Comparative study of prophylaxis with high and low doses of voriconazole in children with malignancy

Document Type : Original Articles

Authors

1 Infectious Diseases Specialist, Сhief of Infection Control Department; Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Borovlyany, Minsk region, Republic of Belarus

2 Scientific Department, Junior Researcher, Laboratory of Genetic Biotechnology; Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Borovlyany, Minsk region, Republic of Belarus

3 Scientific Department, Researcher, Laboratory of Genetic Biotechnology; Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Borovlyany, Minsk region, Republic of Belarus

4 Biologist, Group of Molecular Biology and Transplant Processing; Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Borovlyany, Minsk region, Republic of Belarus

5 Leading Engineer of Automated Control Systems Department; Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Borovlyany, Minsk region, Republic of Belarus

6 Scientific Department, Researcher, Laboratory of Molecular and Genetic Research; Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Borovlyany, Minsk region, Republic of Belarus

7 Corresponding Member of the National Academy of Sciences of Belarus, Scientific Department, Senior Researcher, Laboratory of Cellular Biotechnology and Cytotherapy; Belarusian Research Center for Pediatric Oncology, Hematology and

10.18502/cmm.6.4.5331

Abstract

Background and Purpose:Children with acute myeloid leukemia and relapses of leukemia are at high risk of developing fungal infections and need antifungal prophylaxis. This study aimed to compare the efficacy and toxicity of two different dosage regimens of voriconazole (VRCZ) during prophylactic administration in children with malignancyand neutropenia.
Materials and Methods:This prospective study was conducted at the Belarusian Research Center for Pediatric Oncology, Hematology, and Immunology fromMay 2017 to December 2019. The present study included 21 Caucasian patients with malignant hematological diseases (20 patients with acute myeloid leukemia and relapses of leukemia and 1 patient with Non-Hodgkin's lymphoma) aged 2-18 years. All patients were randomly divided into two groups that received different dosage regimens of VRCZ prophylaxis. Patients in the “high-dose” group received VRCZat a dose of 9 mg/kg twice a day PO, or 8 mg/kg twice a day IV without a loading dose (children of 2-11 and adolescents and of 12-14 years old with
Results:In the high-dosegroup (n=20 episodes of prophylaxis), invasive fungal infections (IFI) signs were recorded in one (5%) case. In the low-dose group (n=20 episodes), IFI signs were observed in six (30%) cases (P=0.0375). The residual serum concentration was significantly higher in patients who received high doses of VRCZ (p <0.0001). Most patients with IFI (n=6, 86%) had a mean value (i.e.,
Conclusion:The likelihood of IFI was significantly lower in children who prophylactically received VRCZ in high doses (P=0.0375) and had ≥ 0.74 μg/ml residual serum concentration of the medication (P=0.0258). Residual serum concentration of VRCZ reached a plateau by day sixth of the treatment. In children, the dosage was the only highly significant factor affecting the metabolism of VRCZ.

Keywords


1. Almaguer M, Aira MJ, Rodríguez-Rajo FJ, Fernandez-Gonzalez M, Rojas-Flores TI. Thirty-four identifiable airborne fungal spores in Havana, Cuba. Ann Agric Environ Med. 2015; 22(2):215-20.
2. Schmiedel Y, Zimmerli S. Common invasive fungal diseases: an overview of invasive candidiasis, aspergillosis, cryptococcosis, and Pneumocystis pneumonia. Swiss Med Wkly. 2016; 146:w14281.
3. Choi SH, Lee SY, Hwang JY, Lee SH, Yoo KH, Sung KW, et al. Importance of voriconazole therapeutic drug monitoring in pediatric cancer patients with invasive aspergillosis. Pediatr Blood Cancer. 2013; 60(1):82-7 .
4. Nucci M, Anaissie E. How we treat invasive fungal diseases in patients with acute leukemia: the importance of an individualized approach. Blood. 2014; 124(26):3858-69.
5. Klyaritskaya IL, Rabotyagova YS. Modern methods for determining the genetic polymorphism of the cytochrome P450 2C19 gene in patients with gastroesophageal reflux disease. Crimean Ther J. 2014; 2:131-7.
6. Goldstein JA. Clinical relevance of genetic polymorphisms in the human CYP2C subfamily. Br J Clin Pharmacol. 2001; 52(4):349-55.
7. Desta Z, Zhao X, Shin JG, Flockhart DA. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet. 2002; 41(12):913-58.
8. Ishizawa Y, Yasui-Furukori N, Takahata T, Sasaki M, Tateishi T. The effect of aging on the relationship between the cytochrome P450 2C19 genotype and omeprazole pharmacokinetics. Clin Pharmacokinet. 2005; 44(11):1179-89.
9. Frye RF, Zgheib NK, Matzke GR, Chaves-Gnecco D, Rabinovitz M, Shaikh OS, et al. Liver disease selectively modulates cytochrome P450--mediated metabolism. Clin Pharmacol Ther. 2006; 80(3):235-45.
10. Desta Z, Modak A, Nguyen PD, Lemler SM, Kurogi Y, Li L, et al. Rapid identification of the hepatic cytochrome P450 2C19 activity using a novel and noninvasive [13C] pantoprazole breath test. J Pharmacol Exp Ther. 2009; 329(1):297-305.
11. Chaudhry AS, Kochhar R, Kohli KK. Genetic polymorphism of CYP2C19 and therapeutic response to proton pump inhibitors. Indian J Med Res. 2008; 127(6):521-30.
12. Thompson GR 3rd, Rinaldi MG, Pennick G, Dorsey SA, Patterson TF, Lewis IJ 2nd. Posaconazole therapeutic drug monitoring: a reference laboratory experience. Antimicrob Agents Chemother. 2009; 53(5):2223-4.
13. Miyakis S, van Hal SJ, Ray J, Marriott D. Voriconazole concentrations and outcome of invasive fungal infections. Clin Microbiol Infect. 2009; 16(7):927-33.
14. 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.
15. Patterson TF, Thompson GR 3rd, Denning DW, Fishman JA, Hadley S, Herbrecht R. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the infectious diseases society of America. Clin Infect Dis. 2016; 63:e1-60.
16. Neely M, Margol A, Fu X, van Guilder M, Bayard D, Schumitzky A, et al.Achieving target voriconazole concentrations more accurately in childrenand adolescents. Antimicrob Agents Chemother. 2015; 59(6):3090-7.
17. Friberg LE, Ravva P, Karlsson MO, Liu P. Integrated population pharmacokineticanalysis of voriconazole in children, adolescents and adults. Antimicrob Agents Chemother. 2012; 56(6):3032-42.
18. Chen J, Chan C, Colantonio D, Seto W. Therapeutic drug monitoring of voriconazole in children. Ther Drug Monit. 2012; 34(1):77–84.
19. Choi SH, Lee SY, Hwang JY, Lee SH, Yoo KH, Sung KW, et al. Importance of voriconazole therapeutic drug monitoring in pediatric cancer patients with invasive aspergillosis. Pediatr Blood Cancer. 2013; 60(1):82-7.
20. Sano H, Kobayashi R, Hori D, Kishimoto K, Suzuki D, Yasuda K, et al. Prophylactic administration of voriconazole with two different doses for invasive fungal infection in children and adolescents with acute myeloid leukemia. J Microbiol Immunol Infect. 2018; 51(2):260-6.
21. Sung L, Gamis A, Alonzo TA, Buxton A, Britton K, Deswarte-Wallace J, et al. Infections and association with different intensity of chemotherapy in children with acute myeloid leukemia. Cancer. 2009; 115(5):1100-8.
22. Sung L, Lange BJ, Gerbing RB, Alonzo TA, Feusner J. Microbiologically documented infections and infection-related mortality in children with acute myeloid leukemia. Blood. 2007; 110(10):3532-9.
23. Donnelly JP, Chen SC, Kauffman CA, Steinbach WJ, Baddley JW, Verweij PE, et al. Revision and update of the consensus definitions of invasive fungal disease from the European organization for research and treatment of cancer and the mycoses study group education and research consortium. Clin Infect Dis. 2020; 71(6):1367-76.
24. US Department of Health and Human Services. Common terminology criteria for adverse events (CTCAE) version 4.0. New York: National Institutes of Health, National Cancer Institute; 2009.
25. Maron GM, Hayden RT, Rodriguez A, Rubnitz JE, Flynn PM, Shenep JL, et al. Voriconazole prophylaxis in children with cancer: changing outcomes and epidemiology of fungal infections. Pediatr Infect Dis J. 2013; 32(12):e451-55.
26. Friberg LE, Ravva P, Karlsson MO, Liu P. Integrated population pharmacokineticanalysis of voriconazole in children, adolescents and adults. Antimicrob Agents Chemother. 2012; 56(6):3032-42. 27. Hope WW, Walsh TJ, Goodwin J, Peloquin CA, Howard A, Kurtzberg J, et al. Voriconazole pharmacokinetics following HSCT: results from the BMT CTN 0101 trial. J Antimicrob Chemother. 2016; 71(8):2234-40.
Volume 6, Issue 4
December 2020
Pages 27-34
  • Receive Date: 29 June 2020
  • Accept Date: 08 November 2020
  • First Publish Date: 22 November 2020
  • Publish Date: 01 December 2020