Therapeutic Drug Monitoring of Posaconazole in Adult Acute Myeloid Leukemia (Aml) Patients Receiving Posaconazole Prophylaxis during Induction: Experience from a Center with High Invasive Fungal Infection (IFI)Burden

Background: Posaconazole has been recommended as an antifungal of choice for IFI prophylaxis in AML during induction therapy. Very high incidence of possible and probable IFI (70%) during induction at our centre led to adoption of posaconazole prophylaxis. However, approximately 50% of patients still require change of antifungal due to suspected breakthrough IFI raising the possibility of inadequate plasma levels due to various factors (variable absorption, metabolism and drug interactions). To address this concern, we evaluated the role of therapeutic drug monitoring (TDM) in AML patients receiving posaconazole prophylaxis to identify whether suboptimal plasma levels (<700 ng/mL) are associated with breakthrough IFI.

Method: This prospective observational study included all patients, 18 years or more, undergoing induction chemotherapy for de novo AML with no evidence of IFI (normal CT chest, and galactomannan assay) and on posaconazole prophylaxis between May2015 to February 2016 at our centre. Posaconazole oral suspension 200 mg three times daily was given for antifungal prophylaxis from day 1 of induction until neutrophil recovery to more than 500 cells/μL, occurrence of a confirmed or suspected IFI or development of drug related toxicity or intolerance. The details regarding demography, weight, BMI at diagnosis were recorded. During therapy all adverse events including vomiting and diarrhea were recorded as per CTCAE version 4.03. Concomitant drug history and use of proton pump inhibitors, antacids, metoclopramide and domperidone during treatment period were noted. Blood samples (7 am) for detecting posaconazole trough levels were collected daily from day 4 till day 12 of induction. If patient developed symptoms and signs suggestive of IFI during induction after day 12, then blood sample was drawn for posaconazole trough levels. Plasma posaconazole levels were estimated at by HPLC method. The diagnosis of IFI was in accordance with the revised European Organization for Research and Treatment of Cancer /Mycoses Study Group definitions published in 2008. Breakthrough invasive fungal infection was also diagnosed if there was failure to respond to intravenous antibiotics along with negative cultures and fever defervescence with change in antifungal therapy. The primary objective of the study was to assess the percentage of patients achieving target posaconazole plasma levels. The secondary objectives included i) impact of achieving target drug concentration in preventing breakthrough fungal infections. ii) identification of factors associated with subtoptimal posaconazole levels. iii) Time to achieve steady state concentration or target trough concentrations of posaconazole.

Results: A total of 366 samples were collected from 45 patients with median number of 8 samples (range 1-9) per patient. Median age of patients was 36 years (range 18-45 years). Thirty two were males. Thirty-nine patients received 3+7 regimen and 6 were treated with cladribine along with daunomycin and cytarabine. Eleven patients (24%) did not achieve target plasma levels (≥700 ng/mL) even once till day 12. Median time to achieve steady state concentration was 5 days (range 4-10). At steady state 20 (44% ) patients had suboptimal plasma levels. On serial monitoring, a declining trend in plasma levels was observed after day 8 in 31 patients. Twenty three patients (51%) developed possible/ probable IFI on posaconazole prophylaxis. The median time to develop IFI was 13 days (range 4-24 days). Twenty out of 23 patients (87%) who developed IFI had suboptimal plasma levels as compared to 13 out of 22 patients (60%) who did not develop IFI (p-0.04). In all but 3 patients, the plasma levels declined before breakthrough IFI. On logistic regression analysis, both the steady state concentration and plasma posaconazole levels before breakthrough were strong predictors of occurrence of breakthrough IFI. Presence of mucositis, vomiting, diarrhea, use of antacid was associated with low plasma levels on univariate analysis. On multivariate analysis presence of mucositis and antacids remained significantly associated with low plasma levels.

Conclusion: TDM has a role in patients receiving posaconazole prophylaxis, however it still needs to be seen if dose adjustments based on plasma levels can reduce the risk of breakthrough IFI.