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

Clin Pharmacokinet. 2018 May;57(5):637-644. doi: 10.1007/s40262-017-0582-9.


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 (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).

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.

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

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism
  • Carcinoma, Renal Cell / drug therapy
  • Carcinoma, Renal Cell / metabolism
  • Cross-Over Studies
  • Everolimus / administration & dosage*
  • Everolimus / adverse effects
  • Everolimus / pharmacokinetics*
  • Female
  • Humans
  • Immunosuppressive Agents / administration & dosage*
  • Immunosuppressive Agents / adverse effects
  • Immunosuppressive Agents / pharmacokinetics*
  • Male
  • Middle Aged
  • Neuroendocrine Tumors / drug therapy
  • Neuroendocrine Tumors / metabolism


  • Antineoplastic Agents
  • Immunosuppressive Agents
  • Everolimus

Associated data

  • EudraCT/2014-004833-25
  • NTR/NTR4908