Japanese guidelines on voriconazole therapeutic drug monitoring (TDM) provide recommendations for the general population. The guideline recommends obtaining trough levels at an achieved steady state, specifically between days 5 and 7 of therapy. A target trough level ≥1-2 μg/mL is recommended in terms of clinical efficacy; a trough level >4-5 μg/mL may suggest elevated liver function test (LFT). Studies have shown that voriconazole blood trough levels are associated with adverse events when the levels exceed 4 mcg/mL. Elevation of hepatic enzymes is typically seen when trough levels are >6 mcg/mL. Unfortunately, these guidelines do not give a dose adjustment protocol based on TDM, nor do they mention TDM guidance for extracorporeal membrane oxygenation (ECMO). [1]
Voriconazole is a highly lipophilic and highly protein-bound (58%) drug, with ex-vivo studies reporting up to 71% drug loss and case studies supporting this data by reporting subtherapeutic drug levels while on ECMO. Both ex-vivo studies and case reports suggest binding site saturation to be the cause for fluctuating drug concentrations in critically ill patients on ECMO. [2], [3]
A 2023 systematic review assessed anti-fungal pharmacokinetics (PK) profiles in critically ill adult and pediatric patients supported by ECMO in hopes of providing guidance for clinicians. The review included 2 retrospective studies and 8 case reports with patients who received voriconazole while on ECMO. Several case reports found significant sequestration of highly lipophilic and protein-bound voriconazole within the ECMO circuit; and therefore recommended TDM. One case report found initial high loading and daily doses of voriconazole to result in drug accumulation over time and PK variability, and also possibly a sudden drop in drug plasma levels after membrane change. However, results from one case report and a retrospective multi-center study did not support these findings. Additional considerations that may impact voriconazole exposure in critically ill patients include the severity of organ dysfunction (SOFA scores), CYP2C19 genotype status, and hypoalbuminemia. [2]
Another 2023 review focused on the potential impact of ECMO on the PK of antifungals in adults. A multi-center retrospective study (N= 69 patients; 337 samples) did not observe a significant difference in subtherapeutic voriconazole plasma levels (<2 mg/L) during ECMO (57% of samples) and before/after ECMO (39% of samples); additionally, no PK variability and independent effects of ECMO were found (see Table 1). On the other hand, a single-center retrospective study (N= 132) demonstrated ECMO patients to have significantly lower median voriconazole trough concentrations compared to non-ECMO patients (p<0.001), with subtherapeutic concentrations (<2 mg/L) being higher in the ECMO group (p<0.001) (see Table 2). Required dose escalation due to subtherapeutic voriconazole levels in ECMO patients has been reported. Case reports include preemptive increased voriconazole dosing in anticipation of drug loss with ECMO initiation, resulting in supratherapeutic trough levels, supporting the hypothesis of saturation of the binding sites in the ECMO circuits. Another case report compared PK profiles before and after initiation of ECMO, with ECMO trough levels being slightly lower than levels without ECMO; however, peak levels and area under the curve (AUC) from 0 to 6 hours were comparable. When discontinuing ECMO, one case report suggested empirically decreasing voriconazole doses by 40-50% in addition to TDM. [3]
Due to the non-linear PK of voriconazole and inconsistent study results, possibly due to differences in materials used for ECMO tubing and oxygenators, experts recommend TDM to optimize voriconazole therapy. Unfortunately, these reviews do not provide specific TDM guidance and recommendations for voriconazole in ECMO patients. It is also worth noting that neither of these systematic reviews included CYP2C19 genetic testing, which can impact voriconazole exposure. [2], [3]