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 (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 .

Methods: A 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.

Results: There 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.

Significance: The 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.

Keywords: TDM; TSC; dose; refractory; seizures.

Figure 1

Everolimus observed C _min concentrations (ng/mL) during the core phase. A, Observed C _min by randomized everolimus treatment arms. HE, high exposure; LE, low exposure. This figure shows that everolimus LE arm achieved the target C _min of 3‐7 ng/mL starting at week 1, with the median C _min maintained within the target range during the core phase. The everolimus HE arm had similar C _min values as the LE arm at week 1 because the same starting doses were administered to both treatment arms, and then gradually increased toward the end of the core phase. Overlapping but notable differences were seen in the exposures achieved in the everolimus LE and HE arms. B, Proportion of patients by exposure ranges based on everolimus (EVE) observed C _min. This figure displays the proportion of patients with their observed everolimus C _min ranges during the core phase. The majority of the patients had their everolimus C _min within the target trough range of 5‐15 ng/mL. The red arrows denote the 2 exposure ranges of everolimus patients who were targeted to achieve LE, 3‐7 ng/mL and HE, 9‐15 ng/mL

Figure 2

Relationship between predose everolimus concentrations (C _min) and dose (mg/m²) in patients with tuberous sclerosis complex (TSC)‐associated seizures in all age ranges. This figure shows a trend indicating an increase in predose everolimus C _min with increase in doses for patients with TSC seizures across all the age ranges

Figure 3

Everolimus exposure‐response relationships. A, Effect of everolimus time‐normalized (TN)‐C _min on response rate. Error bars represent 95% confidence intervals of median. TN‐C _min denotes an estimated average of C _min across the maintenance period of the core phase. This figure shows an improvement in seizure response rates with an increase in everolimus TN‐C _min. Reduction in seizure frequency (SF) among patients with an average exposure of <3 ng/mL was similar to that in patients treated with placebo. B, Effect of everolimus TN‐C _min on median percentage reduction in SF. Error bars represent 95% confidence intervals of median. This figure depicts an improvement in the median percentage reduction in SF with increase in everolimus TN‐C _min. Reduction in SF among patients with an average exposure of <3 ng/mL was similar to that in patients treated with placebo. C, Relationship between median percentage reduction in SF and TN‐C _min. The straight line in the figure stands for a linear regression. This figure depicts the percentage reduction in SF with increase in everolimus TN‐C _min in both everolimus low‐exposure and high‐exposure arms. The modeling data confirm that a twofold increase in TN‐C _min reduced postbaseline SF by 28%. D, Baseline‐adjusted change of SF by TN‐C _min during the maintenance period of the core phase. This figure presents a model‐based approach to determine the lowest TN‐C _min for which a response in SF (represented by fold change from baseline in SF) was statistically different between everolimus and placebo. The predicted fold change from baseline in SF for patients taking placebo was presented as a straight line at −0.25 with light gray colored 95% confidence interval (CI) representing the 15% reduction in SF demonstrated in the placebo treatment arm with zero exposure to everolimus. The predicted fold change from baseline reduction in SF for patients taking everolimus increases as TN‐C _min increases. A TN‐C _min of 5.3 ng/mL was considered the lowest everolimus exposure level for which 95% CI of predicted change from baseline SF (0.537‐0.695) did not overlap with the 95% CI of predicted change from baseline SF of placebo (0.696‐0.879), indicating this as the lower bound of the therapeutic range

Figure 4

Box plots of predicted predose everolimus concentration (C _min) after the starting dose and over 5 dose titrations by age range based on the recommended starting dose scheme. Recommended starting dose scheme: 6 mg/m²/d and 5 mg/m²/d for patients aged <6 years and 5 mg/m²/d for patients > or = 6 years ≥ 6 years, respectively. Titration dose scheme: 1‐4 mg. The figure shows that 25‐75 percentile of the predicted C _min was within the target 5‐15 ng/mL range after 1‐2 dose titrations