HANGİ ARAÇ VORİKONAZOL DOZUNU OPTİMİZE ETMEK İÇİN EN İYİ REHBERDİR: TERAPÖTİK İLAÇ İZLEME Mİ YOKSA SİTOKROM P450 POLİMORFİZMİ Mİ?

Year 2024, Volume: 33 Issue: 2, 182 - 189, 25.07.2024

Eren Demirpolat , Mükerrem Betül , Gökhan Metan , Volkan Kahraman , Gökçe Şeker Karatoprak

https://doi.org/10.34108/eujhs.1337832

Abstract

Vorikonazol (VCZ) invazif asperjilloziste (IA) tedavi seçeneklerinden biridir. Bununla birlikte ilacın dar terapötik penceresi ve değişken farmakokinetiği tedavi başarısını etkilemektedir. VCZ kan konsantrasyonu kendisini metabolize eden CYP2C19 polimorfizmleri başta olmak üzere bazı faktörler tarafından etkilenmektedir. Terapötik ilaç izlemi (TDM) yeterli kan düzeyine ulaşılmasının kontrolünü sağlamaktadır. Bu çalışma kapsamında CYP450 polimorfizmlerinin saptanmasının faydasını araştırmayı hedefledik. Hematolojik malignitesi olan hastalar çalışmaya dahil edildi. VCZ’ nin metabolizmasından sorumluCYP450 polimorfizmleri RT-PCR ile ve TDM ise LC/MS/MS ile yapıldı. 11 hasta çalışmayı tamamlayabildi. CYP2C19 genotiplerinin dağılımı orta dereceli metabolizör için %27, hızlı metabolizör için %36, ultra hızlı metabolizör için %18, normal metabolizör için %18 şeklindeydi. İki hasta dozla ilişkili istenmeyen etkiler yaşadı ve bu hastalardan birinin VCZ kan konsantrasyonu supraterapötik düzeydeydi.
VCZ IA’ da tedavi seçeneği arasında yer alsa da farmakokinetiğindeki belirgin değişiklik tedavisini etkilemektedir. Bu sebeple VCZ’ nin TDM ve RT-PCR gibi metodlar klinikteki hekimin hastalara daha iyi bir bakım sağlamasında yardımcı olabilir, hastanın tedavisi daha iyi hale getirilebilir.

Keywords

Antifungal aktivite, genotipleme, vorikonazol

Supporting Institution

Erciyes Üniversitesi Bilimsel Araştırmalar Birimi

Project Number

TCD-5623

WHICH TOOL IS THE BEST GUIDE OPTIMIZE THE VORICONAZOLE DOSAGE: THERAPEUTIC DRUG MONITORING OR CYTOCHROME P450 POLYMORPHISM?

Abstract

Voriconazole (VCZ) is the drug of choice for invasive aspergillosis (IA). However, narraow therapeutic range and variable pharmacokinetics can effect the success of the therapy. VCZ serum concentration is influenced by several factor including CYP450 polymorphisms primarily by CY2C19. Therapeutic drug monitoring (TDM) of VCZ is highly recommended to check adequate serum concentrations. Herein, we investigated the usefulness of detecting CYP450 polymorphism. Patients with hematological malignancies were included in the study.CYP450 polymorphisms which are responsible for metabolism of VCZ were investigated using RT-PCR. TDM of VCZ was peformed usingLC/MS/MS.11 patients were included in the study. Frequencies of CYP2C19 genotypes are 27% for intermediate metabolizer; 36% rapid metabolizer, 18% for ultra rapid metabolizer, 18% for normal metabolizer. Two patients experienced dose related side effects and one of these patient’s voriconazole blood concentration was supratherapeuticAlthough VCZ is the drug of choice for thetreatment of IA, the variabality of the pharmacokinetics can influence the success of therapy significantly. Therefore implementing the pharmacogenetic testing and therapeutic drug monitoring to clinical practice might help clinicians to provide improved care to patients and improve treatment outcomes.

Keywords

Antifungal activity, genotyping, voriconazole

Project Number

TCD-5623

References

• Lamoureux F, Duflot T, Woillard JB, 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. doi:10.1016/j.ijantimicag.2015.12.003.
• 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. doi:10.1007/s12281-015-0219-0.
• Hamadeh IS, Klinker KP, Borgert SJ, et al. Impact of the CYP2C19 genotype on voriconazole exposure in adults with invasive fungal infections. Pharmacogenet Genomics. 2017;27(5):190-196. doi:10.1097/FPC.0000000000000277.
• Levine MT, Chandrasekar PH. Adverse effects of voriconazole: Over a decade of use. Clin Transplant. 2016;30(11):1377-1386. doi:10.1111/ctr.12834.
• Theuretzbacher U, Ihle F, Derendorf H. Pharmacokinetic/pharmacodynamic profile of voriconazole. Clin Pharmacokinet. 2006;45(7):649-663. doi:10.2165/00003088-200645070-00002.
• Demir SÖ, Atici S, Akkoç G, et al. Neurologic Adverse Events Associated with Voriconazole Therapy: Report of Two Pediatric Cases. Case Rep Infect Dis.2016;2016:3989070. doi:10.1155/2016/3989070.
• Huang R F, Zhou C, Zhang X Y, et al. Impact of CYP2C19 genotype on voriconazole exposure and effect of voriconazole on the activity of CYP3A in patients with haematological malignancies. Xenobiotica. 2021;51(10):1199-1206. doi:10.1080/00498254.2021.1969481
• Bayhan G I, Garipardic M, Karaman K, Akbayram S. Voriconazole-associated visual disturbances and hallucinations. Cutaneous and Ocular Toxicology. 2016;35(1):80-82, doi:10.3109/15569527.2015. 1020544
• Jansen J W, Sumon K S,Moenster R P. Elevated Voriconazole Level Associated With Hallucinations and Suicidal Ideation: A Case Report, Open Forum Infectious Diseases, 2017;4(1):1-3.doi:10.1093/ofid/ofw215
• Moriyama B, Owusu Obeng A, Barbarino J, et al.Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP2C19 and Voriconazole Therapy.Clinical Pharmacology &Therapeutıcs 2017;1021(1):45-51. doi:10.1002/cpt.583.
• Themeli M, Waterhouse M, Finke J, Spyridonidis A. DNA chimerism and its consequences after allogeneic hematopoietic cell transplantation. Chimerism. 2011;2(1):25-8. doi:10.4161/chim.2.1.15276.
• Hamada Y, Tokimatsu I, Mikamo Het al. 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. 2013.19(3):381-92.doi:10.1007/s10156-013-0607-8
• Saini L, Seki JT, Kumar D, et al. Serum voriconazole level variability in patients with hematological malignancies receiving voriconazole therapy. Can J Infect Dis Med Microbiol. 2014;25(5):271-6.doi:10.1155/2014/214813.
• Andes, A. Pascual, O. Marchetti. Antifungal therapeutic drug monitoring: established and emerging indications.Antimicrob Agents Chemother.2009;53:24-34doi: 10.1128/AAC.00705-08.
• Yang HH, Hsiao YP, Shih HC, Yang JH. Acyclovir-induced neuropsychosis successfully recovered after immediate hemodialysis in an end-stage renal disease patient. Int J Dermatol. 2007;46(8):883-884. doi: 10.1111/j.1365-4632.2007.03269.x.
• Sadjadi SA, Regmi S, Chau T. Acyclovir Neurotoxicity in a Peritoneal Dialysis Patient: Report of a Case and Review of the Pharmacokinetics of Acyclovir. Am J Case Rep. 2018;19:1459-1462. doi:10.12659/AJCR.911520.
• M H Nguyen, C Y Yu. Voriconazole against fluconazole-susceptible and resistant candida isolates: in-vitro efficacy compared with that of itraconazole and ketoconazole. Journal ofAntimicrobial Chemotherapy, 1998; 42: 253–256. doi:10.1093/jac/42.2.253
• 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.doi: 10.1002/phar.1400.