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

Abstract

REGISTRATION

This trial was registered in the EurdaCT database (2014-004833-25) and the Netherlands Trial Registry (NTR4908).

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.

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 (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).

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.

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 AUC₂₄. These results merit further investigation of the twice-daily schedule in an effort to reduce everolimus toxicity while maintaining treatment efficacy.