The Dissociation of Gefitinib Trough Concentration and Clinical Outcome in NSCLC Patients with EGFR Sensitive Mutations

Abstract

Gefitinib is an essential drug for NSCLC patients harboring EGFR sensitive mutations. The approved dose 250mg/day is based on limited clinical trials, this research aims to explore the relationship between drug exposure and gefitinib response. Ctrough of 87 NSCLC patients harboring EGFR sensitive mutations were determined by LC-MS/MS. The median of Ctrough was 173.9 ng/ml (P25–P75, 130.5–231.2 ng/ml), and cutoff value 200 ng/ml was determined by X-Tile. The PFS between Ctrough < 200 ng/ml and Ctrough ≥ 200 ng/ml groups were not significantly different (17.3 VS 14.8 months; p = 0.258). Ctrough was not significantly associated with rash, diarrhea and hepatotoxicity. Non-smokers enjoyed longer PFS than smokers (18.7 VS 9.3 months; p = 0.025). The results showed that, for NSCLC patients with EGFR sensitive mutations, the PFS in lower trough concentration group were not inferior to that in higher trough concentration group and dose reduction is a rational suggestion for adjustment of dose regimen for aforementioned patients. More clinical trials are warranted to explore the precision dose schedule of gefitinib.

The analysis of pharmacokinetic and pharmacogenomic impact on gefitinib efficacy in advanced non-small cell lung cancer patients: results from a prospective cohort study

“…Haura's study indicated that gefitinib level in tumor was approximately 40-fold higher than its plasma level (29). These findings indicated that the blood C trough of gefitinib is not a good substitute indicator for its concentration in tumor, insistent with the previous research (20). Third, the ratio of gefitinib concentration in tumor to that in plasma is ranged from 1.12-250 to 1 (median 40 to 1), which demonstrated tremendous inter-individual variability (30).…”

“…Both plasma and white blood cells were stored at −80 ℃ until analysis. The plasma of second blood was collected to measure the trough concentration of gefitinib at steady state using validated high-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS) (20). EGFR mutations in primary tumors, metastatic lymph nodes or pleural effusion were detected using direct sequencing or real-time PCR (RT-PCR).…”

Establishment and application of a predictive model for gefitinib-induced severe rash based on pharmacometabolomic profiling and polymorphisms of transporters in non-small cell lung cancer

“…Regarding to gefitinib dosage, Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL-1 and –2) and NEJ002, the 500 mg dose was correlated with higher commonly rash, but the PFS and overall survival (OS) were similar [31] , [32] , [33] . What's more, steady state trough concentration of gefitinib was disassociated with PFS of patients in NSCLC patients with EGFR sensitive mutation [ 34 , 35 ], which was similar in this study ( Fig. 4 C).…”

Optimized Dosing: The Next Step in Precision Medicine in Non-Small-Cell Lung Cancer

“…An exposureresponse relationship might be expected, since the equilibrium of the bound and unbound drug will play a major role in the target occupancy. However, as shown in Table 1, in the current dosing regimens of both drugs, no relationship between plasma exposure and response has been found [21][22][23][24]. Interestingly, lower doses of erlotinib and gefitinib (25-100 mg once daily [QD] and 250 mg on alternating days, respectively) were noninferior to the approved dose of erlotinib 150 mg QD and gefitinib 250 mg QD [24][25][26][27][28][29].…”