Everolimus pharmacokinetics and its exposure-toxicity relationship in patients with thyroid cancer

Cancer Chemother Pharmacol. 2016 Jul;78(1):63-71. doi: 10.1007/s00280-016-3050-6. Epub 2016 May 11.


Background: Everolimus is a mTOR inhibitor used for the treatment of different solid malignancies. Many patients treated with the registered fixed 10 mg dose once daily are in need of dose interruptions, reductions or treatment discontinuation due to severe adverse events. This study determined the correlation between systemic everolimus exposure and toxicity. Additionally, the effect of different covariates on everolimus pharmacokinetics (PK) was explored.

Methods: Forty-two patients with advanced thyroid carcinoma were treated with 10 mg everolimus once daily. Serial pharmacokinetic sampling was performed on days 1 and 15. Subsequently, a population PK model was developed using NONMEM to estimate individual PK values used for analysis of an exposure-toxicity relationship. Furthermore, this model was used to investigate the influence of patient characteristics and genetic polymorphisms in genes coding for enzymes relevant in everolimus PK.

Results: Patients who required a dose reduction (n = 18) due to toxicity at any time during treatment had significant higher everolimus exposures [mean AUC0-24 (SD) 600 (274) vs. 395 (129) µg h/L, P = 0.008] than patients without a dose reduction (n = 22). A significant association between everolimus exposure and stomatitis was found in the four-level ordered logistic regression analysis (P = 0.047). The presence of at least one TTT haplotype in the ABCB1 gene was associated with a 21 % decrease in everolimus exposure.

Conclusion: The current study showed that dose reductions and everolimus-induced stomatitis were strongly associated with systemic everolimus drug exposure in patients with cancer. Our findings confirm observations from another study in patients with cancer and show us that everolimus is a good candidate for individualized dosing in patients with cancer. CLINICALTRIAL.

Gov number: NCT01118065.

Keywords: Everolimus; Exposure–toxicity; Individualized dosing; Pharmacogenetics; Population pharmacokinetics.

Publication types

  • Clinical Trial, Phase II

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Area Under Curve
  • Dose-Response Relationship, Drug
  • Everolimus / administration & dosage*
  • Everolimus / adverse effects
  • Everolimus / pharmacokinetics
  • Female
  • Humans
  • Logistic Models
  • Male
  • Middle Aged
  • Models, Biological*
  • Nonlinear Dynamics
  • Polymorphism, Genetic
  • Stomatitis / chemically induced*
  • Stomatitis / epidemiology
  • Thyroid Neoplasms / drug therapy*
  • Thyroid Neoplasms / pathology


  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • Antineoplastic Agents
  • Everolimus

Associated data

  • ClinicalTrials.gov/NCT01118065