Optimizing antifungal drug dosing and monitoring to avoid toxicity and improve outcomes in patients with haematological disorders

Abstract

Antifungal prophylaxis, empirical therapy and treatment of established fungal infections in the haematology population may be associated with significant toxicity or drug interactions leading to sub-therapeutic antifungal drug concentrations and poorer clinical outcomes. These risks may be minimised by clinical assessment, laboratory monitoring of biochemical or haematological indices, avoidance of particular drug combinations and dose modification in certain circumstances. Specific measures, such as the optimal timing of oral drug administration in relation to meals, use of pre-hydration and electrolyte supplementation may also be required. For certain agents, therapeutic drug monitoring (TDM) is warranted where non-compliance, non-linear pharmacokinetics, a narrow therapeutic window, suspected drug interaction or unexpected toxicity are encountered. Pharmacokinetics and pharmacodynamics of clinical relevance to the haematology population are discussed for the azole, polyene and echinocandin classes of antifungal agents. The evidence supporting an association between TDM and enhanced treatment outcomes is presented for individual antifungal drugs, and recommendations for clinical practice are provided. Further randomised study of newer antifungal agents, such as posaconazole, is required to explore the potential for improved clinical outcomes in association with TDM.Understanding a drug's pharmacokinetics and its pharmacodynamic effects affords the clinician the capacity to optimize drug exposure while minimizing or avoiding drug interactions and toxicities. Therapeutic drug monitoring (TDM) may also be employed during the treatment period to ensure that the selected drug dosage falls within the therapeutic window for an individual patient.These clinical caveats are particularly relevant to the haematology population where the frequent requirement for polypharmacy and the complexity of comorbidities can significantly influence the success of antifungal therapy. This section of the guidelines describes the potential drugdrug interactions and toxicities related to antifungal use and how they may be avoided. It also considers the latest

Impact of glucuronide interferences on therapeutic drug monitoring of posaconazole by tandem mass spectrometry

“…However, it has been reported that side effects are higher when compared to other triazoles (17,18). TDM of posaconazole has been recommended when drug-drug interactions are suspected (2), and a clinical trial showed that higher posaconazole concentrations were associated with a higher number of responders to treatment of aspergillosis (14). Moreover, posaconazole metabolism shows pronounced individual variability of 38%-82% in cohorts of severely ill patients (1,5,19).…”

“…Triazoles affect ergosterol biosynthesis of yeasts and fungi by specific inhibition of 14a-demethylase (CYP51). Indications for therapeutic drug monitoring (TDM) comprise non-linear pharmacokinetics, high intra-individual metabolic variability, narrow therapeutic range, unexpected toxicity, and possible drug interactions (1)(2)(3). For triazole antifungals with an approval date before 2005, TDM methods have been developed for itraconazole and its main active metabolite, hydroxyitraconazole (4-7), as well as for voriconazole (8)(9)(10)(11).…”

A New HPLC Validated Method for Therapeutic Monitoring Of Triazoles in Human Plasma: First Results in Leukaemic Patients

“…Due to specific metabolic pathways of triazoles, drug interactions in selected patients, such as AML patients, may often cause sub-therapeutic concentrations. In particular, VRC is a substrate and inhibitor of CYP2C19, CYP2C8/9 and CYP3A4 [1,2] and PSC is an inhibitor of CYP3A4, metabolized by glucuronidation 4 . Due to the metabolic bind especially at CYP3A4 site between azoles and current therapy for AML treatment, and to therapeutic window (1-5,5 µg/mL) reported for VRC [8], and thresholds of efficacy reported for PSC (0.7 µg/mL for prophylaxis and 1.25 mg/mL for treatment) 11,12 , antifungal TDM is gaining increasingly importance for selected populations such as AML patients.…”

“…Antifungal agents of the azole class are metabolized by the cytochrome P450 (CYP450) system, such as voriconazole (VRC, Figure 1), a widely used broad-spectrum triazole substrate of CYP2C19, CYP3A4 and CYP2C9 isoforms [2]. Posaconazole (PSC, Figure 2), instead, likewise broad-spectrum triazole, is also substrate of CYP3A4 but primarly undergoes glucuronidation [3,4], leading to a potential for drug-drug interactions minor than that for VRC [1]. Then, co-administration of drugs that induce CYP450 metabolism can result in undetectable circulating levels of VRC and PSC, while coadministration of CYP450 inhibitors may cause an increase of these levels.…”

“…Due to polypharmacy and complexity of comorbidities in haematology patient population, antifungal therapy may be often associated with significant toxicity or drug interactions, leading to sub-therapeutic antifungal drug concentrations and poorer clinical outcomes [1]. Antifungal agents of the azole class are metabolized by the cytochrome P450 (CYP450) system, such as voriconazole (VRC, Figure 1), a widely used broad-spectrum triazole substrate of CYP2C19, CYP3A4 and CYP2C9 isoforms [2].…”