Voriconazole-Induced Hepatotoxicity Concise up-to-date review

Year 2022, Volume: 6 Issue: 1, 325 - 334, 27.01.2022

Özge Akçay , Mukaddes Gümüştekin

https://doi.org/10.30621/jbachs.1051669

Abstract

Voriconazole is a wide spectrum antifungal used primarily for invasive aspergillosis, an invasive mold infection occurs mostly in immunocompromised patients. Hepatotoxicity is the most common voriconazole-related adverse reaction that leads to treatment discontinuation. Even though reported incidence of hepatic adverse reactions during phase 2 and 3 clinical trials were less than 10%, observational studies in post marketing phase revealed much higher incidence reaching up to 69%. Therefore, the burden caused by hepatotoxicity and interruption of antifungal therapy put immunocompromised patients at serious risk.
Currently, there is no biomarker in routine clinical use that can clearly predict susceptibility to voriconazole-induced hepatotoxicity. In effort to identify a predictor, plasma concentrations of voriconazole and cytochrome (CYP) 2C19 genotype/phenotype, which is responsible from substantial inter-individual changes in voriconazole pharmacokinetics, are the most studied subjects. Hepatotoxicity tends to occur at higher concentrations (>4 mg/L), but so far, no significant association has identified in this matter. Although CYP2C19 genotype is strongly associated with voriconazole plasma concentration, current data is insufficient to define a causal relationship between CYP2C19 genotype and voriconazole-induced hepatotoxicity.
This article reviews the epidemiology, mechanism, laboratory features of voriconazole-induced hepatotoxicity and current literature investigating the influence of voriconazole plasma concentration and CYP2C19 genetics on voriconazole-induced hepatotoxicity.

Keywords

voriconazole, hepatotoxicity, drug induced liver injury, plasma voriconazole concentration, CYP2C19 genotype

References

• 1. Andrade RJ, Chalasani N, Björnsson ES, et al. Drug-induced liver injury. Nat Rev Dis Prim 2019; 5(1): 1–22.
• 2. Larson A, Lindor K, Robson K. Drug-induced liver injury. UptoDate 2020 [Retrieved: 2020 Oct 15]. Available from: https://www.uptodate.com/contents/drug-induced-liver-injury
• 3. FDA. Center for Drug Evaluation and Research Center for Biologics Evaluation and Research. Drug-Induced Liver Injury: Premarketing Clinical Evaluation; 2009. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation.
• 4. Devarbhavi H, Dierkhising R, Kremers WK, Sandeep MS, Karanth D, Adarsh CK. Single-Center Experience With Drug-Induced Liver Injury From India: Causes, Outcome, Prognosis, and Predictors of Mortality. Am J Gastroenterol 2010; 105(11): 2396–404. 5. Zhou Y, Yang L, Liao Z, He X, Zhou Y, Guo H. Epidemiology of drug-induced liver injury in China: A systematic analysis of the Chinese literature including 21 789 patients. Eur J Gastroenterol Hepatol 2013; 25(7): 825–9.
• 6. Reuben A, Tillman H, Fontana RJ, et al. Outcomes in adults with acute liver failure between 1998 and 2013: An observational cohort study. Ann Intern Med 2016; 164(11): 724–32.
• 7. Suk KT, Kim DJ, Kim CH, et al. A prospective nationwide study of drug-induced liver injury in korea. Am J Gastroenterol 2012; 107(9): 1380–7.
• 8. Raschi E, Poluzzi E, Koci A, Caraceni P, De Ponti F. Assessing liver injury associated with antimycotics: Concise literature review and clues from data mining of the FAERS database. World J Hepatol 2014; 6(8): 601–12.
• 9. Pfizer. Vfend ® (voriconazole). Highlights of prescribing information. Available from: http://labeling.pfizer.com/ShowLabeling.aspx?format=PDF&id=618
• 10. Cecil JA, Wenzel RP. Voriconazole: A broad-spectrum triazole for the treatment of invasive fungal infections. Expert Rev Hematol 2009; 2(3): 237-54.
• 11. Barbarino JM, Owusu Obeng A, Klein TE, Altman RB. PharmGKB summary: voriconazole pathway, pharmacokinetics. Pharmacogenet Genomics 2017; 27(5): 201–9.
• 12. FDA. VFEND ® I.V. (voriconazole) for Injection VFEND ® Tablets. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021266s032lbl.pdf
• 13. Tan K, Brayshaw N, Tomaszewski K, Troke P, Wood N. Investigation of the potential relationships between plasma voriconazole concentrations and visual adverse events or liver function test abnormalities. J Clin Pharmacol 2006; 46(2): 235–43.
• 14. Zonios D, Yamazaki H, Murayama N, et al. Voriconazole Metabolism, Toxicity, and the Effect of Cytochrome P450 2C19 Genotype. J Infect Dis 2014; 209(12): 1941–8.
• 15. Solís-Muñoz P, López JC, Bernal W, et al. Voriconazole hepatotoxicity in severe liver dysfunction. J Infect 2013; 66(1): 80–6.
• 16. Den Hollander JG, Van Arkel C, Rijnders BJ, Lugtenburg PJ, De Marie S, Levin M-D. Incidence of voriconazole hepatotoxicity during intravenous and oral treatment for invasive fungal infections. J Antimicrob Chemother 2006; 57: 1248–50.
• 17. Saito T, Fujiuchi S, Tao Y, et al. Efficacy and safety of voriconazole in the treatment of chronic pulmonary aspergillosis: Experience in Japan. Infection 2012; 40(6): 661–7.
• 18. Luong M-L, Hosseini-Moghaddam SM, Singer LG, et al. Risk Factors for Voriconazole Hepatotoxicity at 12 Weeks in Lung Transplant Recipients. Am J Transplant 2012; 12(7): 1929–35.
• 19. Amigues I, Cohen N, Chung D, et al. Hepatic Safety of Voriconazole after Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant 2010; 16(1): 46–52.
• 20. Mitsani D, Nguyen MH, Shields RK, et al. Prospective, observational study of voriconazole therapeutic drug monitoring among lung transplant recipients receiving prophylaxis: Factors impacting levels of and associations between serum troughs, efficacy, and toxicity. Antimicrob Agents Chemother 2012; 56(5): 2371–7.
• 21. Wu S-L, Wei T-Y, Lin S-W, Su K-Y, Kuo C-H. Metabolomics Investigation of Voriconazole-Induced Hepatotoxicity in Mice. Chem Res Toxicol 2019; 32(9): 1840-1849
• 22. Wu SL, Cheng CN, Wang CC, Lin SW, Kuo CH. Metabolomics analysis of plasma reveals voriconazole-induced hepatotoxicity is associated with oxidative stress. Toxicol Appl Pharmacol 2020; 403: 115157.
• 23. Doß S, Potschka H, Doß F, Mitzner S, Sauer M. Hepatotoxicity of antimycotics used for invasive fungal infections: In vitro results. BioMed Research International 2017; (3): 1-10
• 24. LiverTox: Clinical and Research Information on Drug- Induced Liver Injury: Voriconazole [Updated 2017 May 17]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases 2012. Available from: https://www.ncbi.nlm.nih.gov/books/NBK547891/
• 25. Denning DW, Ribaud P, Milpied N, et al. Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis. Clin Infect Dis 2002; 34(5): 563–71.
• 26. Purkins L, Wood N, Ghahramani P, Greenhalgh K, Allen MJ, Kleinermans D. Pharmacokinetics and safety of voriconazole following intravenous- to oral-dose escalation regimens. Antimicrob Agents Chemother 2002; 46(8): 2546–53.
• 27. Ullmann AJ, Aguado JM, Arikan-Akdagli S, et al. Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clin Microbiol Infect 2018; 24: e1–38.
• 28. Teusink A, Vinks A, Zhang K, 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.
• 29. Patterson TF, Thompson GR, Denning DW, et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis 2016; 63(4): e1–60.
• 30. Yuan ZQY, Qiao C, Yang ZC, et al. The Impact of Plasma Protein Binding Characteristics and Unbound Concentration of Voriconazole on Its Adverse Drug Reactions. Front Pharmacol. 2020; 1: 505.
• 31. Trifilio S, Ortiz R, Pennick G, et al. Voriconazole therapeutic drug monitoring in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant 2005; 35(5): 509–13.
• 32. 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.
• 33. Chu HY, Jain R, Xie H, Pottinger P, Fredricks DN. Voriconazole therapeutic drug monitoring: Retrospective cohort study of the relationship to clinical outcomes and adverse events. BMC Infect Dis 2013; 13(1): 105.
• 34. Jin H, Tiansheng Wang, Falcione BA, et al. Trough concentration of voriconazole and its relationship with efficacy and safety: a systematic review and meta-analysis. J Antimicrob Chemother 2016; 71(7): 1772–85.
• 35. 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.
• 36. Wang T, Zhu H, Sun J, 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.
• 37. Hamada Y, Seto Y, Yago K, Kuroyama M. Investigation and threshold of optimum blood concentration of voriconazole: A descriptive statistical meta-analysis. J Infect Chemother 2012; 18(4) :501–7.
• 38. Suzuki Y, Tokimatsu I, Sato Y, et al. Association of sustained high plasma trough concentration of voriconazole with the incidence of hepatotoxicity. Clin Chim Acta 2013; 424: 119–22.
• 39. Moriyama B, Obeng AO, Barbarino J, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP2C19 and Voriconazole Therapy. Clin Pharmacol Ther 2017; 102(1): 45–51.
• 40. Theuretzbacher U, Ihle F, Derendorf H. Pharmacokinetic/Pharmacodynamic Profile of Voriconazole. Clin Pharmacokinet 2006; 45(7): 649–63.
• 41. 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.
• 42. Levin MD, den Hollander JG, van der Holt B, Rijnders BJ, van Vliet M, Sonneveld P, et al. Hepatotoxicity of oral and intravenous voriconazole in relation to cytochrome P450 polymorphisms. J Antimicrob Chemother 2007; 60(5): 1104–7.
• 43. Berge M, Guillemain R, Trégouet DA, et al. Effect of cytochrome P450 2C19 genotype on voriconazole exposure in cystic fibrosis lung transplant patients. Eur J Clin Pharmacol 2011; 67(3): 253–60.
• 44. 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.
• 45. Song Y, Jia MX, Yang G, et al. Association of CYP2C19 and UGT1A4 polymorphisms with voriconazole-induced liver injury. Per Med 2019; 17(1): 15–22.
• 46. Levin MD, den Hollander JG, van der Holt B, et al. Hepatotoxicity of oral and intravenous voriconazole in relation to cytochrome P450 polymorphisms. J Antimicrob Chemother 2007; 60(5): 1104–7.
• 47. Whirl-Carrillo M, McDonagh EM, Hebert JM, et al. Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther 2012; 92(4): 414–7.