Pathol. Oncol. Res. (2018) 24:541–545 DOI 10.1007/s12253-017-0264-9 ORIGINAL ARTICLE Influence of CYP2C19 Genotypes on the Occurrence of Adverse Drug Reactions of Voriconazole among Hematological Patients after Allo-HSCT 1 2 2 3 Beata Sienkiewicz & Donata Urbaniak-Kujda & Jarosław Dybko & Andrzej Dryś & 1 2 1 Magdalena Hurkacz & Tomasz Wróbel & Anna Wiela-Hojeńska Received: 3 April 2017 /Accepted: 21 June 2017 /Published online: 6 July 2017 The Author(s) 2017. This article is an open access publication Abstract The aim of this study was to determine the influence of adverse drug reactions during VCZ prophylaxis of different CYP2C19 genotypes on selected liver function pa- among patients after allo-HSCT. rameters, and ADR occurrence during VCZ prophylaxis in adult . . patients after allo-HSCT (allogeneic hematopoietic stem cell Keywords Adverse drug reactions Voriconazole . . transplantation). CYP2C19 mutations were determined in a co- CYP2C19 Genotyping Hematology hort of 30 adults using PCR-RFLP methods established by Sim et al. and Goldstein and Blaisdell. The patients’ protocol included biometrical and biochemical data, information on the underlying Introduction disease, chemotherapy, molds infections occurring during VCZ treatment, adverse drug reactions typical for the use of Antifungal prophylaxis is crucial for the success of each he- voriconazole, and probable drug - drug interactions. The obser- matologic treatment. Especially for patients classified as those vation and reporting of ADR took place from the −1 until the at highest risk of developing invasive fungal infections (IFIs). +20th day of VCZ therapy. For statistical analysis the χ2 test was These are patients receiving intensive chemotherapy for acute used (p < 0.05). Among the examined patients 23 suffered from myeloid leukemia and myelodysplastic syndrome, as well as at least one side effect during VCZ therapy. Most frequent ADR corticosteroid therapy for graft-versus-host disease (GVHD) were gastrointestinal disturbances (n = 15), nervous system after allogeneic hematopoietic stem cell transplantation (allo- (n = 11) and skin (n = 7) disorders. Patients with at least one loss HSCT) . of function allele (*2) were more likely to experience adverse In this group of patients, IFIs are mainly caused by drug reactions than those, with different genotypes. Due to the Aspergillus spp. and Candida spp. The mortality rates are limited number of patients the result could not be proven with a 56% for invasive aspergillosis and approximately 10–25% statistical significance. Previous determination of for candidiasis, what supports the necessity for appropriate CYP2C19 genotype may be a useful tool for prevention antifungal prophylaxis [1–3]. One of the new generation triazol antifungal agents with broad-spectrum activity is voriconazole (VCZ). It is indicated for treatment of invasive aspergillosis, candidemia in non- * Beata Sienkiewicz neutropenic patients, fluconazole-resistant serious invasive firstname.lastname@example.org Candida spp. infections and serious fungal infections caused by Scedosporium spp. and Fusarium spp. VCZ can also be an Department of Clinical Pharmacology, Faculty of Pharmacy, alternative for posaconazole in the prophylaxis of high risk Wrocław Medical University, 211a Borowska St, patients in hematological units [1, 4]. The agent has saturable 50-556 Wrocław, Poland 2 nonlinear pharmacokinetics, which properties are mainly in- Department and Clinic of Haematology, Blood Neoplasms, and Bone fluenced by food intake, inter–individual variability and drug- Marrow Transplantation, Wrocław Medical University, 4 Wybrzeże Pasteura St, 50-367 Wrocław, Poland drug interactions. The drug is almost completely absorbed when administered under fasted conditions. The liver metab- Department of Physical Chemistry, Wrocław Medical University, 211a Borowska St, 50-556 Wrocław, Poland olism is primarily conducted by the hepatic cytochrome P450 542 Sienkiewicz B. et al. CYP2C19 isoenzyme, and to a lesser extent by CYP3A4 and interaction analysis to indicate other factors potentially caus- CYP2C9. Significant genetic polymorphisms in the ing side effects. CYP2C19 gene encoding for the CYP2C19 enzyme may re- sult phenotypically in rapid or slow metabolism of voriconazole, possibly resulting in approximately 30–50% Materials and Methods variation of plasma concentrations [5, 6]. This is why many authors postulate the need for CYP2C19 genotyping as a part In the conducted study, carried out with the permission of the of therapeutic drug monitoring of VCZ concentrations to Bioethics Committee of Wrocław Medical University, a co- avoid adverse drug reactions (ADRs) . hort of 30 patients, 11 women and 19 men, was examined. An Voriconazole may lead to neurological (agitation, dizzi- observation and reporting of ADR took place from the −1day ness, confusion, anxiety, tremor, auditory and visual halluci- before VCZ administration till the +20th day of treatment. nations), respiratory, thoracic and mediastinal, gastrointesti- nal, hepatobiliary (significant transaminitis) and skin disorders DNA Isolation and Genotyping (rash, pruritus, photosensitivity). Pyrexia is another common adverse drug reaction . Dose-related visual disturbances The material used for genetic testing was whole blood, drawn (blurred vision, photophobia, altered visual and color percep- on the anticoagulant ethylenediaminetetraacetic acid (EDTA). tion) occur in 22–45% of patients. Cardiovascular events (QT We isolated DNA using the QIAamp® DNA Blood Mini Kit, prolongation and torsade de pointes) have been reported rare- according to the manufacturer’s instruction in a laminar flow ly, especially with other risk factors e.g. cardiomyopathy or cabinet. Two modified PCR-RFLP methods, previously pro-arrhythmic medications . Drug-drug interactions dur- adapted to the requirements of the Pharmacogenetics and ing hematologic treatment are also important factors leading Pharmacogenomics Laboratory of the Department of to changes in VCZ pharmacokinetic parameters. The co- Clinical Pharmacology, for CYP2C19 allele 1, 2 and 17 de- administration of e.g. cyclosporine A, phenytoin or flucona- termination by Goldstein and Blaisdell and Sim et al. were zole was reported to cause side effects due to variabilities in used [16, 17]. Most important information on the methods pharmacokinetic properties of the drug [9–11]. Other impor- are presented in Table 2. tant drug-drug interaction during VCZ treatment are presented in Table 1. Patients’ Observation Protocol In a previously published article, we describe 4 patients with CYP2C19*2/*17 genotype experiencing more often side Considering literature and summaries of product characteris- effects of voriconazole then others treated with the same pro- tics a patient’s protocol with most important biometrical and tocols . The aim of this study was to determine the influ- biochemical data was evaluated. The protocol also included ence of different CYP2C19 genotypes on selected liver func- information on the underlying disease, chemotherapy, molds tion parameters, and ADR occurrence during voriconazole infections occurring during VCZ treatment, adverse drug re- treatment in a larger number of adult patients after allo- actions typical for the use of voriconazole, and probable drug - HSCT. We also performed a concomitant drug–drug drug interactions. Table 1 Drugs contraindicated Drug Effect of co-medication Recommendation during VCZ treatment [4, 10, 12–14] Astemizol, cisapride, pimozide, quinidine, Prolongation of QTc terfenadine Carbamazepine, long acting barbiturates Lower VCZ concentrations Efavirenz (doses 400 mg or higher) Lower VCZ concentrations Ergot alkaloids Possible egotism Fluconazole Higher VCZ concentrations Contraindicated Fosamprenavir boosted with low-dose ritonavir Lower VCZ concentrations Lopinavir boosted with high-dose ritonavir Lower VCZ concentrations Rifampicin Lower VCZ concentrations St. John’s Wort Lower VCZ concentrations Sirolimus Higher sirolimus concentrations Simvastatin Higher simvastatin concentrations Impact of CYP2C19 Genotype on ADR after Allo-HSCT 543 Table 2 Methodology used for CYP2C19*2 and *17 determination [16, 17] CYP2C19 Primer sequences PCR conditions PCR product Restriction Restriction fragment Marker allele size (base pair) enzyme size (base pair) Wild type Variant allele *17 5′-AATA 2 min at 94 °C; 35 cycles of 30 s. at 500 MnII 280, 224 500 DNA M1 AAGATGACCT 52 °C, 30 s. at 72 °C, 30 s. at 94 °C; Marker TGATCTGG-3′ and 7 min. at 72 °C 5′-GTCTCCTGAAGTGT CTGTAC-3’ *2 5’-CAGAGCTT 5 min at 94 °C; 37 cycles of 30 s. at 321 Sma I 212, 109 321 DNA M1 GGCATATTGTATC-3′ 54 °C, 30 s. at 72 °C, 30 s. Marker 5′-GTAAACACACAA at 94 °C; and5min. at 72 °C CTAGTCAATG-3’ Treatment Protocol relation to CYP2C19 genotypes are shown in Fig. 2. Most frequent ADR were gastrointestinal disturbances (n =15),ner- Twenty-three patients were treated with reduced-intensity vous system (n = 11) and skin (n =7) disorders. conditioning (RIC) and 7, suffering from ALL, with Patients demonstrating the CYP2C19*1/*17 genotype suf- myeloablative conditioning (MAC). The treatment protocols fered mainly from skin (rash, erythema), nervous system were described previously by Sienkiewicz et al. . (headache, vertigo), and gastrointestinal disorders (nausea, gastritis). Patients with CYP2C19*1/*2 genotype experienced nervous system (headache, vertigo) and gastrointestinal disor- Statistical Analysis ders (constipation, nausea), CYP2C19*2/*17 patients suf- fered from gastrointestinal (nausea, vomiting), nervous sys- Statistical analysis was performed with the STATISTICA sta- tem (headache, vertigo), skin disorders (erythema, rash), tistical software (STATISTICA 12, StatSoft, Tulsa, Okl.). P haematuria and elevated GGT values. Patients with values less than 0.05 were considered statistically significant. CYP2C19*17/*17 genotype experienced vomiting and skin To determine the influence of variables such as BMI and ge- disorders whereas wild type genotype was connected with notype on the occurrence and frequencies of ADR the χ2test swelling (face and peripheral oedema). According to the pre- was used. sented results, patients with at least one loss of function allele (*2) experienced adverse drug reactions more often than those with different genotypes. Due to the limited number of pa- Results tients the result could not be proven with a statistical signifi- cance. As for published case reports suggesting an impact of In the examined cohort the median age was 52 years and BMI on ADR we also tried to determine if there is such an the median BMI was 26. Ten patients were overweight (with BMI values over 25). All of the recruited patients underwent hematopoietic stem cell transplantation at the *1/*17 Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation of Wrocław Medical University between 2015 and 2016 *2/*17 due to; acute myeloid leukemia (AML) 11 cases, acute lymphoblastic leukemia (ALL) 7 cases, myelodysplastic syndrome (MDS) 6 cases, aplastic anemia (AA) 2 cases, *17/*17 multiple myeloma (MM) 2 cases, myeloproliferative syn- drome (MPS) 1 case, and lymphoma in 1 case. The CYP2C19 genotypes found by performed genetic test- *1/*2 ing are presented in Fig. 1. VCZ prophylaxis failed in two cases, where an invasive 10 *1/*1 pulmonary aspergillosis occurred. Twenty-three patients suf- fered from at least one side effect during therapy. The experi- Fig. 1 CYP2C19 genotypes among the examined patients enced adverse drug reactions among the patients’ cohort in 544 Sienkiewicz B. et al. Fig. 2 ADR in relation to CYP2C19 among the examined patients cohort *1/*17 *1/*2 *2/*17 *17/*17 *1/*1 influence among the examined cohort of patients [18, 19]. No with lower (allele*17) or higher (allele*2) VCZ concen- relationship between BMI and frequency of side effects was trations after standard dosing, an impact on the toxicity found. The presented complications were temporary and had of the drug is plausible. Pascual et al. found a correla- no impact on the dosage regimen nor the conducted pharma- tion between high VCZ concentrations and neurological cotherapy. After convalescence, the patients were discharged disorders . In a review Dolton et al. also identified from hospital. a relationship between voriconazole concentrations hepatobiliary and visual disorders . Our different findings can be due to a limited number of patients, Discussion similarly to the study conducted by Kim et al., where no correlation between CYP2C19 genotypes and VCZ Thirty patients were recruited for our study. The most concentrations was found . Another factor having frequent adverse effects were gastrointestinal distur- an impact on our results could be the concomitant use bances, skin disorders, headache, swelling, liver abnor- of cyclosporine A and methotrexate. Voriconazole is an malities (elevated GGT), pyrexia, chills, haematuria, hy- P-gp inhibitor leading to elevated cyclosporine A con- pertension and depression respectively. To our knowl- centrations, and its ADR . Methotrexate use may also edge there are few studies on the topic of adverse drug cause adverse drug reactions such as depression, head- reactions caused by voriconazole in the group of adult ache, pneumonia and haematuria . HSCT-patients. In a study by Brüggemann et al. visual and gastrointestinal disorders appeared most often . Kim et al. and Chu et al. reported liver function abnor- Conclusion malities, gastrointestinal, renal, skin and visual disor- ders, appearing with different frequencies [21, 22]. Adult patients after allo-HSCT, demonstrating minimum one In our cohort ten patients were overweight, no correlation loss of function allele of CYP2C19 isoenzyme, are more like- with an increased number of adverse drug reactions among ly to experience adverse drug reactions during VCZ this group could be proven. Our findings are consistent with prophylaxis. Previous determination of CYP2C19 geno- those from Koselke et al. who also did not observe toxicity type may be a useful tool for prevention of adverse differences in a group of 21 overweight patients, although a drug reactions during VCZ prophylaxis among hemato- correlation between strongly obese patients and sub- logic patients after allo-HSCT. therapeutic concentrations of voriconazole (used in standard There is a need for more investigation on the topic of doses) was found . voriconazoles’ ADR in relation to CYP2C19 genotype, which In the conducted study no statistical correlation be- could help to identify patients potentially more likely to expe- tween CYP2C19 genotype and the frequencies of ad- rience side effects. verse drug reactions, but a tendency of patients with loss of function allele to experience side effects more Acknowledgements This study was founded by the Ministry of often was found. 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