment for the CYP2C19*2 and *3 was done by PCR–RFLP and *17 by ARMS-PCR. Statistical analysis and genotype-phenotype correlation was done by comparing the drug levels with the CYP2C19 genotype. Main outcome measure CYP2C19 polymorphisms influence voriconazole metabolism. Results A wide variability is seen in plasma levels with only 51 % attaining therapeutic levels. The allele frequency of *2, *3 and *17 variant were found to be 33.3, 0.7 and 18 % respectively. The drug levels in carriers of *2 allele (poor metabolizers) was twofold higher than that in extensive metabolizers. However, the influence of *2 allele was compromised in presence of *17 allele and patients had low voriconazole levels. In addition to the genotype, co-medication and clinical condition remarkably influenced voriconazole concentration. Conclusion Plasma voriconazole levels are influenced by CYP2C19 variants, drug interactions and clinical condition of the patient. Genotype assessment at initiation of therapy followed by drug monitoring would help optimizing therapeutic efficacy and minimizing toxicity.

Keywords

CYP2C19 Genotype-phenotype correlation India Therapeutic drug monitoring Voriconazole 

Notes

Acknowledgments

We acknowledge National Health and Education Society (NHES) of P. D. Hinduja Hospital and Medical Research Centre for all their help.

Funding

No specific funding was obtained for the study.

Conflicts of interest

All authors declare that they have no conflict of interest.

References

  1. 1.
    VFEND® I.V. (voriconazole) for injection, VFEND® tablets (voriconazole), VFEND® (voriconazole) for oral suspension [US physician prescribing information] New York (NY) Roerig Division of Pfizer Inc; revised 2008 Mar [cited 2008 Sep 3]. http://media.pfizer.com/files/products/uspi_vfend.pdf. Last Accessed 5 Dec 2013.
  2. 2.
    Briefing document for voriconazole (oral and intravenous formulations). Prepared for submission to US Food and Drug Administration, Food and Drugs Advisory Committee. Pfizer; 2001 Oct 4 [cited 2008 Sep 3]. http://www.fda.gov/ohrms/dockets/ac/01/briefing/3792b2_01_Pfizer.pdf. Last Accessed 20 Jan 2014.
  3. 3.
    Scholz I, Oberwittler H, Riedel K, et al. Pharmacokinetics, metabolism and bioavailability of the triazole antifungal agent voriconazole in relation to CYP2C19 genotype. Br J Clin Pharmacol. 2009;68(6):906–15. doi: 10.1111/j.1365-2125.2009.03534.x.PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Li-Wan-Po A, Girard T, Farndon P, Cooley C, Lithgow J. Pharmacogenetics of CYP2C19: functional and clinical implications of a new variant CYP2C19*17. Br J Clin Pharmacol. 2010;69(3):222–30. doi: 10.1111/j.1365-2125.2009.03578.x.PubMedCentralCrossRefPubMedGoogle Scholar
  5. 5.
    Hussaini T, Ruping M, Farowski F, Vehreschild J, Cornely O. Therapeutic drug monitoring of voriconazole and posaconazole. Pharmacotherapy. 2011;31(2):214–25. doi: 10.1592/phco.31.2.214.CrossRefPubMedGoogle Scholar
  6. 6.
    Pasqualotto A, Xavier M, Andreolla H, Linden R. Voriconazole therapeutic drug monitoring: focus on safety. Expert Opin Drug Saf. 2010;9(1):125–37. doi: 10.1517/14740330903485637.CrossRefPubMedGoogle Scholar
  7. 7.
    Han K, Bies R, Johnson H, Capitano B, Venkataramanan R. Population pharmacokinetic evaluation with external validation and bayesian estimator of voriconazole in liver transplant recipients. Clin Pharm. 2011;50(3):201–14. doi: 10.2165/11538690-000000000-00000.CrossRefGoogle Scholar
  8. 8.
    Leveque D, Nivoix Y, Jehl F, Herbrecht R. Clinical pharmacokinetics of voriconazole. Int J Antimicrob Agents. 2006;27(4):274–84. doi: 10.1016/j.ijantimicag.2006.01.003.CrossRefPubMedGoogle Scholar
  9. 9.
    Perea S, Pennick G, Modak A, et al. Comparison of high-performance liquid chromatographic and microbiological methods for determination of voriconazole levels in plasma. Antimicrob Agents Chemother. 2000;44(5):1209–13. doi: 10.1128/aac.44.5.1209-1213.2000.PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Pascual A, Calandra T, Bolay S, Buclin T, Bille J, Marchetti O. Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clin Infect Dis. 2008;46(2):201–11. doi: 10.1086/524669.CrossRefPubMedGoogle Scholar
  11. 11.
    Koselke E, Kraft S, Smith J, Nagel J. Evaluation of the effect of obesity on voriconazole serum concentrations. J Antimicrob Chemother. 2012;67(12):2957–62. doi: 10.1093/jac/dks312.CrossRefPubMedGoogle Scholar
  12. 12.
    Sandherr M, Maschmeyer G. Pharmacology and metabolism of voriconazole and posaconazole in the treatment of invasive aspergillosis-review of the literature. Eur J Med Res. 2011;16(4):139. doi: 10.1186/2047-783x-16-4-139.PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Johnson L, Kauffman C. Voriconazole: a new triazole antifungal agent. Clin Infect Dis. 2003;36(5):630–7. doi: 10.1086/367933.CrossRefPubMedGoogle Scholar
  14. 14.
    Weiss J, ten Hoevel M, Burhenne J, et al. CYP2C19 genotype is a major factor contributing to the highly variable pharmacokinetics of voriconazole. J Clin Pharmacol. 2009;49(2):196–204. doi: 10.1177/0091270008327537.CrossRefPubMedGoogle Scholar
  15. 15.
    Scott S, Sangkuhl K, Stein C, et al. Clinical pharmacogenetics implementation consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther. 2013;94(3):317–23. doi: 10.1038/clpt.2013.105.PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    Anichavezhi D, Chakradhara Rao U, Shewade D, Krishnamoorthy R, Adithan C. Distribution of CYP2C19*17 allele and genotypes in an Indian population. J Clin Pharm Ther. 2011;37(3):313–8. doi: 10.1111/j.1365-2710.2011.01294.x.CrossRefPubMedGoogle Scholar
  17. 17.
    Guidance for the Industry: Bioanalytical Method Validation. Washington, DC: US Department of health and Human Services, FDA, CDER and CVM; 2001 BP.Google Scholar
  18. 18.
    Husain S, Paterson D, Studer S, et al. Voriconazole prophylaxis in lung transplant recipients. Am J Transpl. 2006;6(12):3008–16. doi: 10.1111/j.1600-6143.2006.01548.x.CrossRefGoogle Scholar
  19. 19.
    Trifilio S, Pennick G, Pi J, et al. Monitoring plasma voriconazole levels may be necessary to avoid subtherapeutic levels in hematopoietic stem cell transplant recipients. Cancer. 2007;109(8):1532–5. doi: 10.1002/cncr.22568.CrossRefPubMedGoogle Scholar
  20. 20.
    Neely M, Rushing T, Kovacs A, Jelliffe R, Hoffman J. Voriconazole pharmacokinetics and pharmacodynamics in children. Clin Infect Dis. 2010;50(1):27–36. doi: 10.1086/648679.PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Miller S, Dykes D, Polesky H. A simple salting out procedure for extracting DNA from human nucleated cells. Nucl Acids Res. 1988;16(3):1215. doi: 10.1093/nar/16.3.1215.PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Ghodke Y, Joshi K, Arya Y, et al. Genetic polymorphism of CYP2C19 in Maharashtrian population. Eur J Epidemiol. 2007;22(12):907–15. doi: 10.1007/s10654-007-9196-0.CrossRefPubMedGoogle Scholar
  23. 23.
    Berge M, Guillemain R, Trégouet D, et al. Effect of cytochrome P450 2C19 genotype on voriconazole exposure in cystic fibrosis lung transplant patients. Eur J Clin Pharmacol. 2010;67(3):253–60. doi: 10.1007/s00228-010-0914-2.CrossRefPubMedGoogle Scholar
  24. 24.
    Matsumoto K, Ikawa K, Abematsu K, et al. Correlation between voriconazole trough plasma concentration and hepatotoxicity in patients with different CYP2C19 genotypes. Int J Antimicrob Agents. 2009;34(1):91–4. doi: 10.1016/j.ijantimicag.2009.01.008.CrossRefPubMedGoogle Scholar
  25. 25.
    Dolton M, McLachlan A. Clinical importance of the CYP2C19*17 variant allele for voriconazole. Br J Clin Pharmacol. 2010;71(1):137–8. doi: 10.1111/j.1365-2125.2010.03801.x.CrossRefGoogle Scholar
  26. 26.
    Wang G, Lei H, Li Z, et al. The CYP2C19 ultra-rapid metabolizer genotype influences the pharmacokinetics of voriconazole in healthy male volunteers. Eur J Clin Pharmacol. 2008;65(3):281–5. doi: 10.1007/s00228-008-0574-7.CrossRefPubMedGoogle Scholar
  27. 27.
    Jose R, Chandrasekaran A, Sam S, et al. CYP2C9 and CYP2C19 genetic polymorphisms: frequencies in the south Indian population. Fundam Clin Pharmacol. 2005;19(1):101–5. doi: 10.1111/j.1472-8206.2004.00307.x.CrossRefPubMedGoogle Scholar
  28. 28.
    Jeong Y, Tantry U, Kim I et al. Effect of CYP2C19*2 and *3 loss-of-function alleles on platelet reactivity and adverse clinical events in East Asian acute myocardial infarction survivors treated with clopidogrel and aspirin. Circ Cardiovasc Interv. 2011;4(6):585–94. doi: 10.1161/circinterventions.111.962555.

Copyright information

© Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2015

Authors and Affiliations

  • Prerna K. Chawla
    • 1
  • Shweta R. Nanday
    • 2
  • Alpa J. Dherai
    • 1
    • 2
  • Rajeev Soman
    • 3
  • Rohan V. Lokhande
    • 2
  • Prasad R. Naik
    • 2
  • Tester F. Ashavaid
    • 1
    • 2
    Email author
  1. 1.Research LaboratoriesP.D. Hinduja Hospital and Medical Research CentreMumbaiIndia
  2. 2.Department of Laboratory MedicineP.D. Hinduja Hospital & Medical Research CentreMumbaiIndia
  3. 3.Department of Internal MedicineP.D. Hinduja Hospital & Medical Research CentreMumbaiIndia

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