Pharmacokinetic Models to Characterize the Absorption Phase and the Influence of a Proton Pump Inhibitor on the Overall Exposure of Dacomitinib

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.

Effect of Food on the Pharmacokinetics of Limertinib (ASK120067) and its Main Metabolite in Healthy Chinese Volunteers

“…However, coadministration with food does not affect osimertinib exposure, with GMR of 106.05% (range, 94.82%–118.60%) for AUC 0–t and 92.75% (81.40%–105.68%) for C max 21 . A high‐fat, high‐calorie meal has no clinically meaningful effect on the PK of gefitinib 22 or dacomitinib 23 . Therefore, gefitinib, dacomitinib, and osimertinib can be administered with or without food.…”

“…21 A high-fat, high-calorie meal has no clinically meaningful effect on the PK of gefitinib 22 or dacomitinib. 23 Therefore, gefitinib, dacomitinib, and osimertinib can be administered with or without food.…”

Total bodyweight and sex both drive pharmacokinetic variability of fluconazole in obese adults

“…Oneand two-compartment disposition models with linear elimination were tested. Tested approaches to describe oral absorption included first-order absorption (with and without absorption lag time), transit compartment models, 22,23 mixed first-order and zero-order absorption 24,25 and a Weibull function. 25 Since peak concentrations were not discernible within 2 h for most individuals, a simulation and re-estimation approach was performed to confirm the identifiability of F, which was then included with a logit function.…”

Effects of H2-Receptor Antagonists on the Exposure of Dacomitinib

“…The aqueous solubility of dacomitinib is pH dependent, with the highest solubility observed at acidic pH [ 9 ]. A few of clinical studies have been conducted to assess whether the absorption of dacomitinib may be affected by ARAs that increase stomach pH [ 9 , 10 , 11 ].…”