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Presenter: Deborah, Marriott, Sydney, Australia
Authors: Deborah Marriott
Fungal infections are an important cause of morbidity and mortality in solid organ transplantation. The associated high mortality rate has resulted in increasingly widespread use of antifungal prophylaxis with azole drugs (voriconazole, posaconazole, itraconazole and fluconazole) the most commonly administered agents. TDM is rarely systematically performed for these drugs; however, more broadly, there is increasing recognition, of the important role of TDM for azole antifungal agents when used for both prophylaxis and treatment.
There is a growing body of evidence highlighting the importance of azole TDM for both efficacy and toxicity in the hematology/bone marrow transplantation setting. However, data in the solid organ transplantation setting is extremely limited, making extrapolation from other patient groups necessary. It is now well recognized in other populations that adequate trough levels are required for efficacy and that high plasma/serum levels may be associated with toxicity, particularly in case of voriconazole.
Voriconazole exhibits linear pharmacokinetics with rapid clearance in children and non-linear pharmacokinetics in adults, and is primarily metabolized by 2C19, 2C9 and, to a lesser extent, 3A4 enzymes of the CyP450 system. Genetic polymorphisms may result in ultra-rapid or slow metabolism. Slow metabolism predominates in the northern Asian populations. Voriconazole levels may vary up to 100-fold following fixed dosing, with the variation apparently unrelated to weight or genotype.
The large degree of inter- and intra-patient variation in voriconazole levels, the question concerning the appropriateness of the recommended dosing regimen and the numerous drug-drug interactions that may influence voriconazole pharmacokinetics suggest an important role for TDM, particularly in view of the increasing evidence that a trough level ≥1.5mg/L is associated with improved outcome and that voriconazole has challenging issues in terms of toxicity.
Evidence for posaconazole TDM in treatment of invasive fungal infection (IFI) is limited to one study by Walsh and colleagues who reported improved clinical outcomes with progressively higher average posaconazole plasma concentrations (PPCs) in the setting of salvage therapy for invasive aspergillosis. A clinical response rate of 74% was achieved in patients with an average PPC of 1.25mg/L, while response dropped to 24% in patients with an average PPC of 0.13mg/L. It is reasonable to aim for a steady state PPC of at least 1mg/L, acknowledging that it may not be possible to achieve this target with dose optimisation or escalation due to saturable absorption. However more recent studies from several authors have confirmed the increased risk of breakthrough invasive fungal infection associated with low posaconazole serum levels. The only publication to measure posaconazole serum levels in cardiothoracic transplant recipients reported 56 levels obtained from 17 patients. Initial levels were ≤0.5, 0.51-0.99 and ≥1mg/L in 47, 29 and 24% of patients respectively. Higher median trough levels (1.55mg/L v 0.34mg/L; p=0.006) were associated with therapeutic success versus failure, and patients with levels consistently >0.5mg/L were more likely to have a successful outcome (p=0.055). In summary there is a limited but evolving body of evidence to support TDM for posaconazole, particularly for patients with recognized risk factors for low serum levels such as use of a proton pump inhibitor or diarrhea.
Fluconazole is generally perceived to be a very safe drug with predictable pharmacokinetics so TDM is rarely performed, regardless of the clinical setting. Treatment guidelines suggest that TDM may be appropriate for sanctuary site infections, treatment of isolates with reduced susceptibility or children. However, published PK data were mainly obtained from healthy volunteers and stable patients with mucosal candidiasis and there is increasing evidence that current dosing regimens may be inadequate in specific patient groups. For example it has been demonstrated by several groups that patients undergoing continuous renal replacement therapy have higher fluconazole clearance and doses of 800 – 1200 mg /day are recommended. Critically ill patients also demonstrate increased fluconazole clearance and may require increased doses (Marriott et al, unpublished data) to achieve serum levels predicted from normal volunteer studies.
In conclusion, it is increasingly recognized that in complex patients such as transplant recipients receiving poly-pharmacy with interacting immuno-suppressive and other agents, and with underlying conditions that alter drug distribution and metabolism such as cystic fibrosis, therapeutic drug monitoring is strongly recommended to optimize efficacy and minimize toxicity.
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