Consensus guidelines for optimising antifungal drug delivery and monitoring to avoid toxicity and improve outcomes in patients with haematological malignancy, 2014

Abstract

Antifungal agents may be associated with significant toxicity or drug interactions leading to sub-therapeutic antifungal drug concentrations and poorer clinical outcomes for patients with haematological malignancy. These risks may be minimised by clinical assessment, laboratory monitoring, avoidance of particular drug combinations and dose modification. 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. Therapeutic drug monitoring (TDM) of antifungal agents is warranted, especially where non-compliance, non-linear pharmacokinetics, inadequate absorption, a narrow therapeutic window, suspected drug interaction or unexpected toxicity are encountered. Recommended indications for voriconazole and posaconazole TDM in the clinical management of haematology patients are provided. With emerging knowledge regarding the impact of pharmacogenomics upon metabolism of azole agents (particularly voriconazole), potential applications of pharmacogenomic evaluation to clinical practice are proposed.

Therapeutic Drug Monitoring and Genotypic Screening in the Clinical Use of Voriconazole

“…While CYP2C19 genotype data may explain variability of voriconazole serum levels, they alone are not sufficient to guide initial dosing. This is in agreement with several reviews that state further research is needed before the widespread implementation of clinical voriconazole pharmacogenomics [12,14,93,94]. …”

“…However, there is a paucity of guidelines for pharmacogenomic testing in patients treated with voriconazole. Common side effects of voriconazole include hepatotoxicity, neurotoxicity, blurry vision, skin rash and hyperfluorosis [14]. Some of these adverse effects are more likely to occur at higher than necessary voriconazole serum/plasma concentrations, while low voriconazole levels may result in therapeutic failure [12].…”

Bioassay for Determining Voriconazole Serum Levels in Patients Receiving Combination Therapy with Echinocandins

“…A small volume of serum was utilized, which may be particularly important for neonates. The LLOQ and the linearity range obtained by our in-house technique are slightly better than those of previously reported methods (9,11,12), covering what is currently believed to be the therapeutic range for voriconazole concentrations in human blood (25,26), while the concordance with the reference method is improved (9,11,12) or comparable (8,10,13) to that from other studies. Like in a previously published assay (9), voriconazole concentrations measured by HPLC were marginally higher than bioassay levels, although nonsignificantly higher drug concentrations were also found with bioassays than those with HPLC (8).…”

“…1. The lower limit of quantification (LLOQ) was determined to be 0.25 mg/ liter, and the bioassay was internally validated over the range of 0.25 to 8 mg/liter, which includes the therapeutic window, as previously found (25,26). Drug concentrations correlated linearly with the inhibition zone diameter (r 2 ϭ 0.98, P Ͻ 0.0001) with mean (range) intra-and interexperimental variation of 6% (0 to 12%) among all drug concentrations tested, which is within the limits of acceptability of data established by international guidelines (27,28).…”

Critical review of current clinical practice guidelines for antifungal therapy in paediatric haematology and oncology

“…We were pleased that a previous version of the Australasian paediatric antifungal guidelines (2007) was included [3], yet note that the comprehensive update of paediatric and adult Australian and New Zealand antifungal guidelines were omitted [4][5][6][7][8][9][10][11][12]. Published in December 2014, these expanded guidelines included manuscripts on prophylaxis, empiric and diagnostic-driven antifungal strategies, treatment of yeast, invasive mould and Pneumocystis jirovecii infection.…”