Model-Informed Drug Development for Everolimus Dosing Selection in Pediatric Infant Patients

Abstract

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/m² 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/m² 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.

Figure 1

Workflow for modeling and simulation framework. EXIST‐1, NCT00789828; EXIST‐2, NCT00790400; EXIST‐3, NCT01713946; PBPK, physiologically‐based pharmacokinetic; PD, pharmacodynamics; PK, pharmacokinetics; PopPD, population PD; PopPK, population PK.

Figure 2

Physiologically‐based pharmacokinetic model prediction of everolimus concentrations in a 6 month old during a 1‐year period. In these simulations, 6 month olds (n = 100) were treated with 2 mg once daily for 1 year either age‐redefining the population with time or not. The blue simulated concentration‐time profile depicts simulations where demographics and physiology are changing with time (age‐redefining with time, i.e., patient is 1.5 years old at the end of the simulation). The gray profile depicts no age refinement with time (i.e., the infant is still 6 months old at the end of the simulation). A difference in exposure (C_min) and clearance at the end of the simulation is apparent for the two modeling scenarios. BSA, body surface area; CL_po, clearance per os; C_min, trough plasma concentration.

Figure 3

Physiologically‐based pharmacokinetic model predicted median daily everolimus blood trough concentration (C_min,blood) values during a 2‐month period in pediatric patients with tuberous sclerosis complex aged 6–24 months at the initial dose in the absence of cytochrome P450 3A4/phosphoglycoprotein inducers. The triangle and circle symbols represent, respectively, 2 and 3 mg doses. Of note, the patients starting everolimus at 8 months had their dose increased to 3 mg at 9 months (green triangles).

Figure 4

Predicted short‐term efficacy of everolimus. RSF, reduction in seizure frequency.

Figure 5

Boxplots of predicted percentage reduction from baseline in SF during 12‐week intervals by baseline SF and by age at start of everolimus. SF, seizure frequency.