The Genetic Polymorphism UGT1A4*3 Is Associated with Low Posaconazole Plasma Concentrations in Hematological Malignancy Patients Receiving the Oral Suspension [PublishAheadOfPrint]

The metabolism of posaconazole is mediated mainly by uridine 5' -diphospho-glucuronosyltransferase (UGT) enzymes, especially the UGT1A4. The aim of this study was to investigate the effects of genetic polymorphisms on the posaconazole plasma concentration (PPC). This prospective study was conducted from September 2014 to August 2016. We enrolled patients with acute myeloid leukemia or myelodysplastic syndrome treated with posaconazole oral suspension (200 mg) three times daily for fungal prophylaxis. The multi-drug resistance gene 1 3435C>T and 2677G>T/A variations, and UGT1A4*3 were examined by direct sequencing of DNA from peripheral whole blood samples. We defined poor absorbers as those with PPCs <200 ng/mL and the optimal PPC as ≥700 ng/mL on day 8. The associations between genetic polymorphisms and the PPC were evaluated using multivariate logistic regression analysis including clinical variables. In the study period, 132 patients were enrolled. Six patients (4.5%) were defined as poor absorbers and 49 patients (37.1%) did not reach the optimal PPC on day 8. In multivariate analysis, the independent risk factors for a poor absorber were at least one UGT1A4*3 allele (adjusted odds ratio [lsqb]aOR[rsqb], 18.81; 95% confidence interval [lsqb]CI[rsqb], 1.09-324.44; p = 0.043) and poor oral food intake (aOR per -100 kcal, 1.44; 95% CI, 1.04-1.99; p = 0.029). There was no statistically significant association between the genetic polymorphisms and reaching the optimal PPC on day 8. The UGT1A4*3 polymorphism is an independent risk factor for being a poor absorber of posaconazole oral suspension in patients with hematologic malignancies.

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