@article{a0cffe5aa38644f0b4bd86d7a8de6bd7,
title = "Everolimus dosing recommendations for tuberous sclerosis complex–associated refractory seizures",
abstract = "Objective: The present analysis examined the exposure-response relationship by means of the predose everolimus concentration (Cmin) and the seizure response in patients with tuberous sclerosis complex–associated seizures in the EXIST-3 study. Recommendations have been made for the target Cmin range of everolimus for therapeutic drug monitoring (TDM) and the doses necessary to achieve this target Cmin. Methods: A model-based approach was used to predict patients' daily Cmin. Time-normalized Cmin (TN-Cmin) was calculated as the average predicted Cmin in a time interval. TN-Cmin 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-Cmin 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-Cmin were not associated with statistically significant increases in the risk of stomatitis or infections. Significance: The recommended TDM is to target everolimus Cmin 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 CYP3A4/P-glycoprotein inducers/inhibitors.",
keywords = "TDM, TSC, dose, refractory, seizures",
author = "Franz, {David N.} and Lawson, {John A.} and Zuhal Yapici and Christian Brandt and Kohrman, {Michael H.} and Michael Wong and Mathieu Milh and Adelheid Wiemer-Kruel and Maurizio Voi and Neva Coello and Wing Cheung and Kai Grosch and French, {Jacqueline A.}",
note = "Funding Information: We thank the patients and their families, the study investigators, and the study site personnel for their participations and contributions to this study. Medical writing and editorial assistance was provided by Ambrin Fatima and Rama Mylapuram, Novartis Healthcare. Funding Information: D.N.F. received speaker honoraria and travel reimbursements from Novartis. His employer, Cincinnati Children{\textquoteright}s Hospital, has received funds for consulting work and research grants from Novartis. J.A.L. received consultation fees and research funding from Novartis. Z.Y. reports no disclosures. C.B. received consultation fees from Novartis and received honoraria from UCB, Eisai, Desitin, USL, SKS, Idorsia, and Novartis. M.H.K. received research funding from Novartis. M.W.{\textquoteright}s employer received research funding from Novartis. M.M. received honoraria from Novartis, Levidcen, Eisai, and Shire for scientific congress, advisory board meetings, and symposiums. A.W.-K. received research funding from Novartis and Nutricia as well as speakers honoraria from UCB, Novartis, Nutricia, and Desitin. M.V. is a Novartis employee. N.C. is a Novar-tis employee. W.C. was an employee of Novartis. K.G. is a Novartis employee. J.A.F. receives New York University (NYU) salary support from the Epilepsy Foundation and for consulting work on behalf of the Epilepsy Study Consortium for Acorda, Adamas, Alexza, Anavex, Axcella Health, Biogen, BioPharm Solutions, Cerecor, Concert Pharmaceuticals, Engage, Eisai, GlaxoSmithKline, GW Pharma, Marinus, Nestle Health Science, Neurelis, Novar-tis, Pfizer, Pfizer-Neusentis, Otzuka, Ovid, Sage Therapeutics, SK Life Sciences, Sunovion, Takeda, UCB, Upsher-Smith, Xenon Pharmaceuticals, Zogenix, and Zynerba. J.A.F. has also received research grants from Acorda, Alexza, Eisai Medical Research, LCGH, Lundbeck, Pfizer, SK Life Sciences, Sunovion, Takeda, and UCB, as well as grants from the Epilepsy Research Foundation, Epilepsy Study Consortium, Epilepsy Therapy Project, and NINDS. She is on the scientific advisory boards of Ovid, Sage Therapeutics, and Blackfynn. She is on the editorial board of Lancet Neurology, Neurology Today, and Epileptic Disorders. She is Scientific Officer for the Epilepsy Foundation, for which NYU receives salary support. She has received travel reimbursement related to research, advisory meetings, or presentation of results at scientific meetings from the Epilepsy Study Consortium, the Epilepsy Foundation, Eisai, GW Pharma, Marinus, Nestle Life Science, Pfizer, Sage, SK Life Sciences, Takeda, UCB, Upsher-Smith, Zogenix, and Zynerba. We confirm that we have read the Journal{\textquoteright}s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Publisher Copyright: {\textcopyright} 2018 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.",
year = "2018",
month = jun,
doi = "10.1111/epi.14085",
language = "English",
volume = "59",
pages = "1188--1197",
journal = "Epilepsia",
issn = "0013-9580",
number = "6",
}