OBJECTIVE: To assess the influence of the CYP3A4 enzyme inducer rifampin on the pharmacokinetics of the immunosuppressant everolimus to provide guidance for their coadministration. METHODS: In this open-label, single-sequence, crossover study, 12 healthy subjects received a single oral 4-mg dose of everolimus alone and again after an 8-day pretreatment with rifampin 600 mg/d. Urinary excretion of 6β-hydroxycortisol was measured at various time points during rifampin treatment as a marker of CYP3A4 induction. RESULTS: Urine excretion of 6β-hydroxycortisol was significantly elevated during treatment with rifampin compared with prestudy, indicating enzyme induction. When everolimus was coadministered during rifampin treatment, the apparent clearance of everolimus was significantly increased, on average by 172%. This was manifested as a decrease in maximum concentration in all subjects, on average by 58% (range 14–73%). The AUC remained unaffected in 1 subject (although 6β-hydroxycortisol indicated enzyme induction) and decreased in the other 11 subjects. The average decrease in AUC in the full study population was 63% (range 0–82%). Everolimus half-life was reduced significantly, from an average of 32 hours to 24 hours. CONCLUSIONS: In everolimus-treated patients for whom rifampin is indicated, alternative agents with less enzyme induction potential than rifampin could be considered. Alternatively, the dose of everolimus could be individually titrated based on everolimus therapeutic drug monitoring during rifampin therapy.
Carbohydrate Repression of Enzyme Induction in Rat Liver