Necessity for a Significant Maintenance Dosage Reduction of Voriconazole in Patients with Severe Liver Cirrhosis (Child–Pugh Class C)

Abstract

Therapeutic drug monitoring for voriconazole, an antifungal agent, is essential for maximizing efficacy and preventing toxicity. The aim of this study was to elucidate the optimal maintenance dose of voriconazole in patients with severe liver cirrhosis (Child-Pugh class C) by reviewing the plasma trough concentrations obtained by therapeutic drug monitoring and daily doses of voriconazole. We retrospectively evaluated 6 patients with Child-Pugh class C cirrhosis who received oral voriconazole treatment and were liver transplant recipients or were awaiting liver transplantation. We compared their voriconazole trough concentrations and daily maintenance doses to those of patients who did not have liver cirrhosis (n=56). We found that plasma voriconazole trough concentrations in all patients with Child-Pugh class C were almost within therapeutic range, and the median plasma trough concentration at steady state was not significantly different from that of patients who did not have liver cirrhosis. In addition, the median daily maintenance dose of voriconazole was significantly lower (2.13 mg/kg/d) than that of the control patients (6.27 mg/kg/d), suggesting that trough voriconazole concentrations are elevated in Child-Pugh class C patients. Thus, we conclude that oral voriconazole maintenance doses in patients with Child-Pugh class C should be reduced to approximately one-third that of patients with normal liver function, with the follow-up dose adjusted by therapeutic drug monitoring.

Pharmacokinetics Modeling and Simulation of Voriconazole Dosing and Safety in Patients with Liver Cirrhosis

“…Thus, the halved dose may be inappropriate in cirrhotic patients for an amount of supratherapeutic voriconazole C min emerged. For CP-C patients, only Yamada et al (25). has provided an optimal voriconazole maintenance dose in CP-C patients; those authors used clinical data from six CP-C patients and concluded that the oral voriconazole maintenance doses should be reduced to one-third of the normal dose.…”

Pre-Existing Liver Disease and Toxicity of Antifungals

“…Individuals with pre-existing liver disease treated with voriconazole had higher rates of severe liver injury than recipients of voriconazole without underlying hepatic disease [81]. A recent single-center retrospective study compared 6 patients with severe liver cirrhosis (Child–Pugh Class C) who were treated with oral voriconazole based on TDM, with 56 individuals without severe liver cirrhosis who received voriconazole in the recommended dosage for IFIs, also under TDM [101]. The daily maintenance doses of voriconazole of the severe cirrhotic patients were in the range of 50 to 200 mg, with a median daily dose at one-third of the median daily dose of the individuals without severe cirrhosis.…”

“…The median trough serum concentration of the drug was within recommended levels in both groups of patients. Thus, the authors argued that a dose reduction to about one-third that of the standard maintenance dose is required in patients with Child–Pugh Class C cirrhosis [101].…”

“…It is well established in the literature that an elevated drug’s level in the serum is correlated with increased risk of toxicity [104,105,106]. Thus, voriconazole TDM is of paramount importance in patients with pre-existing liver disease, since the drug is extensively metabolized by the liver and this population is more difficult to tolerate a deterioration of hepatic function due to voriconazole-induced liver injury [101,102,103,107]. Various target trough concentrations associated with efficacy and safety have been reported, and most experts aim for voriconazole trough serum concentration of more than 1–1.5 μg/mL for efficacy but less than 5–6 μg/mL for avoiding toxicity [58,89,98,104].…”

“…While reduction of voriconazole’s maintenance dose by 50% is recommended in patients with Child–Pugh Class A or B cirrhosis, data for patients with more severe hepatic impairment were lacking until recently. New evidence suggests that dose should be lowered more than 50% in patients with Child–Pugh Class C hepatic dysfunction, and always under TDM for safety and efficacy enhancement [101,102,103,163]. However, optimal dosage in this setting has not formally been defined and this is a noteworthy area of active research.…”