Using a compartmental approach to estimate the absolute bioavailability of erlotinib, a small molecule inhibitor of the epidermal growth factor receptor (EGFR)

Background Erlotinib hydrochloride (E) as a single agent has been demonstrated to prolong survival in patients with advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. An absolute oral bioavailability (F) study of the 150 mg tablet was performed in healthy volunteers. A relatively conservative dose of 25 mg IV was selected for this study to assure safety. Using the non‐compartmental approach, the absolute F was estimated to be >100%. The different half‐lives (21 h oral vs. 13h i.v.) suggested possible differences in CL in the two dose groups. Objective To determine if a compartmental approach that considered the CL difference in the two dose groups would provide a more reliable estimate of F. Methods Data included 18 subjects receiving erlotinib 25 mg as a 30‐minute infusion and 150 mg tablet in a 2‐way randomized cross over study. Four different models were evaluated to determine the most appropriate model to fit the data. Individual F and other PK parameters were estimated by fitting oral and i.v. data simultaneously using the POSTHOC option in NONMEM. Results A two‐compartment model with nonlinear elimination provided the best fit of the data and was able to account for the differences in elimination of erlotinib, presumably due to the 6‐fold difference in dose. The model‐based analysis provided an estimate of F of 59%, which was consistent with observed preclinical data. Conclusion The results indicate that the compartmental model provided a reasonable estimate of F of E. Clinical Pharmacology & Therapeutics (2005) 77 , P37–P37; doi: 10.1016/j.clpt.2004.12.035