Related Experiment Video

Updated: Jul 5, 2025

Encapsulation of Cancer Therapeutic Agent Dacarbazine Using Nanostructured Lipid Carrier
07:53

Encapsulation of Cancer Therapeutic Agent Dacarbazine Using Nanostructured Lipid Carrier

Published on: April 26, 2016

11.1K

Effects of H2-Receptor Antagonists on the Exposure of Dacomitinib

Jian Liu1, Swan Lin2, Anthony Huynh3

  • 1Clinical Pharmacology, Pfizer Investment Co., Ltd., Beijing 100010, China.

Pharmaceutics
|January 23, 2024
PubMed

Insights

Histamine-2 receptor antagonists (H2RAs) do not significantly alter dacomitinib exposure in advanced non-small-cell lung cancer (NSCLC) patients. This finding supports the concurrent use of H2RAs with dacomitinib, crucial for managing NSCLC.

Area of Science:

  • Pharmacology
  • Oncology
  • Drug Interactions

Background:

  • Dacomitinib, an irreversible EGFR tyrosine kinase inhibitor, treats advanced non-small-cell lung cancer (NSCLC) with EGFR mutations.
  • Previous studies indicated proton-pump inhibitors reduce dacomitinib exposure.
  • The impact of Histamine-2 receptor antagonists (H2RAs) on dacomitinib exposure required further investigation.

Purpose of the Study:

  • To evaluate the effect of H2RAs on dacomitinib exposure in patients with NSCLC.
  • To assess the clinical relevance of potential drug interactions between dacomitinib and H2RAs.

Main Methods:

  • A within-patient analysis compared steady-state trough concentrations (Ctrough,ss) of dacomitinib and its metabolites with and without H2RAs.
  • Pooled data from 11 clinical studies in NSCLC patients were analyzed using a linear mixed effects model.
  • A physiologically based pharmacokinetic (PBPK) model was developed to simulate the impact of H2RA-induced gastric pH changes on dacomitinib pharmacokinetics.

Main Results:

  • Co-administration with H2RAs resulted in adjusted geometric mean Ctrough,ss values of 86% (parent drug), 104% (metabolite), and 100% (active moiety) relative to dacomitinib alone (p > 0.05).
  • PBPK modeling indicated negligible changes in dacomitinib maximum concentration (Cmax) and area under the curve (AUC) with H2RA use.
  • Statistical analyses showed no significant difference in dacomitinib exposure when used concurrently with H2RAs.

Conclusions:

  • Concomitant use of H2RAs with dacomitinib is not expected to have a clinically significant impact on dacomitinib exposure.
  • These findings support the co-administration of H2RAs and dacomitinib in NSCLC patients.
  • The study provides valuable pharmacokinetic data for managing dacomitinib therapy in combination with acid-reducing agents.
Keywords:
EGFR inhibitordacomitiniboverall survivalpharmacokineticsprogression-free survivalproton-pump inhibitors

More Related Videos

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure09:38

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure

Published on: August 11, 2017

8.8K
Direct Measurement of KDM1A Target Engagement Using Chemoprobe-based Immunoassays11:17

Direct Measurement of KDM1A Target Engagement Using Chemoprobe-based Immunoassays

Published on: June 13, 2019

7.3K

Related Concept Videos

Anticoagulant Drugs: Vitamin K Antagonists and Direct Oral Anticoagulants01:18

Anticoagulant Drugs: Vitamin K Antagonists and Direct Oral Anticoagulants

Oral anticoagulants are vital tools in preventing and treating blood clotting disorders. This diverse class of medications can be categorized as vitamin K antagonists, exemplified by warfarin, and direct thrombin inhibitors (DTIs), such as dabigatran, as well as factor Xa inhibitors, including rivaroxaban.
Warfarin, a prominent vitamin K antagonist family member, exerts its effect by inhibiting the enzyme VKORC1 (vitamin K epoxide reductase complex 1). By hindering this enzyme, warfarin...
1.2K
Acid Suppressive Drugs for Peptic Ulcer Disease: Histamine H2-Receptor Antagonists01:28

Acid Suppressive Drugs for Peptic Ulcer Disease: Histamine H2-Receptor Antagonists

Histamine H2 receptors, which are intricately located on the basolateral membrane of parietal cells, play a crucial role in modulating gastric acid secretion. When released from enterochromaffin-like cells, histamine engages H2 receptors, initiating the cyclic AMP (cAMP) pathway. In this pathway, adenylyl cyclase converts ATP into cAMP, elevating intracellular cAMP levels. The activation of protein kinase A follows, stimulating the proton pump. This stimulation prompts the secretion of hydrogen...
485
Drug-Receptor Interaction: Antagonist01:28

Drug-Receptor Interaction: Antagonist

An antagonist is a drug that binds strongly to a receptor without activating it. An antagonist prevents other molecules, such as neurotransmitters or hormones, from binding to the receptor and triggering a cellular response. Such interaction effectively hinders the normal physiological processes mediated by the receptor, resulting in various pharmacological effects depending on the specific receptor targeted.
Antagonists can be classified as competitive or noncompetitive based on their...
2.9K
Antiplatelet Drugs: Prostaglandin Synthesis, P2Y12 and Glycoprotein IIb/IIIa Inhibitors01:20

Antiplatelet Drugs: Prostaglandin Synthesis, P2Y12 and Glycoprotein IIb/IIIa Inhibitors

Antiplatelet drugs emerge as frontline defenders against the insidious threat of thromboembolic diseases, where abnormal clots obstruct vital blood vessels. These drugs stand as bulwarks, inhibiting platelet aggregation and clot formation, thereby mitigating the risk of life-threatening conditions like myocardial infarction, coronary artery disease, and thrombotic strokes.
Prostaglandin synthesis inhibitors, exemplified by the widely known aspirin, wield their power by irreversibly acetylating...
525
Drug-Receptor Interactions01:29

Drug-Receptor Interactions

Drug-receptor interaction describes the binding of receptors by drugs, but not all drug-receptor interactions result in activation and tissue response. For instance, the binding of agonists activates the receptor to generate a cellular reaction, while antagonists bind to receptors without causing their activation.
Several parameters, such as the drug's affinity for its receptor and its efficacy, which is its ability to activate the receptor, determine the drug's effect on the tissue....
5.2K
Antihypertensive Drugs: Direct Renin Inhibitors01:25

Antihypertensive Drugs: Direct Renin Inhibitors

The renin-angiotensin-aldosterone system (RAAS) is an intricate physiological pathway involving numerous enzymes and hormones, including renin, angiotensin-converting enzyme (ACE), angiotensin I and II, and aldosterone. Imbalances within this system increase the production of angiotensin II and aldosterone. Increased angiotensin II levels promote vasoconstriction and blood pressure elevation. Concurrently, higher aldosterone levels stimulate sodium and water reabsorption in the kidneys,...
631