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Applying Pharmacogenomics to Antifungal Selection and Dosing: Are We There Yet?

  • Pharmacology and Pharmacodynamics of Antifungal Agents (J Amsden, Section Editor)
  • Published:
Current Fungal Infection Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

This review summarizes recent literature for applying pharmacogenomics to antifungal selection and dosing, providing an approach to implementing antifungal pharmacogenomics in clinical practice.

Recent Findings

The Clinical Pharmacogenetics Implementation Consortium published guidelines on CYP2C19 and voriconazole, with recommendations to use alternative antifungals or adjust voriconazole dose with close therapeutic drug monitoring (TDM). Recent studies demonstrate an association between CYP2C19 phenotype and voriconazole levels, clinical outcomes, and adverse events. Additionally, CYP2C19-guided preemptive dose adjustment demonstrated benefit in two prospective studies for prophylaxis. Pharmacokinetic–pharmacodynamic modeling studies have generated proposed voriconazole treatment doses based on CYP2C19 phenotypes, with further validation studies needed.

Summary

Sufficient evidence is available for implementing CYP2C19-guided voriconazole selection and dosing among select patients at risk for invasive fungal infections. The institution needs appropriate infrastructure for pharmacogenomic testing, integration of results in the clinical decision process, with TDM confirmation of goal trough achievement, to integrate antifungal pharmacogenomics into routine clinical care.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Webb BJ, Ferraro JP, Rea S, Kaufusi S, Goodman BE, Spalding J. Epidemiology and Clinical Features of Invasive Fungal Infection in a US health care network. Open Forum Infect Dis. 2018;5(8):ofy187. https://doi.org/10.1093/ofid/ofy187.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Evans WE, McLeod HL. Pharmacogenomics--drug disposition, drug targets, and side effects. N Engl J Med. 2003;348(6):538–49. https://doi.org/10.1056/NEJMra020526.

    Article  CAS  PubMed  Google Scholar 

  3. Lewis RE. Current concepts in antifungal pharmacology. Mayo Clin Proc. 2011;86(8):805–17. https://doi.org/10.4065/mcp.2011.0247.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ashbee HR, Barnes RA, Johnson EM, Richardson MD, Gorton R, Hope WW. Therapeutic drug monitoring (TDM) of antifungal agents: guidelines from the British Society for Medical Mycology. J Antimicrob Chemother. 2014;69(5):1162–76. https://doi.org/10.1093/jac/dkt508.

    Article  CAS  PubMed  Google Scholar 

  5. Buil JB, Bruggemann RJM, Wasmann RE, Zoll J, Meis JF, Melchers WJG, et al. Isavuconazole susceptibility of clinical Aspergillus fumigatus isolates and feasibility of isavuconazole dose escalation to treat isolates with elevated MICs. J Antimicrob Chemother. 2018;73(1):134–42. https://doi.org/10.1093/jac/dkx354.

    Article  CAS  PubMed  Google Scholar 

  6. Lepak AJ, Marchillo K, Vanhecker J, Andes DR. Isavuconazole (BAL4815) pharmacodynamic target determination in an in vivo murine model of invasive pulmonary aspergillosis against wild-type and cyp51 mutant isolates of Aspergillus fumigatus. Antimicrob Agents Chemother. 2013;57(12):6284–9. https://doi.org/10.1128/AAC.01355-13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ketoconazole [package insert], Morgantown, WV: Mylan Pharmaceuticals Inc.; 2018.

  8. Diflucan (Fluconazole) [package insert], NY, NY: Pfizer Inc,; 2019.

  9. Tolsura (itraconazole) [package insert]. Greenville, NC: Mayne Pharma Inc.; 2019.

  10. Sporanox (itraconazole) [package insert]. Titusville, NJ: Janssen Pharmaceutical Companies; 2019.

  11. Vfend (voriconazole) [package insert]. NY, NY: Pfizer Inc.; 2019.

  12. Posaconazole [package insert]. Chestnut Ridge, NY: Par Pharmaceutical.; 2019.

  13. Isavuconazonium sulfate [package insert], Northbrook, IL: Astellas Pharma US; 2018.

  14. •• Amsden JR, Gubbins PO. Pharmacogenomics of triazole antifungal agents: implications for safety, tolerability and efficacy. Expert Opin Drug Metab Toxicol. 2017;13(11):1135–46. https://doi.org/10.1080/17425255.2017.1391213. A review of the impact of CYP450 enzymes on the different azoles.

    Article  CAS  Google Scholar 

  15. Weiss J, Ten Hoevel MM, Burhenne J, Walter-Sack I, Hoffmann MM, Rengelshausen 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. https://doi.org/10.1177/0091270008327537.

    Article  CAS  PubMed  Google Scholar 

  16. Shao B, Ma Y, Li Q, Wang Y, Zhu Z, Zhao H, et al. Effects of cytochrome P450 3A4 and non-genetic factors on initial voriconazole serum trough concentrations in hematological patients with different cytochrome P450 2C19 genotypes. Xenobiotica. 2017;47(12):1121–9. https://doi.org/10.1080/00498254.2016.1271960.

    Article  CAS  PubMed  Google Scholar 

  17. •• Moriyama B, Obeng AO, Barbarino J, Penzak SR, Henning SA, Scott SA, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for CYP2C19 and voriconazole therapy. Clin Pharmacol Ther. 2017;102(1):45–51. Doi: 1002/cpt.583. This shows the pharmacogenetic guidelines for CYP2C19-voriconazole.

  18. PharmGKB [Available from: https://www.pharmgkb.org/].

  19. Klein TE, Chang JT, Cho MK, Easton KL, Fergerson R, Hewett M, et al. Integrating genotype and phenotype information: an overview of the PharmGKB project. Pharmacogenetics Research Network and Knowledge Base. Pharm J. 2001;1(3):167–70. https://doi.org/10.1038/sj.tpj.6500035.

    Article  CAS  Google Scholar 

  20. Relling MV, Klein TE, Gammal RS, Whirl-Carrillo M, Hoffman JM, Caudle KE. The clinical pharmacogenetics implementation consortium: 10 years later. Clin Pharmacol Ther. 2019. https://doi.org/10.1002/cpt.1651.

    Article  Google Scholar 

  21. Tomblyn M, Chiller T, Einsele H, Gress R, Sepkowitz K, Storek J, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant. 2009;15(10):1143–238. https://doi.org/10.1016/j.bbmt.2009.06.019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. • Barbarino JM, Owusu Obeng A, Klein TE, Altman RB. PharmGKB summary: voriconazole pathway, pharmacokinetics. Pharmacogenet Genomics. 2017;27(5):201–9. https://doi.org/10.1097/FPC.0000000000000276. The PharmGKB summary of voriconazole.

    Article  CAS  Google Scholar 

  23. Owusu Obeng A, Egelund EF, Alsultan A, Peloquin CA, Johnson JA. CYP2C19 polymorphisms and therapeutic drug monitoring of voriconazole: are we ready for clinical implementation of pharmacogenomics? Pharmacotherapy. 2014;34(7):703–18. https://doi.org/10.1002/phar.1400.

    Article  CAS  PubMed  Google Scholar 

  24. Mangal N, Hamadeh IS, Arwood MJ, Cavallari LH, Samant TS, Klinker KP, et al. Optimization of voriconazole therapy for the treatment of invasive fungal infections in adults. Clin Pharmacol Ther. 2018;104(5):957–65. https://doi.org/10.1002/cpt.1012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Levine MT, Chandrasekar PH. Adverse effects of voriconazole: over a decade of use. Clin Transpl. 2016;30(11):1377–86. https://doi.org/10.1111/ctr.12834.

    Article  Google Scholar 

  26. Moriyama B, Kadri S, Henning SA, Danner RL, Walsh TJ, Penzak SR. Therapeutic drug monitoring and genotypic screening in the clinical use of voriconazole. Curr Fungal Infect Rep. 2015;9(2):74–87. https://doi.org/10.1007/s12281-015-0219-0.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Weigel JD, Hunfeld NG, Koch BC, Egal M, Bakker J, van Schaik RH, et al. Gain-of-function single nucleotide variants of the CYP2C19 gene (CYP2C19*17) can identify subtherapeutic voriconazole concentrations in critically ill patients: a case series. Intensive Care Med. 2015;41(11):2013–4. https://doi.org/10.1007/s00134-015-4002-z.

    Article  PubMed  Google Scholar 

  28. Gautier-Veyret E, Bailly S, Fonrose X, Tonini J, Chevalier S, Thiebaut-Bertrand A, et al. Pharmacogenetics may influence the impact of inflammation on voriconazole trough concentrations. Pharmacogenomics. 2017;18(12):1119–23. https://doi.org/10.2217/pgs-2017-0054.

    Article  CAS  PubMed  Google Scholar 

  29. Lamoureux F, Duflot T, Woillard JB, Metsu D, Pereira T, Compagnon P, et al. Impact of CYP2C19 genetic polymorphisms on voriconazole dosing and exposure in adult patients with invasive fungal infections. Int J Antimicrob Agents. 2016;47(2):124–31. https://doi.org/10.1016/j.ijantimicag.2015.12.003.

    Article  CAS  PubMed  Google Scholar 

  30. Hicks JK, Gonzalez BE, Zembillas AS, Kusick K, Murthy S, Raja S, et al. Invasive Aspergillus infection requiring lobectomy in a CYP2C19 rapid metabolizer with subtherapeutic voriconazole concentrations. Pharmacogenomics. 2016;17(7):663–7. https://doi.org/10.2217/pgs-2015-0014.

    Article  CAS  PubMed  Google Scholar 

  31. Chuwongwattana S, Jantararoungtong T, Chitasombat MN, Puangpetch A, Prommas S, Dilokpattanamongkol P, et al. A prospective observational study of CYP2C19 polymorphisms and voriconazole plasma level in adult Thai patients with invasive aspergillosis. Drug Metab Pharmacokinet. 2016;31(2):117–22. https://doi.org/10.1016/j.dmpk.2015.12.005.

    Article  CAS  PubMed  Google Scholar 

  32. Niioka T, Fujishima N, Abumiya M, Yamashita T, Ubukawa K, Nara M, et al. Relationship between the CYP2C19 phenotype using the voriconazole-to-voriconazole N-oxide plasma concentration ratio and demographic and clinical characteristics of Japanese patients with different CYP2C19 genotypes. Ther Drug Monit. 2017;39(5):514–21. https://doi.org/10.1097/FTD.0000000000000441.

    Article  CAS  PubMed  Google Scholar 

  33. Hamadeh IS, Klinker KP, Borgert SJ, Richards AI, Li W, Mangal N, et al. Impact of the CYP2C19 genotype on voriconazole exposure in adults with invasive fungal infections. Pharmacogenet Genomics. 2017;27(5):190–6. https://doi.org/10.1097/FPC.0000000000000277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ebrahimpour S, Namazi S, Mohammadi M, Nikbakht M, Hadjibabaie M, Masoumi HT, et al. Impact of CYP2C19 polymorphisms on serum concentration of voriconazole in Iranian hematological patients. J Res Pharm Pract. 2017;6(3):151–7. https://doi.org/10.4103/jrpp.JRPP_17_31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. You H, Dong Y, Zou Y, Zhang T, Lei J, Chen L, et al. Voriconazole therapeutic drug monitoring: factors associated with supratherapeutic and subtherapeutic voriconazole concentrations. Int J Clin Pharmacol Ther. 2018;56(5):239–46. https://doi.org/10.5414/CP203184.

    Article  CAS  PubMed  Google Scholar 

  36. Miao Q, Tang JT, van Gelder T, Li YM, Bai YJ, Zou YG, et al. Correlation of CYP2C19 genotype with plasma voriconazole exposure in South-western Chinese Han patients with invasive fungal infections. Medicine (Baltimore). 2019;98(3):e14137. https://doi.org/10.1097/MD.0000000000014137.

    Article  CAS  Google Scholar 

  37. Wang T, Zhu H, Sun J, Cheng X, Xie J, Dong H, et al. Efficacy and safety of voriconazole and CYP2C19 polymorphism for optimised dosage regimens in patients with invasive fungal infections. Int J Antimicrob Agents. 2014;44(5):436–42. https://doi.org/10.1016/j.ijantimicag.2014.07.013.

    Article  CAS  PubMed  Google Scholar 

  38. Trubiano JA, Crowe A, Worth LJ, Thursky KA, Slavin MA. Putting CYP2C19 genotyping to the test: utility of pharmacogenomic evaluation in a voriconazole-treated haematology cohort. J Antimicrob Chemother. 2015;70(4):1161–5. https://doi.org/10.1093/jac/dku529.

    Article  CAS  PubMed  Google Scholar 

  39. Beata S, Donata UK, Jaroslaw D, Tomasz W, Anna WH. Influence of CYP2C19*2/*17 genotype on adverse drug reactions of voriconazole in patients after allo-HSCT: a four-case report. J Cancer Res Clin Oncol. 2017;143(6):1103–6. https://doi.org/10.1007/s00432-017-2357-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Danion F, Jullien V, Rouzaud C, Abdel Fattah M, Lapusan S, Guery R, et al. Is it time for systematic voriconazole pharmacogenomic investigation for central nervous system aspergillosis. Antimicrob Agents Chemother. 2018;62(9). https://doi.org/10.1128/AAC.00705-18.

  41. Lin XB, Li ZW, Yan M, Zhang BK, Liang W, Wang F, et al. Population pharmacokinetics of voriconazole and CYP2C19 polymorphisms for optimizing dosing regimens in renal transplant recipients. Br J Clin Pharmacol. 2018;84(7):1587–97. https://doi.org/10.1111/bcp.13595.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kim Y, Rhee SJ, Park WB, Yu KS, Jang IJ, Lee S. A Personalized CYP2C19 phenotype-guided dosing regimen of voriconazole using a population pharmacokinetic analysis. J Clin Med. 2019;8(2). https://doi.org/10.3390/jcm8020227.

    Article  CAS  Google Scholar 

  43. Teusink A, Vinks A, Zhang K, Davies S, Fukuda T, Lane A, et al. Genotype-directed dosing leads to optimized voriconazole levels in pediatric patients receiving hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2016;22(3):482–6. https://doi.org/10.1016/j.bbmt.2015.11.011.

    Article  CAS  PubMed  Google Scholar 

  44. Fulco PP, Beaulieu C, Higginson RT, Bearman G. Pharmacogenetic testing for the treatment of aspergillosis with voriconazole in two HIV-positive patients. Pharmacogenet Genomics. 2019;29(6):155–7. https://doi.org/10.1097/FPC.0000000000000377.

    Article  CAS  PubMed  Google Scholar 

  45. • Patel JN, Hamadeh IS, Robinson M, Shahid Z, Symanowski J, Steuerwald N, et al. Evaluation of CYP2C19 genotype-guided voriconazole prophylaxis after allogeneic hematopoietic cell transplant. Clin Pharmacol Ther. 2019. https://doi.org/10.1002/cpt.1642. A prospective study comparing CYP2C19-guided versus standard voriconazole prophylactic dosing in allogeneic hematopoietic cell transplant patients.

    Article  Google Scholar 

  46. • Hicks JK, Quilitz RE, Komrokji RS, Kubal TE, Lancet JE, Pasikhova Y, et al. Prospective CYP2C19-guided voriconazole prophylaxis in patients with neutropenic acute myeloid leukemia reduces the incidence of subtherapeutic antifungal plasma concentrations. Clin Pharmacol Ther. 2019. https://doi.org/10.1002/cpt.1641. A prospective study comparing CYP2C19-guided versus standard voriconazole prophylactic dosing in acute myeloid leukemia patients.

    Article  Google Scholar 

  47. Pratt VM, Del Tredici AL, Hachad H, Ji Y, Kalman LV, Scott SA, et al. Recommendations for clinical CYP2C19 genotyping allele selection: a report of the association for molecular pathology. J Mol Diagn. 2018;20(3):269–76. https://doi.org/10.1016/j.jmoldx.2018.01.011.

    Article  CAS  PubMed  Google Scholar 

  48. Rubinstein WS, Maglott DR, Lee JM, Kattman BL, Malheiro AJ, Ovetsky M, et al. The NIH genetic testing registry: a new, centralized database of genetic tests to enable access to comprehensive information and improve transparency. Nucleic Acids Res. 2013;41(Database issue):D925–35. https://doi.org/10.1093/nar/gks1173.

    Article  CAS  PubMed  Google Scholar 

  49. Vo TT, Bell GC, Owusu Obeng A, Hicks JK, Dunnenberger HM. Pharmacogenomics implementation: considerations for selecting a reference laboratory. Pharmacotherapy. 2017;37(9):1014–22. https://doi.org/10.1002/phar.1985.

    Article  PubMed  Google Scholar 

  50. Caraballo PJ, Bielinski SJ, St Sauver JL, Weinshilboum RM. Electronic medical record-integrated pharmacogenomics and related clinical decision support concepts. Clin Pharmacol Ther. 2017;102(2):254–64. https://doi.org/10.1002/cpt.707.

    Article  CAS  PubMed  Google Scholar 

  51. Hicks JK, Dunnenberger HM, Gumpper KF, Haidar CE, Hoffman JM. Integrating pharmacogenomics into electronic health records with clinical decision support. Am J Health Syst Pharm. 2016;73(23):1967–76. https://doi.org/10.2146/ajhp160030.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Klein ME, Parvez MM, Shin JG. Clinical implementation of pharmacogenomics for personalized precision medicine: barriers and solutions. J Pharm Sci. 2017;106(9):2368–79. https://doi.org/10.1016/j.xphs.2017.04.051.

    Article  CAS  PubMed  Google Scholar 

  53. Rouzaud C, Jullien V, Herbrecht A, Palmier B, Lapusan S, Morgand M, et al. Isavuconazole diffusion in infected human brain. Antimicrob Agents Chemother. 2019;63(10). https://doi.org/10.1128/AAC.02474-18.

  54. Schwartz S, Cornely OA, Hamed K, Marty FM, Maertens J, Rahav G, et al. Isavuconazole for the treatment of patients with invasive fungal diseases involving the central nervous system. Med Mycol. 2019. https://doi.org/10.1093/mmy/myz103.

  55. Williams K, Arron ST. Association of CYP2C19 *17/*17 genotype with the risk of voriconazole-associated squamous cell carcinoma. JAMA Dermatol. 2016;152(6):719–20. https://doi.org/10.1001/jamadermatol.2016.0351.

    Article  PubMed  Google Scholar 

  56. Zhu L, Bruggemann RJ, Uy J, Colbers A, Hruska MW, Chung E, et al. CYP2C19 genotype-dependent pharmacokinetic drug interaction between voriconazole and ritonavir-boosted atazanavir in healthy subjects. J Clin Pharmacol. 2017;57(2):235–46. https://doi.org/10.1002/jcph.798.

    Article  CAS  PubMed  Google Scholar 

  57. Owusu Obeng A, Fei K, Levy KD, Elsey AR, Pollin TI, Ramirez AH, et al. Physician-reported benefits and barriers to clinical implementation of genomic medicine: a multi-site IGNITE-network survey. J Pers Med. 2018;8(3). https://doi.org/10.3390/jpm8030024.

    Article  Google Scholar 

  58. Sperber NR, Carpenter JS, Cavallari LH, LJ Damschroder, Cooper-DeHoff RM, Denny JC, et al. Challenges and strategies for implementing genomic services in diverse settings: experiences from the Implementing GeNomics In pracTicE (IGNITE) network. BMC Med Genet. 2017;10(1):35. Doi:https://doi.org/10.1186/s12920-017-0273-2.

  59. Luzum JA, Pakyz RE, Elsey AR, Haidar CE, Peterson JF, Whirl-Carrillo M, et al. The pharmacogenomics research network translational pharmacogenetics program: outcomes and metrics of pharmacogenetic implementations across diverse healthcare systems. Clin Pharmacol Ther. 2017;102(3):502–10. https://doi.org/10.1002/cpt.630.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Dapia I, Garcia I, Martinez JC, Arias P, Guerra P, Diaz L, et al. Prediction models for voriconazole pharmacokinetics based on pharmacogenetics: an exploratory study in a Spanish population. Int J Antimicrob Agents. 2019;54(4):463–70. https://doi.org/10.1016/j.ijantimicag.2019.06.026.

    Article  CAS  PubMed  Google Scholar 

  61. Shah RR, Smith RL. Inflammation-induced phenoconversion of polymorphic drug metabolizing enzymes: hypothesis with implications for personalized medicine. Drug Metab Dispos. 2015;43(3):400–10. https://doi.org/10.1124/dmd.114.061093.

    Article  CAS  PubMed  Google Scholar 

  62. Veringa A, Ter Avest M, Span LF, van den Heuvel ER, Touw DJ, Zijlstra JG, et al. Voriconazole metabolism is influenced by severe inflammation: a prospective study. J Antimicrob Chemother. 2017;72(1):261–7. https://doi.org/10.1093/jac/dkw349.

    Article  CAS  PubMed  Google Scholar 

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Funding

Study authors are supported by the Colorado Clinical and Translational Sciences Institute (CCTSI). The CCTSI is supported in part by Colorado CTSA Grant UL1TR001082 from NCATS/NIH.

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Authors and Affiliations

  1. Department of Pharmacy Services, University of Colorado Hospital, Aurora, CO, USA

    Matthew A. Miller

  2. Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, 12850 E Montview Blvd, Mail Stop C238, Aurora, CO, 80045, USA

    Matthew A. Miller & Yee Ming Lee

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Correspondence to Yee Ming Lee.

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Matthew A. Miller reports personal fees from Allergan outside the submitted work. Yee Ming Lee reports personal fees from Dynamed Plus (EBSCO Health) outside the submitted work.

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Miller, M.A., Lee, Y.M. Applying Pharmacogenomics to Antifungal Selection and Dosing: Are We There Yet?. Curr Fungal Infect Rep 14, 63–75 (2020). https://doi.org/10.1007/s12281-020-00371-w

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