Abstract
Invasive aspergillosis (IA) is a life-threatening complication in hematological cancer patients. Voriconazole (VCZ) is the established first-line treatment of IA. VCZ has a nonlinear pharmacokinetic profile and exhibits considerable variability of drug exposure. Therefore, therapeutic drug monitoring (TDM) of VCZ may help to improve treatment results in IA patients, but evidence-based data on the clinical use of TDM in patients treated with VCZ for IA are scarce. Evidence-based guidance is needed to support decisions on the use of TDM in routine VCZ therapy of IA. Our present analysis assessed published studies for evidence-based criteria for TDM of VCZ to improve efficacy and safety of IA therapy in cancer patients. Literature searches of MEDLINE and Cochrane database were performed. We identified 27 clinical studies reporting on the use of plasma level monitoring and/or TDM for VCZ. For each study, strength of recommendation and quality of evidence were categorized according to predefined criteria. A number of studies were published on plasma level monitoring (PLM) and TDM in VCZ therapy of IA. Across studies, VCZ levels >5–5.5 mg/L were found to be associated with toxicity, while reaching minimum levels of >1–2 mg/L appeared to improve efficacy. Timing, frequency, and intervention thresholds and dosage increments of VCZ for adjustment of plasma levels remain to be established. Currently, there is still no conclusive evidence for recommendations in routine clinical practice. More data from prospective randomized studies with TDM are desirable to provide a solid evidence basis for these approaches.
Similar content being viewed by others
References
Karthaus M, Buchheidt D (2013) Invasive aspergillosis: new insights into disease, diagnostic and treatment. Curr Pharm Des 19(20):3569–3594
Herbrecht R, Denning DW, Patterson TF, Bennett JE, Greene RE, Oestmann JW, Kern WV, Marr KA, Ribaud P, Lortholary O, Sylvester R, Rubin RH, Wingard JR, Stark P, Durand C, Caillot D, Thiel E, Chandrasekar PH, Hodges MR, Schlamm HT, Troke PF, de Pauw B, Invasive Fungal Infections Group of the European Organisation for Research and Treatment of Cancer and the Global Aspergillus Study Group (2002) Voriconazole versus amphotericin B forprimarytherapyof invasive aspergillosis. N Engl J Med 347(6):408–415
Karthaus M (2002) Voriconazole versus amphotericin B for invasive aspergillosis. N Engl J Med 347(25):2080–2081
ESCMID guidelines for diagnosis and treatment of Aspergillus diseases. Presented at ECCMID 2014; EW19.
Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr KA, Morrison VA, Segal BH, Steinbach WJ, Stevens DA, van Burik JA, Wingard JR, Patterson TF, Infectious Diseases Society of America (2008) Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 46(3):327–360
Maertens J, Marchetti O, Herbrecht R, Cornely OA, Flückiger U, Frêre P, Gachot B, Heinz WJ, Lass-Flörl C, Ribaud P, Thiebaut A, Cordonnier C (2011) Third European Conference on Infections in Leukemia. European guidelines for antifungal management in leukemia and hematopoietic stem cell transplant recipients: summary of the ECIL 3–2009 update. Bone Marrow Transplant 46(5):709–718
Drew RH, Townsend ML, Pound MW, Johnson SW, Perfect JR (2013) Recent advances in the treatment of life-threatening, invasive fungal infections. Expert Opin Pharmacother 14(17):2361–2374
Andes D (2013) Optimizing antifungal choice and administration. Curr Med Res Opin 29(Suppl 4):13–18
Hulin A, Dailly E, Le Guellec C, Groupe Suivi Therapeutique Pharmacologique de la Societe Francaise de Pharmacologie et de Therapeutique (2011) Level of evidence for therapeutic drug monitoring of voriconazole. Therapie 66(2):109–114
Hamada Y, Tokimatsu I, Mikamo H, Kimura M, Seki M, Takakura S, Ohmagari N, Takahashi Y, Kasahara K, Matsumoto K, Okada K, Igarashi M, Kobayashi M, Mochizuki T, Nishi Y, Tanigawara Y, Kimura T, Takesue Y (2013) Practice guidelines for therapeutic drug monitoring of voriconazole: a consensus review of the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring. J Infect Chemother 19(3):381–392
Seyedmousavi S, Mouton JW, Verweij PE, Brüggemann RJ (2013) Therapeutic drug monitoring of voriconazole and posaconazole for invasive aspergillosis. Expert Rev Anti Infect Ther 11(9):931–941
Kish MA (2001) Infectious Diseases Society of America. Guide to development of practice guidelines. Clin Infect Dis 32(6):851–854
Park WB, Kim NH, Kim KH, Lee SH, Nam WS, Yoon SH, Song KH, Choe PG, Kim NJ, Jang IJ, Oh MD, Yu KS (2012) The effect of therapeutic drug monitoring on safety and efficacy of voriconazole in invasive fungal infections: a randomized controlled trial. Clin Infect Dis 55(8):1080–1087
Theuretzbacher U, Ihle F, Derendorf H (2006) Pharmacokinetic/pharmacodynamic profile of voriconazole. Clin Pharmacokinet 45(7):649–663
Andes D, Marchillo K, Stamstad T, Conklin R (2003) In vivo pharmacokinetics and pharmacodynamics of a new triazole, voriconazole, in a murine candidiasis model. Antimicrob Agents Chemother 47(10):3165–3169
Siopi M, Mavridou E, Mouton JW, Verweij PE, Zerva L, Meletiadis J (2014) Susceptibility breakpoints and target values for therapeutic drug monitoring of voriconazole and Aspergillus fumigatus in an in vitro pharmacokinetic/pharmacodynamic model. J Antimicrob Chemother 69(6):1611–1619
Trifilio S, Pennick G, Pi J, Zook J, Golf M, Kaniecki K, Singhal S, Williams S, Winter J, Tallman M, Gordon L, Frankfurt O, Evens A, Mehta J (2007) Monitoring plasma voriconazole levels may be necessary to avoid subtherapeutic levels in hematopoietic stem cell transplant recipients. Cancer 109(8):1532–1535
Kainer MA, Reagan DR, Nguyen DB, Wiese AD, Wise ME, Ward J, Park BJ, Kanago ML, Baumblatt J, Schaefer MK, Berger BE, Marder EP, Min JY, Dunn JR, Smith RM, Dreyzehner J, Jones TF, Tennessee Fungal Meningitis Investigation Team (2012) Fungal infections associated with contaminated methylprednisolone in Tennessee. N Engl J Med 367(23):2194–2203
Purkins L, Wood N, Ghahramani P, Greenhalgh K, Allen MJ, Kleinermans D (2002) Pharmacokinetics and safety of voriconazole following intravenous- to oral-dose escalation regimens. Antimicrob Agents Chemother 46(8):2546–2553
Lee S, Kim BH, Nam WS, Yoon SH, Cho JY, Shin SG, Jang IJ, Yu KS (2011) Effect of CYP2C19 polymorphism on the pharmacokinetics of voriconazole after single and multiple doses in healthy volunteers. J Clin Pharmacol 71(1):137–138
Eiden C, Cociglio M, Hillaire-Buys D, Eymard-Duvernay S, Ceballos P, Fegueux N, Peyrière H (2010) Pharmacokinetic variability of voriconazole and N-oxide voriconazole measured as therapeutic drug monitoring. Xenobiotica 40(10):701–706
Dolton MJ, Mikus G, Weiss J, Ray JE, McLachlan AJ (2014) Understanding variability with voriconazole using a population pharmacokinetic approach: implications for optimal dosing. J Antimicrob Chemother 69(6):1633–1641
Kurose K, Sugiyama E, Saito Y (2012) Population differences in major functional polymorphisms of pharmacokinetics/pharmacodynamics-related genes in Eastern Asians and Europeans: implications in the clinical trials for novel drug development. Drug Metab Pharmacokinet 27(1):9–54
Marinac JS, Balian JD, Foxworth JW, Willsie SK, Daus JC, Owen R, Flockhart DA (1996) Determination of CYP2C19 phenotype in black Americans with omeprazole: correlation with genotype. Clin Pharmacol Ther 60(2):138–144
Hassan A, Burhenne J, Riedel KD, Weiss J, Mikus G, Haefeli WE, Czock D (2011) Modulators of very low voriconazole concentrations in routine therapeutic drug monitoring. Ther Drug Monit 33(1):86–93
Malingré MM, Godschalk PC, Klein SK (2012) A case report of voriconazole therapy failure in a homozygous ultrarapid CYP2C19*17/*17 patient comedicated with carbamazepine. Br J Clin Pharmacol 74(1):205–206
Choi SH, Lee SY, Hwang JY, Lee SH, Yoo KH, Sung KW, Koo HH, Kim YJ (2013) Importance of voriconazole therapeutic drug monitoring in pediatric cancer patients with invasive aspergillosis. Pediatr Blood Cancer 60(1):82–87
Koselke E, Kraft S, Smith J, Nagel J (2012) Evaluation of the effect of obesity on voriconazole serum concentrations. J Antimicrob Chemother 67(12):2957–2962
Jeong S, Nguyen PD, Desta Z (2009) Comprehensive in vitro analysis of voriconazole inhibition of eight cytochrome P450 (CYP) enzymes: major effect on CYPs 2B6, 2C9, 2C19, and 3A. Antimicrob Agents Chemother 53(2):541–51
Trifilio SM, Scheetz MH, Pi J, Mehta J (2010) Tacrolimus use in adult allogeneic stem cell transplant recipients receiving voriconazole: preemptive dose modification and therapeutic drug monitoring. Bone Marrow Transplant 45(8):1352–1356
Cronin S, Chandrasekar PH (2010) Safety of triazole antifungal drugs in patients with cancer. J Antimicrob Chemother 65(3):410–416
Voriconazole; Summary of product characteristics; EMA January 2014. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000387/WC500049756.pdf. Accessed 14 Jul 2014
FDA Antiviral Drugs Advisory Committee Briefing Document for Voricoanzole. FDA 2001. http://www.fda.gov/ohrms/dockets/ac/01/briefing/3792b2_01_pfizer.pdf. Accessed 14 Jul 2014
Pascual A, Csajka C, Buclin T, Bolay S, Bille J, Calandra T, Marchetti O (2012) Challenging recommended oral and intravenous voriconazole doses for improved efficacy and safety: population pharmacokinetics-based analysis of adult patients with invasive fungal infections. Clin Infect Dis 55(3):381–390
Perea S, Pennick GJ, Modak A, Fothergill AW, Sutton DA, Sheehan DJ, Rinaldi MG (2000) Comparison of high-performance liquid chromatographic and microbiological methods for determination of voriconazole levels in plasma. Antimicrob Agents Chemother 44(5):1209–1213
Brüggemann RJ, Touw DJ, Aarnoutse RE, Verweij PE, Burger DM (2009) International interlaboratory proficiency testing program for measurement of azole antifungal plasma concentrations. Antimicrob Agents Chemother 53(1):303–305
Trifilio S, Ortiz R, Pennick G, Verma A, Pi J, Stosor V, Zembower T, Mehta J (2005) Voriconazole therapeutic drug monitoring in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant 35(5):509–513
Kim SH, Yim DS, Choi SM, Kwon JC, Han S, Lee DG, Park C, Kwon EY, Park SH, Choi JH, Yoo JH (2011) Voriconazole-related severe adverse events: clinical application of therapeutic drug monitoring in Korean patients. Int J Infect Dis 15(11):e753–e758
Ueda K, Nannya Y, Kumano K, Hangaishi A, Takahashi T, Imai Y, Kurokawa M (2009) Monitoring trough concentration of voriconazole is important to ensure successful antifungal therapy and to avoid hepatic damage in patients with hematological disorders. Int J Hematol 89(5):592–599
Hoenigl M, Duettmann W, Raggam RB, Seeber K, Troppan K, Fruhwald S, Prueller F, Wagner J, Valentin T, Zollner-Schwetz I, Wölfler A, Krause R (2013) Potential factors for inadequate voriconazole plasma concentrations in intensive care unit patients and patients with hematological malignancies. Antimicrob Agents Chemother 57(7):3262–3267
Eiden C, Peyrière H, Cociglio M, Djezzar S, Hansel S, Blayac JP, Hillaire-Buys D, Network of the French Pharmacovigilance Centers (2007) Adverse effects of voriconazole: analysis of the French Pharmacovigilance Database. Ann Pharmacother 41(5):755–763
Racil Z, Winterova J, Kouba M, Zak P, Malaskova L, Buresova L, Toskova M, Lengerova M, Kocmanova I, Weinbergerova B, Timilsina S, Rolencova M, Cetkovsky P, Mayer J (2012) Monitoring trough voriconazole plasma concentrations in haematological patients: real life multicentre experience. Mycoses 55(6):483–492
Hope WW (2012) Population pharmacokinetics of voriconazole in adults. AntimicrobAgentsChemother 56(1):526–531
Pascual A, Calandra T, Bolay S, Buclin T, Bille J, Marchetti O (2008) Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clin Infect Dis 46(2):201–211
Soler-Palacín P, Frick MA, Martín-Nalda A, Lanaspa M, Pou L, Roselló E, de Heredia CD, Figueras C (2012) Voriconazole drug monitoring in the management of invasive fungal infection in immunocompromised children: a prospective study. J Antimicrob Chemother 67(3):700–706
Heinz W, Höhl R, Karthaus M, Lipp HP, Scherer M (2012) Optimierte therapie invasiver aspergillosen mit voriconazol. Thieme Praxis Report 4(5):1–16
Suzuki Y, Tokimatsu I, Sato Y, Kawasaki K, Sato Y, Goto T, Hashinaga K, Itoh H, Hiramatsu K, Kadota J (2013) Association of sustained high plasma trough concentration of voriconazole with the incidence of hepatotoxicity. Clin Chim Acta 424:119–122
Smith J, Safdar N, Knasinski V, Simmons W, Bhavnani SM, Ambrose PG, Andes D (2006) Voriconazole therapeutic drug monitoring. Antimicrob Agents Chemother 50(4):1570–1572
Denning DW, Ribaud P, Milpied N, Caillot D, Herbrecht R, Thiel E, Haas A, Ruhnke M, Lode H (2002) Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis. Clin Infect Dis 34(5):563–571
Dolton MJ, Ray JE, Chen SC, Ng K, Pont LG, McLachlan AJ (2012) Multicenter study of voriconazole pharmacokinetics and therapeutic drug monitoring. Antimicrob Agents Chemother 56(9):4793–4799
Imhof A, Schaer DJ, Schanz U, Schwarz U (2006) Neurological adverse events voriconazole: evidence fort herapeutic drug monitoring. Swiss Med Wkly 136(45–46):739–742
Neely M, Rushing T, Kovacs A, Jelliffe R, Hoffman J (2010) Voriconazole pharmacokinetics and pharmacodynamics in children. Clin Infect Dis 50(1):27–36
Lemaitre F, Barbaz M, Scailteux LM, Uhel F, Tadié JM, Verdier MC, Bellissant E (2013) A Case-report of unpredictable and massive voriconazole intoxication in a patient with extensive CYP2C19 and CYP2C9 polymorphisms. Drug Metab Pharmacokinet 28(5):439–441
Lazarus HM, Blumer JL, Yanovich S, Schlamm H, Romero A (2002) Safety and pharmacokinetics of oral voriconazole in patients at risk of fungal infection: a dose escalation study. J ClinPharmacol 42(4):395–402
Michael C, Bierbach U, Frenzel K, Lange T, Basara N, Niederwieser D, Mauz-Körholz C, Preiss R (2010) Voriconazole pharmacokinetics and safety in immunocompromised children compared to adult patients. Antimicrob Agents Chemother 54(8):3225–3232
Pieper S, Kolve H, Gumbinger HG, Goletz G, Würthwein G, Groll AH (2012) Monitoring of voriconazole plasma concentrations in immunocompromised paediatric patients. J Antimicrob Chemother 67(11):2717–2724
Troke PF, Hockey HP, Hope WW (2011) Observational study of the clinical efficacy of voriconazole and its relationship to plasma concentrations in patients. Antimicrob Agents Chemother 55(10):4782–4788
Bartelink IH, Wolfs T, Jonker M, de Waal M, Egberts TC, Ververs TT, Boelens JJ, Bierings M (2013) Highly variable plasma concentrations of voriconazole in pediatric hematopoietic stem cell transplantation patients. Antimicrob Agents Chemother 57(1):235–240
Pasqualotto AC, Shah M, Wynn R, Denning DW (2008) Voriconazole plasma monitoring. Arch Dis Child 93(7):578–581
Spriet I, Cosaert K, Renard M, Uyttebroeck A, Meyts I, Proesmans M, Meyfroidt G, de Hoon J, Verbesselt R, Willems L (2011) Voriconazole plasma levels in children are highly variable. Eur J Clin Microbiol Infect Dis 30(2):283–287
Mitsani D, Nguyen MH, Shields RK, Toyoda Y, Kwak EJ, Silveira FP, Pilewski JM, Crespo MM, Bermudez C, Bhama JK, Clancy CJ (2012) 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 56(5):2371–2377
Chu HY, Jain R, Xie H, Pottinger P, Fredricks DN (2013) Voriconazole therapeutic drug monitoring: retrospective cohort study of the relationship to clinical outcomes and adverse events. BMC Infect Dis 13(1):105
Myrianthefs P, Markantonis SL, Evaggelopoulou P, Despotelis S, Evodia E, Panidis D, Baltopoulos G (2010) Monitoring plasma voriconazole levels following intravenous administration in critically ill patients: an observational study. Int J Antimicrob Agents 35(5):468–472
Trifilio S, Singhal S, Williams S, Frankfurt O, Gordon L, Evens A, Winter J, Tallman M, Pi J, Mehta J (2007) Breakthrough fungal infections after allogeneic hematopoietic stem cell transplantation in patients on prophylactic voriconazole. Bone Marrow Transplant 40(5):451–456
Trifilio SM, Yarnold PR, Scheetz MH, Pi J, Pennick G, Mehta J (2009) Serial plasma voriconazole concentrations after allogeneic hematopoietic stem cell transplantation. Antimicrob Agents Chemother 53(5):1793–1796
Acknowledgments
This work was supported by an unrestricted grant by Pfizer Inc. Editorial support was provided by M. Fischer (Fischer BioMedical, Homburg, Germany).
Disclosures
M.K.: Advisory board for Pfizer, MSD, Gilead, Astellas.
T.L.: Speaker’s bureau of Astellas, Gilead Sciences, GlaxoSmithKline, Merck/MSD, and Pfizer; research grant from Gilead Sciences; consultant to Astellas, Gilead Sciences, and Merck/MSD.
D.B.: Consultations for Gilead, research support from Gilead and Pfizer, speakers bureau of Astellaa, Gilead, and Pfizer, MSD; travel grants from Astellas, MSD, and Pfizer
H.-P. L.: Speaker’s bureau of Astellas, Gilead Sciences, Merck/MSD, and Pfizer; advisory board for Astellas, Gilead Sciences, Merck/MSD, and Pfizer.
S.K.: Speaker’s bureau of Astellas, Gilead Sciences, MSD and Pfizer, research grant from Pfizer, advisory board for Astellas, Gilead Sciences, MSD and Pfizer.
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Karthaus, M., Lehrnbecher, T., Lipp, HP. et al. Therapeutic drug monitoring in the treatment of invasive aspergillosis with voriconazole in cancer patients—an evidence-based approach. Ann Hematol 94, 547–556 (2015). https://doi.org/10.1007/s00277-015-2333-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00277-015-2333-z