Effects of proton pump inhibitor co-administration on the plasma concentration of erlotinib in patients with non-small cell lung cancer.

BACKGROUND: Erlotinib is used for treating non-small cell lung cancer (NSCLC). Intestinal absorption of erlotinib is impaired under gastric pH elevation, therefore, co-administration of gastric acid suppressants may provide lower blood concentration of erlotinib. We investigated the effects of erlotinib co-administration with proton pump inhibitors (PPI) and histamine H2 receptor blockers (H2RB) on the plasma concentration of erlotinib and erlotinib-induced adverse reaction in NSCLC patients.

METHODS: Forty-two patients receiving erlotinib therapy for NSCLC were recruited for this study. Association of adverse reactions (rash and diarrhea) with plasma concentration of erlotinib was examined. Plasma concentration-to-dose (C/D) ratios and oral clearance (CL/F), which was estimated by population pharmacokinetic (PPK) analysis of plasma concentrations of erlotinib, were compared among 3 patient groups: without co-administration of gastric acid suppressants (control group), with co-administration of PPI (PPI group), and co-administration of H2RB (H2RB group).

RESULTS: Patients with grade ≥ 2 rash had higher plasma concentrations of erlotinib compared with those with grade ≤ 1 (1.02 [0.43-2.60] vs. 0.67 [0.10-1.85] µg/mL, P < 0.01). The C/D ratios of erlotinib in the PPI and H2RB groups were lower than that in the control group (0.39 [0.08-0.76], 0.48 [0.33-0.81] vs. 0.51 [0.28-1.28] µg/mL/mg/kg), where statistical significance was observed between PPI and control groups (P < 0.05). The PPK estimated oral CL/F in the PPI and H2RB groups were higher than the control group (5.55 [3.36-14.52], 4.82 [2.08-6.32] vs. 3.95 [2.01-10.44] L/h), where statistical significance was observed between PPI and control groups (P < 0.05).

CONCLUSIONS: Plasma concentrations of erlotinib in patients under co-administration of gastric acid suppressants were lower than those without gastric acid suppressants via drug interaction suppressing the intestinal absorption of erlotinib. The magnitude of this drug interaction was more pronounced in the co-administration of PPI compared with H2RB.