PP-46 Voriconazole dosing strategies in young children: challenges and recommendations

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Abstract

Background

Voriconazole pharmacokinetics (PK) have been studied in paediatric studies and described by popu-lation pharmacokinetic modelling.1 Using the currently approved intravenous (IV) dosing regimen,2,3 paediatric patients provided 30 trough samples resulting in a ob-served median (range) of 1.2 (0.11–17.4) mg/L.1 This illustrates the highly variable pharmacokinetic (PK) pro-file of voriconazole in children. The aim of this case series is to evaluate the effectiveness of dosing guidelines in combination with routine therapeutic drug monitoring (TDM) to achieve therapeutic serum concentrations of voriconazole in young cancer patients (age 0–6 years old).

Methods

At the VUmc, paediatric patients are treated using TDM. Voriconazole plasma concentrations are monitored and dosing regimens are individualised, aiming at trough levels of 1–6 mg/L depending on the location of the Asper-gillus. A case series of 4 children (age 0–6 years) is presented.

Results

Highly variable voriconazole exposure (n=4) were observed. Case 1 Boy, 13 months, acute myeloid leukaemia: Loading dose 9 mg/kg tid (IV), maintenance 8 mg/kg tid (IV) [2] resulted in supratherapeutic levels, hepatic toxicity and circulatory insufficiency. Root cause: CYP2C inhibition by previous prophylactic Itraconazole treatment. Itraconazole has a half-life time up to two days. Therapeutic voriconazole levels achieved at 6 mg/kg tid (IV); Case 2 Boy, 5 years, acute lymphatic leukaemia: Doses varying between 7 mg/kg tid IV and 11 mg/kg tid IV during 4 months of IV therapy. Highly variable trough concentrations varying from 0.10–13.3 mg/L; 65% within the target range of 2–6 mg/L for cerebral Aspergillus: Case 3 Girl, 7 months, mixed phenotype acute leukaemia: Load-ing dose 6 mg/kgbid (IV), maintenance 9 mg/kgbid (PO) resulted in subtherapeutic trough levels (0.1–0.2 mg/L), possibly due to high first pass metabolism. Case 4 Girl, 5 years, acute lymphatic leukaemia: Loading dose 10 mg/kgbid (PO), high maintenance dose of 23 mg/kgbid (PO) re-sulted in therapeutic levels. Higher doses of 30 mg/kgbid resulted in a more than dose-proportional increase of ex-posure (trough level 22 mg/L), suggesting non-linear PK.

Conclusion

Voriconazole PK is highly variable in pedi-atric cancer patients, which can only partly be attributed to drug interactions and co-morbidities. A starting dose of 18 mg/kg (IV) is recommended and could be adminis-tered as 6 mg/kg tid (IV).2 Intensive TDM (at least twice weekly) and daily in-depth status reviews are recom-mended to achieve therapeutic drug levels.

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