Pharmacogenetics and Pharmacokinetics of Posaconazole in Patients with Acute Myeloid Leukemia: Useful Tools for Antifungal Stewardship
Authors: Corcione Silvia , Grosso Cecilia , Audisio Ernesta , Cusato Jessica , Antonucci Miriam , Busca Alessandro , Bruno Benedetto , Gulla Annamaria , d'Avolio Antonio , de Rosa francesco Giuseppe 
Published: December 2023

DISCUSSION
INTRODUCTION Antifungal prophylaxis with posaconazole in patients with acute myeloid leukemia (AML) undergoing induction chemotherapy is usually recommended [1]. Few studies described the clinical impact of suboptimal posaconazole plasma concentrations during prophylaxis, which may be associated with a higher risk of invasive fungal infections (IFI) and a strong impact on clinical outcome [2].
ENDPOINT: The primary endpoint of this study was to evaluate weekly posaconazole Cthrough plasma concentration in AML patients treated with induction chemotherapy. Since polymorphisms of genes encoding enzymes, transporters and transcription factors were also analyzed a possible association amongst plasma exposure, genetic polymorphisms, risk of breakthrough infection and clinical outcam was evaluated .
MATERIALS AND METODS: This was a prospective, single center study at “City of Health and Science”, Molinette Hospital in Turin, Italy. Adult Patients with AML undergoing induction chemotherapy admitted to Haematological wards, were enrolled between March 2023 and July 2023.
Antifungal prophylaxis with oral posaconazole, 300mg bid the first day and 300 mg qd thereafter was given. Biological samples (plasma for posaconazole quantificatication and whole blood for genetics) were obtained for each patient after loading dose and then posaconazole C trough were evaluated weekly (at 7, 14, 21 and 28 days). The Following genes were evaluated: UGT1A1, UGT1A3, ABCB1, ABCG2, ABCC2, ABCB11, SLCO1B1, SLCO1B3, SLC22A6, PXR, CAR, VDR, CYP27B1, CYP24A1, GC. The mortality was assessed at day 28 from hospital admission.
Invasive fungal disease (IFD) was defined as the occurence of a proven or probable IFD according to the European Organization for Research and Treatment of Cancer/National insitute of Allergy and Infection Diseases Micoses Study Group Criteria (EORTC/MSG) revised definitions [3]. Furthermore, according to the clinical suspicion of breakthrough infection, the switch from prophylaxis to antifungal therapy was also recorded as well as antifungal restaging before treatment change.
RESULTS: Twenty patients were included: 9 were women (45%) with a median age of 67 years old (±10.5) and a median Charlson Comorbidity Index of 5 (±1.3). Mean posaconazole C through plasma concentrations are reported in Table 1 and were in range for all the different timepoints. According to EORTC criteria, two patients (10%) had a probable IFI on day 14, and antifungal therapy with liposomal amphotericin B was started [3]. One of those patients had low C trough value at time of suspected breaktrough infection (T 14; 0.2 microg/L 9). The 28 day mortality was 10%, due to the haematological underlying disease.
Regarding pharmacogenetic analysis, posaconazole C trough at day 7 and 14 was associated with ABCB1 1236 polymorphism with p=0.022 and p=0.038, respectively. Furthermore, VDR ApaI (p=0.010), VDR TaqI (p=0.023), VDR BsmI (p=0.042), ABCB11 (p=0.023) and UGT1A3 023 (p=0.023) genetic variants were reported in patients with probable IFI.
There is a potential impact of the use of posaconazole plasma levels monitoring and associated pharmacogenetics to evaluate the risk of underexposure during antifungal prophylaxis, but also at antifungal restaging before treatment switch. These useful tools may help clinicians to identify patients with a higher risk for under-effective plasma concentrations of posaconazole and can be used to improve antifungal stewardship approach in this setting. The utility of such approaches should also be evaluated in azole-to-azole strategies
BIBLIOGRAPHY Olivia White et al. Isavuconazonium or posaconazole for antifungal prophylaxis in patients with acute myeloid leukemia. J Oncol Pharm Pract 2023 May 15;10781552231175825. doi: 10.1177/10781552231175825. Tang LA et al. Risk factors for subtherapeutic levels of posaconazole tablet. J Antimicrob Chemother. 2017 Oct 1;72(10):2902-2905. doi: 10.1093/jac/dkx228. PMID: 29091205 Peter Donnelly et al. Revision and update of the Consensus definition of Invasive Fungal Disease from the European Organization for Research adn Treatment of Cancer and the Mycoses study Group Education and Research Consortium. Clin Infect Dis 2020 Sep 12;71(6):1367-1376. doi: 10.1093/cid/ciz1008.