A study published in Epilepsia demonstrates that the recommended therapeutic drug monitoring (TDM) strategy in patients with tuberous sclerosis complex-associated seizures should be comprised of targeting the pre-dose everolimus concentration (Cmin) within an initial range of 5 to 7 ng/mL as well as 5 to 15 ng/mL if clinical response is inadequate.

Participants with tuberous sclerosis complex and refractory partial onset seizures from the EXIST-3 (EXamining everolimus In a Study of Tuberous sclerosis complex) study were randomly assigned to receive either low-exposure everolimus (3 to 7 ng/mL, n=117), high-exposure everolimus (9 to 15 ng/mL, n=130), or placebo (n=119). In the EXIST-3 trial, patients were stratified by age subgroups, including age <6, 6 to 12, 12 to 18, and ≥18. For this secondary analysis, investigators used a model-based approach to predict daily Cmin in this population. Change from baseline in seizure frequency for each everolimus target ranges comprised the primary efficacy outcome.

Response rates for exposure ranges of 3 to 7 ng/mL, >7 to 9 ng/mL, and 9 to 15 ng/mL were 29.9% (95% CI, 22.7%-38.0%), 44.2% (95% CI, 30.5%-58.7%) and 50% (95% CI, 31.3%-68.7%), respectively. The primary efficacy outcome was achieved in a higher percentage of patients in the exposure range of 9 to 15 ng/mL compared with patients in the 3 to 7 ng/mL and >7 to 9 ng/mL ranges (47.7%; 95% CI, 36.5%-66.3% vs 35.6%; 95% CI, 24.4%-41.9% and 39.7%; 95% CI, 28.0%-62.8%, respectively). An analysis stratified by age group demonstrated a 2-fold increase in time-normalized Cmin that correlated with a 2.17-fold increase in response odds (95% CI, 1.339-3.524).

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The researchers noted that there were limited data on Cmin values of >15 ng/mL, which limited safety assessments for exposure to additional ranges.

Additional findings from this study demonstrated that initial “starting doses to achieve such a target TDM range with flexible titration increments of 1 to 4 mg are recommended based on age and status of CYP3A4/P-glycoprotein inducers.”


Franz DN, Lawson JA, Yapici Z, et al. Everolimus dosing recommendations for tuberous sclerosis complex-associated refractory seizures [published online May 4, 2018]. Epilepsia. doi:10.1111/epi.14085