Abstract
Introduction: Dacomitinib is an epidermal growth factor receptor (EGFR) inhibitor approved for the treatment of metastatic non-small cell lung cancer (NSCLC) in the first line in patients with EGFR activating mutations. Dacomitinib is taken orally once daily at 45 mg with or without food, until disease progression or unacceptable toxicity occurs. Oncology patients often can develop gastroesophageal reflux disease (GERD), which may require management with an acid-reducing agent. Proton pump inhibitors (PPIs), such as rabeprazole, inhibit sodium-potassium adenosine triphosphatase (H+/K+-ATPase) pumps that stimulate acid secretion in the stomach and have a prolonged pharmacodynamic effect that extends beyond 24 h post-administration. The aim of this work was to characterize the absorption of dacomitinib via modeling with a particular interest in quantifying the impact of rabeprazole on the pharmacokinetics (PK) of dacomitinib. Materials and Methods: The pooled dataset consisted of five clinical pharmacology healthy volunteer studies, which collected serial pharmacokinetic concentration-time profiles of dacomitinib. Non-linear mixed effects modeling was carried out to characterize dacomitinib pharmacokinetics in the presence and absence of the concomitant use of a PPI, rabeprazole. Several absorption models, some more empirical, and some more physiologically based, were tested: transit compartment, first-order absorption with and without lag time, and variations of combined zero- and first-order absorption kinetics models. Results: The presence of a PPI was a significant covariate affecting the extent (F) and rate (ka) of dacomitinib absorption, as previously reported in the dedicated clinical study. A transit compartment model was able to best describe the absorption phase of dacomitinib.
Highlights
Dacomitinib is an epidermal growth factor receptor (EGFR) inhibitor approved for the treatment of metastatic non-small cell lung cancer (NSCLC) in the first line in patients with EGFR activating mutations
Dacomitinib is currently approved for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations [1]
When dacomitinib was co-administered with dextromethorphan, the exposure (AUC and Cmax) of dextromethorphan was markedly increased (855.4% and 873.5%, respectively). These results suggest that dacomitinib may increase the exposure of other drugs primarily metabolized by CYP2D6
Summary
Dacomitinib is an epidermal growth factor receptor (EGFR) inhibitor approved for the treatment of metastatic non-small cell lung cancer (NSCLC) in the first line in patients with EGFR activating mutations. Non-linear mixed effects modeling was carried out to characterize dacomitinib pharmacokinetics in the presence and absence of the concomitant use of a PPI, rabeprazole. Dacomitinib is currently approved for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations [1]. In clinical studies in healthy volunteers, following a single oral administration of dacomitinib at 45 mg under fasted conditions, the median time to reach the maximum observed plasma concentration (Tmax) of dacomitinib ranged from 8 to 10 h after dosing. Following a single 45 mg oral dose of dacomitinib, the mean plasma half-life of dacomitinib ranged from 55 to 90 h, and the geometric mean apparent plasma clearance of dacomitinib was approximately 27 to 38 L/h [6,7,8,9,10]
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