Autoinduction of Voriconazole Metabolism in a Child with Invasive Pulmonary Aspergillosis

Abstract

Inter- and intra-patient variability in voriconazole pharmacokinetics has been described in children as the result of age-specific differences in hepatic metabolism, saturable nonlinear pharmacokinetics, CYP450 2C19 polymorphisms, decreased bioavailability compared with adults, and drug-drug interactions. We introduce dose-dependent autoinduction of metabolism as another cause for altered voriconazole pharmacokinetics in children and summarize previously published literature on this phenomenon. A 10-year-old girl with severe aplastic anemia developed invasive pulmonary aspergillosis after high-dose cyclophosphamide therapy and required high doses of voriconazole for longer than 2 months. She initially achieved a therapeutic trough of 1.4 μg/ml on voriconazole 11 mg/kg/dose orally every 12 hours but required dose escalations to 9.3 mg/kg/dose orally every 8 hours to maintain a trough above 1 μg/ml. Because there were no changes in concomitant medications, route of administration, adherence, or oral intake, we conclude that the only plausible explanation for the precipitous drop in voriconazole troughs was autoinduction of metabolism, a phenomenon previously reported in adults receiving higher than usual doses or prolonged courses (longer than 2 months). These data highlight the need for continued therapeutic drug monitoring of voriconazole after initial therapeutic troughs are achieved because autoinduction of metabolism can lead to significant declines in subsequent voriconazole troughs, potentially leading to treatment failure.

An Optimized Voriconazole Dosing Strategy to Achieve Therapeutic Serum Concentrations in Children Younger than 2 Years Old

“…Although expression of FMO3 is similar in children and adults, it seems to contribute to higher metabolic clearance of voriconazole in children versus adults . In addition, autoinduction has been reported, which may further explain the difficulty in achieving and maintaining voriconazole serum trough concentrations in the desired range …”

“…22 In addition, autoinduction has been reported, which may further explain the difficulty in achieving and maintaining voriconazole serum trough concentrations in the desired range. 24 Additional strategies have been proposed to inform voriconazole dosing decisions before obtaining the first TDM result. Bayesian modeling-based tools are in development to use existing pharmacokinetic data to rapidly individualize voriconazole therapy in children.…”

Voriconazole Autoinduction and Saturable Metabolism After Cessation of Rifampin in a Patient With Invasive Central Nervous System Aspergillus: Importance of Therapeutic Drug Monitoring

“…Her initial trough level was therapeutic at 1.4 mg/mL on voriconazole 11 mg/kg/dose PO every 12 hours but required dose titration up to 9.3 mg/kg/dose PO every 8 hours to keep the trough level above 1 mg/mL. 24 More recently, Ferguson et al reported a case of autoinduction with voriconazole in a 36-year-old female being treated for CNS aspergillosis after immunosuppression treatment of suspected atypical hemolytic uremic syndrome/thrombotic thrombocytopenic purpura. She was started on voriconazole IV 6 mg/kg (500 mg) every 12 hours  2 doses followed by 4 mg/kg (320 mg) every 12 hours.…”

Voriconazole-Induced Periostitis & Enthesopathy in Solid Organ Transplant Patients: Case Reports

“…Voriconazole inhibits metabolism of the immunosupressant tacrolimus [24] [25]. Whether impaired voriconazole clearance and/or altered metabolism leads to periosteal changes, needs further study [28]. In 2015, Naito et al .…”