Clinical pharmacokinetics of erlotinib in patients with solid tumors and exposure-safety relationship in patients with non-small cell lung cancer

Clin Pharmacol Ther. 2006 Aug;80(2):136-45. doi: 10.1016/j.clpt.2006.04.007.


Objective: Our objective was to assess the pharmacokinetics of erlotinib in a large patient population with solid tumors, identify covariates, and explore relationships between exposure and safety outcomes (rash and diarrhea) in patients with non-small cell lung cancer receiving single-agent erlotinib.

Methods: The population pharmacokinetic analysis was performed by use of NONMEM based on 4068 concentration samples from 1047 patients receiving erlotinib as a single agent or in combination with chemotherapy. By use of a 1-compartment model with first-order absorption, the influence of demographic and clinical characteristics on clearance and volume was examined. Spearman rank correlation analyses were performed to test for correlations between maximum grades of rash and diarrhea and erlotinib exposure in non-small cell lung cancer patients treated with single-agent erlotinib.

Results: On the basis of the final model developed from patients treated with erlotinib as a single agent, the oral clearance was 3.95 L/h, the oral volume of distribution was 233 L, and the absorption rate was 0.95 h(-1). The median erlotinib half-life based on this patient population was 36.2 hours. Total bilirubin, alpha1-acid glycoprotein, and smoking status were the most important factors affecting clearance. The clearance in current smokers was 24% faster than that in former smokers or those who never smoked. There was a statistically significant correlation between drug exposure and rash (P < .05). However, there was significant overlap in the range of values for patients who had no rash (grade = 0) and those who had any grade of rash. No significant correlation was found between exposure and diarrhea.

Conclusions: The long half-life of erlotinib supports the current once-daily dosing regimen at 150 mg/d. Effects of covariates on erlotinib clearance and correlations with adverse event severity were provided to aid in the detection of a treatment-emergent effect.

Publication types

  • Clinical Trial, Phase III
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Algorithms
  • Analysis of Variance
  • Area Under Curve
  • Biotransformation
  • Carcinoma, Non-Small-Cell Lung / complications*
  • Diarrhea / chemically induced
  • Drug Eruptions / epidemiology
  • Erlotinib Hydrochloride
  • Female
  • Humans
  • Lung Neoplasms / complications*
  • Male
  • Middle Aged
  • Models, Statistical
  • Neoplasms / metabolism*
  • Population
  • Protein Kinases / administration & dosage
  • Protein Kinases / adverse effects*
  • Protein Kinases / pharmacokinetics*
  • Quinazolines / administration & dosage
  • Quinazolines / adverse effects*
  • Quinazolines / pharmacokinetics*


  • Quinazolines
  • Erlotinib Hydrochloride
  • Protein Kinases