SummaryObjectiveThe 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.MethodsA 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.ResultsThere 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.SignificanceThe 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 CYP3A4/P‐glycoprotein inducers/inhibitors.

Tegaserod (6 mg twice daily) appears to be safe, well-tolerated and effective in the treatment of non-D-IBS over 8 weeks.

Everolimus is currently approved in Europe as an adjunctive therapy for patients aged ≥ 2 years with tuberous sclerosis complex (TSC)-associated treatment-refractory partial-onset seizures, based on the EXIST-3 study (NCT01713946) results. As TSC-associated seizures can also affect children aged between 6 months and 2 years, a modeling and simulation (M&S) approach was undertaken to extrapolate exposure (trough plasma concentration (C min )) after a dose of 6 mg/m 2 and reduction in seizure frequency (RSF). A physiologically based pharmacokinetic model using Simcyp was developed to predict C min in adult and pediatric patients, which was then used by a population pharmacodynamic model and a linear mixed effect model to predict short-term and long-term efficacy in adults (for validation) and in children, respectively. Based on the results of the M&S study, everolimus at the dose of 6 mg/m 2 is anticipated to be an efficacious treatment in children 6 months to 2 years of age (up to 77.8% RSF) with concentrations within the recommended target range.Tuberous sclerosis complex (TSC) is a genetic disorder characterized by multiple benign tumors throughout the body. It is caused by mutations in either the TSC1 or TSC2 genes, resulting in constitutive overactivation of mammalian target of rapamycin. 1 TSC-associated partial-onset seizures (POS), reported in up to 90% of patients, are one of the most common presenting symptoms of TSC. The seizure semiology varies and can change throughout a patient's lifetime. 2 Approximately 60% of the patients remain treatment refractory. 3,4 Everolimus, a mammalian target of rapamycin inhibitor, achieves antitumor activity by inhibiting the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway and by downregulating angiogenesis.5Everolimus received approval in Europe for the adjunctive treatment of patients aged 2 years and older with TSC-associated refractory POS, with or without secondary generalization. This approval was based on the results of EXIST-3 (EXamining everolimus In a Study of Tuberous sclerosis, NCT01713946), a large phase III study in 294 pediatric patients aged 2-18 years with TSC-associated refractory POS, 6 along with data from two previous phase III studies, EXIST-1 (NCT00789828) and EXIST-2 (NCT00790400), 7,8 performed in patients with TSC. The starting dose of everolimus in patients < 6 years of age was 9 and 6 mg/m 2 , respectively, with and without the concomitant administration of cytochrome P450 3A4 (CYP3A4) or phosphoglycoprotein (P-gp) inducers.To inform dosing selection in patients younger than the age of 2 years, we conducted a modeling and simulation (M&S) study to estimate the exposure and efficacy (short term and long term) of everolimus as adjunctive treatment in patients aged > 2 years and extrapolate for patients with TSC-associated refractory POS who started everolimus at 6 months to 2 years of age. Although neonates may also suffer from epilepsy, these are part of a different indication,

Everolimus is approved in Europe and in the USA for the adjunctive treatment of patients aged 2 years and older whose refractory partial-onset seizures, with or without secondary generalization, are associated with tuberous sclerosis complex. The objective of this analysis was to establish a population pharmacokinetic (PK)/pharmacodynamic model describing the relationship between seizure frequency and everolimus exposure to confirm the recommended target concentration range of 5-15 ng/mL. The PK model was a two-compartment model with first order absorption and clearance. CYP3A and P-gp inducers and body-surface area were shown to impact everolimus exposure, justifying dose adjustments. A Poisson distribution was found to adequately describe the random nature of daily seizure counts during the screening phase. A placebo effect on the Poisson seizure mean was implemented as an asymptotic exponential function of time leading to a new steady-state seizure mean. The everolimus effect was implemented as an inhibitory E function of C on the seizure mean, where E exhibited an asymptotic exponential increase over time to a higher steady-state value. Increasing age was found to decrease the baseline seizure mean and to prolong the half-life of the increase in E. The dependence of seizure frequencies on C was explored by simulation. The responder rate increased with increasing C. As C decreased below 5 ng/mL, variability in response became larger and responder rates decreased more rapidly. The results supported the recommended target concentration range for everolimus of 5-15 ng/mL to ensure treatment efficacy.

We provide a brief introduction to estimands and share our perspective on why we think estimands are helpful for the practicing pharmacometrician. The discussion is motivated by the recent release of the International Council for Harmonisation (ICH) E9(R1) guideline on estimands, which describes an aligned framework for planning, conducting, and analyzing clinical trials as well as interpreting sensitivity analyses. We also draw connections to earlier work by Lewis Sheiner.