Impact of UGT1A4 Polymorphisms on the Posaconazole Serum Trough Concentrations in Patients With Acute Myeloid Leukemia Receiving Delayed-Release Tablets

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BACKGROUND: Posaconazole (PCZ) is recommended for antifungal prophylaxis in neutropenic patients with acute myeloid leukemia (AML). Although the delayed-release (DR) tablet of PCZ has better bioavailability than the oral suspension, the serum target trough concentrations of PCZ are not achieved in all patients. Because the metabolism of PCZ is mainly mediated by uridine diphosphate glucuronosyltransferase 1A4 (UGT1A4), we investigated whether UGT1A4 polymorphisms affect PCZ exposure. METHODS: This single-center prospective cohort study included 88 adult patients with AML undergoing myelosuppressive chemotherapy and receiving PCZ prophylaxis with DR tablets. PCZ and PCZ-glucuronide concentrations were measured on days 3, 7, 14, and 21 after chemotherapy initiation using liquid chromatography-tandem mass spectrometry. The patients were genotyped for UGT1A4 polymorphisms using high-throughput sequencing. Logistic regression tested the association between suboptimal PCZ concentrations defined as median PCZ concentrations below 0.5 mg/L during the prophylaxis course and the 2 common UGT1A4 polymorphisms: UGT1A4 (c.70C>A) and UGT1A4 (c.142T>G) (referred to as UGT1A4*2 and *3 , respectively). RESULTS: Suboptimal PCZ concentrations were common despite treatment with PCZ DR tablets in induction chemotherapy: 13/88 (15%) and consolidation chemotherapy: 6/28 (21%). An increased risk of suboptimal PCZ concentrations was significantly associated with younger age ( P = 0.029), male sex ( P = 0.034), and presence of the UGT1A4*3 haplotype ( P = 0.031). In addition, patients with the UGT1A4*3 haplotype tended to have higher metabolite-to-parent drug ratios than noncarriers ( P = 0.069). CONCLUSIONS: The UGT1A4*3 polymorphism independently contributed to the risk of suboptimal PCZ concentrations in patients with AML taking DR tablets.

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