Pharmacokinetic Optimization of Everolimus Dosing in Oncology: A Randomized Crossover Trial

Abstract

BackgroundThe mammalian target of rapamycin (mTOR) inhibitor everolimus is used in the treatment of breast cancer, neuroendocrine tumors, and renal cancer. The approved 10 mg once-daily dose is associated with considerable adverse effects and it has been suggested that these are associated with the maximum concentration (C max) of everolimus. Twice-daily dosing might be an alternative strategy with improved tolerability; however, a direct pharmacokinetic comparison of 10 mg once-daily with 5 mg twice-daily dosing is lacking.MethodsWe performed a prospective, randomized, pharmacokinetic, crossover trial comparing everolimus 10 mg once daily with 5 mg twice daily. Patients received the first dose schedule for 2 weeks and then switched to the alternative regimen for 2 weeks. Pharmacokinetic sampling was performed on days 14 and 28.ResultsEleven patients were included in the study, of whom 10 were evaluable for pharmacokinetic analysis. On the 10 mg once-daily schedule, C max, minimum concentration (C min), and area under the concentration-time curve from time zero to 24 h (AUC24) were 61.5 ng/mL [mean percentage coefficient of variation (CV%) 29.6], 9.6 ng/mL (CV% 35.0), and 435 ng h/mL (CV% 28.1), respectively. Switching to the 5 mg twice-daily schedule resulted in a reduction of C max to 40.3 ng/mL (CV% 46.6) (p = 0.013), while maintaining AUC24 at 436 ng h/mL (CV% 34.8) (p = 0.952). C min increased to 13.7 ng/mL (CV% 53.9) (p = 0.018). The overall reduction in C max was 21.2 ng/mL, or 32.7%. The C max/C min ratio was reduced from 6.44 (CV% 36.2) to 3.18 (CV% 35.5) (p < 0.001).ConclusionsWe demonstrated that switching from a once-daily to a twice-daily everolimus dose schedule reduces C max without negatively impacting C min or AUC24. These results merit further investigation of the twice-daily schedule in an effort to reduce everolimus toxicity while maintaining treatment efficacy.RegistrationThis trial was registered in the EurdaCT database (2014-004833-25) and the Netherlands Trial Registry (NTR4908).

Co-targeting EGFR and mTOR with gefitinib and everolimus in triple-negative breast cancer cells

“…The growth inhibitory effects of everolimus and gefitinib were analysed by XTT assay in three TNBC cell lines. The drug concentrations used in this study are close to the median peak plasma concentrations reported in clinical pharmacokinetics studies [31][32][33][34] . We examined the in vitro sensitivity of TNBC cell lines to increasing concentrations (0.1, 1, 10, 100 and 1000 nM) of everolimus alone (Fig.…”

A pharmacological rationale for improved everolimus dosing in oncology and transplant patients

“…Together with the recent study by Verheijen et al . , who showed that dose splitting everolimus 10 mg once daily in 5 mg twice daily resulted in lower maximum concentrations, our findings encourage a prospective study in cancer patients investigating everolimus 10 mg once daily vs . 3.75 mg twice daily in terms of noninferiority for efficacy and superiority for toxicity.…”

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

“…Improvement of formulation and dosing could be beneficial. A twice daily 5 mg dosing instead of once-daily 10 mg regimen conducted on a randomized pharmacokinetic crossover trial of everolimus suggested that such dosing could be promising to reduce adverse toxicity while maintaining treatment efficacy [370]. Nanoparticle-based mTOR targeting would need to be improved as well in order to have more specific effects on tumors and prevent undesirable cellular perturbations [371].…”