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

Background: The 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. Methods: We 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. Results: Eleven 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 (AUC ₂₄ ) 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 AUC ₂₄ 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). Conclusions: We demonstrated that switching from a once-daily to a twice-daily everolimus dose schedule reduces C _max without negatively impacting C _min or AUC ₂₄ . These results merit further investigation of the twice-daily schedule in an effort to reduce everolimus toxicity while maintaining treatment efficacy. Registration: This trial was registered in the EurdaCT database (2014-004833-25) and the Netherlands Trial Registry (NTR4908).