Search

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., (© 2020 Novartis Pharmaceutical Company. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

We compared the powers of the likelihood ratio test (LRT) and the Pearson correlation test (CT) from empirical Bayes estimates (EBEs) for various designs and shrinkages in the context of nonlinear mixed-effect modeling. Clinical trial simulation was performed with a simple pharmacokinetic model with various weight (WT) effects on volume (V). Data sets were analyzed with NONMEM 7.2 using first-order conditional estimation with interaction and stochastic approximation expectation maximization algorithms. The powers of LRT and CT in detecting the link between individual WT and V or clearance were computed to explore hidden or induced correlations, respectively. Although the different designs and variabilities could be related to the large shrinkage of the EBEs, type 1 errors and powers were similar in LRT and CT in all cases. Power was mostly influenced by covariate effect size and, to a lesser extent, by the informativeness of the design. Further studies with more models are needed.