ArticleMolecular cancer therapeutics2009
Demonstration of the equivalent pharmacokinetic/pharmacodynamic dosing strategy in a multiple-dose study of gefitinib.
Article in Molecular cancer therapeutics, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
17 citing papers in PubMed.
- Comparing the Efficacy of Two Generations of EGFR-TKIs: An Integrated Drug-Disease Mechanistic Model Approach in EGFR-Mutated Lung Adenocarcinoma.Biomedicines · 2024Article
- Hybrid physiologically-based pharmacokinetic model for remdesivir: Application to SARS-CoV-2.Clinical and translational science · 2021Article
- Therapeutic development of group B Streptococcus meningitis by targeting a host cell signaling network involving EGFR.EMBO molecular medicine · 2021Article
- Array of translational systems pharmacodynamic models of anti-cancer drugs.Journal of pharmacokinetics and pharmacodynamics · 2016Review
- Developing a Physiologically-Based Pharmacokinetic Model Knowledgebase in Support of Provisional Model Construction.PLoS computational biology · 2016Article
- A Whole-Body Physiologically Based Pharmacokinetic Model of Gefitinib in Mice and Scale-Up to Humans.The AAPS journal · 2016Article
- Pharmacokinetics and Pharmacodynamics in Breast Cancer Animal Models.Methods in molecular biology (Clifton, N.J.) · 2016Article
- Successful treatment of EGFR-mutated non-small cell lung cancer with reduced-dose gefitinib: A case report.Experimental and therapeutic medicine · 2015Article
- NT113, a pan-ERBB inhibitor with high brain penetrance, inhibits the growth of glioblastoma xenografts with EGFR amplification.Molecular cancer therapeutics · 2014Article
- Preclinical pharmacological evaluation of a novel multiple kinase inhibitor, ON123300, in brain tumor models.Molecular cancer therapeutics · 2014Article
- Systems pharmacological analysis of paclitaxel-mediated tumor priming that enhances nanocarrier deposition and efficacy.The Journal of pharmacology and experimental therapeutics · 2013Article
- Screening candidate anticancer drugs for brain tumor chemotherapy: pharmacokinetic-driven approach for a series of (E)-N-(substituted aryl)-3-(substituted phenyl)propenamide analogues.Investigational new drugs · 2012Article
- MK-2206, a novel allosteric inhibitor of Akt, synergizes with gefitinib against malignant glioma via modulating both autophagy and apoptosis.Molecular cancer therapeutics · 2012Article
- Evaluation of α2-integrin expression as a biomarker for tumor growth inhibition for the investigational integrin inhibitor E7820 in preclinical and clinical studies.The AAPS journal · 2011Article
- The pharmacokinetic/pharmacodynamic pipeline: translating anticancer drug pharmacology to the clinic.The AAPS journal · 2011Review
- Tyrosine kinase inhibitor gefitinib enhances topotecan penetration of gliomas.Cancer research · 2010Article
- Pharmacokinetic/ pharmacodynamic-driven drug development.The Mount Sinai journal of medicine, New YorkReview
Corrections and comments
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Authors and funding
3 authors.
Funding
Abstract
The goals of this investigation were to illustrate the use of pharmacokinetic (PK)/pharmacodynamic (PD) modeling strategies in drug development based on a multiple-dose study of gefitinib in a preclinical tumor model. Mice bearing s.c. LN229-wild-type epidermal growth factor receptor or LN229-EGFRvIII mutant (a sensitizing mutation) tumors were administered gefitinib at oral doses of either 55 mg/kg/d p.o. x 15 days or 30 mg/kg/d p.o. x 15 days, respectively, as dictated by the equivalent PK/PD dosing strategy. In each tumor group, gefitinib plasma and tumor concentrations were quantitated, as well as the tumoral amounts of phosphorylated-extracellular signal-regulated kinase 1/2 (pERK), a selected PD end point, and tumor size. The resultant data provided the basis to develop hybrid physiologically based PK/PD/tumor growth models for each tumor type. It was found that the 1.83-fold dose difference administered to the two tumor groups resulted in analogous pERK profiles on both days 1 and 15, and further induced similar antitumor efficacy based on tumor size. In addition, using brain tumor patient PK data linked to the pERK PD model, simulations were conducted to illustrate potential applications of a target tumor model to patients. The simulations provided insight on the relationships between blood-brain barrier penetration, brain tumor gefitinib concentrations, and the extent of inhibition of pERK. The implementation of the PK/PD equivalent dosing strategy offers a new approach to drug development.
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Registered trials
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