Everolimus dosing recommendations for <scp>tuberous sclerosis complex–</scp>associated refractory seizures

Abstract

Summary Objective The present analysis examined the exposure‐response relationship by means of the predose everolimus concentration ( C min ) and the seizure response in patients with tuberous sclerosis complex–associated seizures in the EXIST ‐3 study. Recommendations have been made for the target C min range of everolimus for therapeutic drug monitoring ( TDM ) and the doses necessary to achieve this target C min . Methods A model‐based approach was used to predict patients' daily C min . Time‐normalized C min ( TN ‐ C min ) was calculated as the average predicted C min in a time interval. TN ‐ C min was used to link exposure to efficacy and safety end points via model‐based approaches. A conditional logistic regression stratified by age subgroup was used to estimate the probability of response in relation to exposure. A multiplicative linear regression model was used to estimate the exposure‐response relationship for seizure frequency ( SF ). An extended Cox regression model was used to link exposure to the time to first adverse event. Results There was a strong, consistent, and highly significant relationship between everolimus exposure and efficacy, measured by TN ‐ C min and SF , regardless of patient's age and concomitant use of cytochrome P450 3A4 (CYP3A4) inhibitors/inducers. Results of an extended Cox regression analyses indicated that twofold increases in TN ‐ C min were not associated with statistically significant increases in the risk of stomatitis or infections. Significance The recommended TDM is to target everolimus C min within a range of 5‐7 ng/mL initially and 5‐15 ng/mL in the event of an inadequate clinical response, and safety is consistent with previous reports. Starting doses depend on age and the concomitant use of CYP 3A4/P‐glycoprotein inducers/inhibitors.