Table 5.

Pharmacokinetic considerations for using triazole antifungals for CAPA

Pharmacokinetic	Clinical manifestation	Recommendations	References
Critical illness (sepsis, altered fluid balance, altered protein binding/hypo-albuminemia, inflammation)	Voriconazole exposures unpredictable in critically ill patients; both low exposures with poor clinical outcomes and elevated exposures increased CNS toxicity are reported especially in the setting of systemic inflammation (0.015 mg/L increase in voriconazole Cmin for every 1 mg/L increase in C-reactive protein)	TDM to confirm adequate voriconazole drug exposuresa Fewer data in critically ill for isavuconazole but TDM could still be considered	[51–53]
Obesity	Increased Vd and CL of posaconazole, decreased serum drug exposures	Voriconazole dose based on adjusted body weight; no adjustment of fixed isavuconazole dose recommended. Posaconazole exposures reduced in obese patients	[54–56]
Renal replacement therapy	No effect on voriconazole or isavuconazole pharmacokinetics, sulfobutylether-β-cyclodextrin in IV voriconazole formulation is removed by CRRT at rate similar to ultrafiltration rate	TDM of voriconazole recommended even though voriconazole is not cleared by RRT	[57, 58]
ECMO	Initial voriconazole doses are extracted into ECMO circuit; once circuit is saturated “redosing” of patient can occur; limited data with isavuconazole suggested exposures may be reduced by 50%	Patients at risk of voriconazole and isavuconazole underdosing at initiation of ECMO, overdosing of voriconazole at discontinuation. Limited data for isavuconazole Routine TDM-guided dosing essential for voriconazole and may be indicated for isavuconazole	[48, 49]
Drug-interactions	Dexamethasone, methylprednisolone	Limited evidence that corticosteroids reduce voriconazole exposure, TDM-adjusted dosing indicated	[59]

^aVoriconazole C_min of 1–6 mg/L² C_mean 2.98 ± 1.09 mg/L