Ohgami Masahiro, Kaburagi Takayuki, Kurosawa Atsuhiko, Doki Kosuke, Shiozawa Toshihiro, Hizawa Nobuyuki, Homma Masato
Department of Pharmaceutical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
Departments of Pharmacy and.
Ther Drug Monit. 2018 Dec;40(6):699-704. doi: 10.1097/FTD.0000000000000552.
Erlotinib is used for treating non-small cell lung cancer (NSCLC). Intestinal absorption of erlotinib is impaired under gastric pH elevation; therefore, coadministration of gastric acid suppressants may provide lower blood concentration of erlotinib. We investigated the effects of erlotinib coadministration with proton pump inhibitors (PPIs) and histamine H2 receptor blockers (H2RBs) on the plasma concentration of erlotinib and erlotinib-induced adverse reaction in patients with NSCLC.
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 analysis of plasma concentrations of erlotinib, were compared among 3 patient groups: without coadministration of gastric acid suppressants (control group), with coadministration of PPI (PPI group), and coadministration of H2RB (H2RB group).
Patients with grade ≥2 rash had higher plasma concentrations of erlotinib compared with those with grade ≤1 [1.02 (0.43-2.60) versus 0.67 (0.10-1.85) mcg/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) and 0.48 (0.33-0.81) versus 0.51 (0.28-1.28) mcg·mL·mg·kg], where statistical significance was observed between PPI and control groups (P < 0.05). The population pharmacokinetic estimated oral CL/F in the PPI and H2RB groups were higher than that in the control group [5.55 (3.36-14.52) and 4.82 (2.08-6.32) versus 3.95 (2.01-10.44) L/h], where statistical significance was observed between PPI and control groups (P < 0.05).
Plasma concentrations of erlotinib in patients under coadministration of gastric acid suppressants were lower than those without gastric acid suppressants through drug interaction, suppressing the intestinal absorption of erlotinib. The magnitude of this drug interaction was more pronounced in the coadministration of PPI compared with H2RB.
厄洛替尼用于治疗非小细胞肺癌（NSCLC）。在胃内pH值升高时，厄洛替尼的肠道吸收会受损；因此，同时使用胃酸抑制剂可能会使厄洛替尼的血药浓度降低。我们研究了厄洛替尼与质子泵抑制剂（PPI）和组胺H2受体阻滞剂（H2RB）联用对NSCLC患者厄洛替尼血药浓度及厄洛替尼所致不良反应的影响。
本研究招募了42例接受厄洛替尼治疗的NSCLC患者。研究了不良反应（皮疹和腹泻）与厄洛替尼血药浓度之间的关联。比较了3组患者的血浆浓度与剂量（C/D）比值以及口服清除率（CL/F），后者通过对厄洛替尼血浆浓度进行群体药代动力学分析来估算。这3组患者分别为：未同时使用胃酸抑制剂（对照组）、同时使用PPI（PPI组）和同时使用H2RB（H2RB组）。
与皮疹≤1级的患者相比，皮疹≥2级的患者厄洛替尼血浆浓度更高[1.02（0.43 - 2.60）对0.67（0.10 - 1.85）mcg/mL，P < 0.01]。PPI组和H2RB组厄洛替尼的C/D比值低于对照组[0.39（0.08 - 0.76）和0.48（0.33 - 0.81）对0.51（0.28 - 1.28）mcg·mL·mg·kg]，其中PPI组与对照组之间存在统计学差异（P < 0.05）。PPI组和H2RB组群体药代动力学估算的口服CL/F高于对照组[5.55（3.36 - 14.52）和4.82（2.08 - 6.32）对3.95（2.01 -
