The role of uridine diphosphate glucuronosyltransferase 1A4 polymorphisms on posaconazole exposure

Posaconazole is used to treat and prevent invasive fungal infections. Posaconazole metabolism is mediated by the uridine 5'-diphopho-glucuronosyltransferase (UGT) 1A4 enzyme; prior studies have suggested UGT1A4*3 contributes to low posaconazole exposure, while the impact of UGT1A4*2 is unclear. This study aimed to further understand the relationship between posaconazole exposure and UGT1A4 genotypes. Steady-state posaconazole plasma concentrations (PPCs) and demographics of patients who received the oral tablet formulation of posaconazole were collected, retrospectively, regardless of the patient's underlying diagnoses. UGT1A4 genotypes were obtained from the institutional research biorepository. The patients' dose-controlled PPCs, PPCs, and clinical PPC categorizations by institutional prophylaxis and treatment targets were analyzed among UGT1A4 genotypes. Breakthrough infection data were also collected in patients receiving posaconazole prophylaxis. A total of 103 patients were included, with 21 (20.3%) UGT1A4 *1/*3, 76 (73.7%) UGT1A4 *1/*1, and 6 (5.8%) UGT1A4 *1/*2. The dose-controlled PPCs [(ng/ml)/(mg/day)] were 3.63 (2.45-6.92) for UGT1A4 *1/*3, 5.07 (3.04-7.11) for *1/*1, and 4.92 (2.89-6.12) for *1/*2 (P = 0.62). Additionally, no statistically significant differences in median PPC or clinical PPC prophylaxis and treatment classifications were found among UGT1A4 genotypes. One UGT1A4 *1/*3 and two *1/*1 patients experienced possible breakthrough fungal infections. This study did not confirm the previously reported association between UGT1A4*3 and reduced posaconazole exposure and found no association with UGT1A4*2. Further studies are needed to determine the impact of homozygous UGT1A4 variants on posaconazole exposure.