Significant effect of infection and food intake on sirolimus pharmacokinetics and exposure in pediatric patients with acute lymphoblastic leukemia.

BACKGROUND

Sirolimus is increasingly investigated as a new targeted therapy in pediatric populations. To date, population pharmacokinetic (PK) studies have identified several factors that explain in part the large between-patient variability in sirolimus PK. However, within-patient variability in sirolimus PK is not well documented. This study presents examples of model-based PK-guided dosing of sirolimus in children with acute lymphoblastic leukemia (ALL), where patients experienced significant changes in sirolimus blood concentrations due to infection and food intake during the treatment period.

METHODS

Clinical PK data were obtained as part of a prospective pilot study of sirolimus combined with multiagent chemotherapy in pediatric patients with ALL (ClinicalTrial.gov identifier: NCT01658007). A PK model-informed loading dose of 1.8 mg/m2 every 8 h was started on the first day of sirolimus treatment. Subsequent doses were adjusted based on concentration measurements the first blood draw scheduled 24 h into the regimen on the morning of day 2. Sirolimus blood concentrations were determined by a validated LC-MS/MS assay. All dosing recommendations were generated in real time using the PK model with Bayesian estimation.

RESULTS

Three patients were enrolled in this study. Two patients achieved target concentration attainment with the PK model-informed loading dose on day 1 of sirolimus treatment. Subsequent unexpected high sirolimus concentrations were observed in two patients, where patients had flulike symptoms such as fever and cough. A sudden decrease in sirolimus concentrations was observed in one patient after switching sirolimus administration from the fed to the fasting state.

CONCLUSIONS

This study highlights within-patient fluctuations in sirolimus concentrations associated with intercurrent infection and with changes in diet. These findings highlight the challenge of maintaining a target sirolimus concentration as a patient's clinical status changes, and the benefit of intensive monitoring of therapeutic drug levels in children treated with sirolimus. Intra-patient alternations in sirolimus PK due to similar disease/food interactions may be relevant in pediatric patients treated with sirolimus for other disease indications.