Trial reportPloS one2015
Lapatinib Plasma and Tumor Concentrations and Effects on HER Receptor Phosphorylation in Tumor.
Trial report in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT00359190 (A Phase I, Open Label Study of the Safety, Pharmacokinetics and Pharmacodynamics of GW572016 in Once Daily Versus Twice Daily Dosing Regimens in Patients With Treatment- Naive Breast Cancer), which is not on this map. Cited by 20 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
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.
A Phase I, Open Label Study of the Safety, Pharmacokinetics and Pharmacodynamics of GW572016 in Once Daily Versus Twice Daily Dosing Regimens in Patients With Treatment- Naive Breast Cancer
Who cites it
20 citing papers in PubMed, 30 citations in OpenAlex.
- STAT3 Pathways Contribute to β-HCH Interference with Anticancer Tyrosine Kinase Inhibitors.International journal of molecular sciences · 2024Article
- Proteomic assessment of SKBR3/HER2+ breast cancer cellular response to Lapatinib and investigational Ipatasertib kinase inhibitors.Frontiers in pharmacology · 2024Article
- Anticancer pan-ErbB inhibitors reduce inflammation and tissue injury and exert broad-spectrum antiviral effects.The Journal of clinical investigation · 2023Article
- Dissecting sources of variability in patient response to targeted therapy: anti-HER2 therapies as a case study.European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences · 2023Article
- Developing SHP2-based combination therapy for KRAS-amplified cancer.JCI insight · 2023Article
- Pharmacodynamic model of slow reversible binding and its applications in pharmacokinetic/pharmacodynamic modeling: review and tutorial.Journal of pharmacokinetics and pharmacodynamics · 2022Review
- The SARS-CoV-2 targeted human RNA binding proteins network biology to investigate COVID-19 associated manifestations.International journal of biological macromolecules · 2022Article
- Pharmacologic profiling reveals lapatinib as a novel antiviral against SARS-CoV-2 in vitro.Virology · 2022Article
- HROP68: A rare case of medullary pancreatic cancer-characterization and chemosensitivity of the first patient-derived cell line.Frontiers in oncology · 2022Article
- Post-transcriptional screen of cancer amplified genes identifies ERBB2/Her2 signaling as AU-rich mRNA stability-promoting pathway.Oncogenesis · 2021Article
- Selective ERBB2 and BCL2 Inhibition Is Synergistic for Mitochondrial-Mediated Apoptosis in MDS and AML Cells.Molecular cancer research : MCR · 2021Article
- Targeted drug delivery strategies for precision medicines.Nature reviews. Materials · 2021Article
- A quantitative systems pharmacological approach identified activation of JNK signaling pathway as a promising treatment strategy for refractory HER2 positive breast cancer.Journal of pharmacokinetics and pharmacodynamics · 2021Article
- Identification of candidate repurposable drugs to combat COVID-19 using a signature-based approach.Scientific reports · 2021Article
- High Levels of Receptor Tyrosine Kinases in CCM3-Deficient Cells Increase Their Susceptibility to Tyrosine Kinase Inhibition.Biomedicines · 2020Article
- Lapatinib‑induced inhibition of ovarian function is counteracted by the STAT3 pathway both in vivo and in vitro.Oncology reports · 2020Article
- Deregulating MYC in a model of HER2+ breast cancer mimics human intertumoral heterogeneity.The Journal of clinical investigation · 2020Article
- A kinase inhibitor screen identifies a dual cdc7/CDK9 inhibitor to sensitise triple-negative breast cancer to EGFR-targeted therapy.Breast cancer research : BCR · 2019Article
- Hepatocellular Toxicity Associated with Tyrosine Kinase Inhibitors: Mitochondrial Damage and Inhibition of Glycolysis.Frontiers in pharmacology · 2017Article
- Pharmacokinetic-pharmacodynamic-efficacy modeling of the MDM2 inhibitor brigimadlin in glioblastoma patient-derived xenografts.Neuro-oncology advancesArticle
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
13 authors at 7 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeThe paradigm shift in cancer treatment from cytotoxic drugs to tumor targeted therapies poses new challenges, including optimization of dose and schedule based on a biologically effective dose, rather than the historical maximum tolerated dose. Optimal dosing is currently determined using concentrations of tyrosine kinase inhibitors in plasma as a surrogate for tumor concentrations. To examine this plasma-tumor relationship, we explored the association between lapatinib levels in tumor and plasma in mice and humans, and those effects on phosphorylation of human epidermal growth factor receptors (HER) in human tumors. EXPERIMENTAL
designMice bearing BT474 HER2+ human breast cancer xenografts were dosed once or twice daily (BID) with lapatinib. Drug concentrations were measured in blood, tumor, liver, and kidney. In a randomized phase I clinical trial, 28 treatment-naïve female patients with early stage HER2+ breast cancer received lapatinib 1000 or 1500 mg once daily (QD) or 500 mg BID before evaluating steady-state lapatinib levels in plasma and tumor.
resultsIn mice, lapatinib levels were 4-fold higher in tumor than blood with a 4-fold longer half-life. Tumor concentrations exceeded the in vitro IC90 (~ 900 nM or 500 ng/mL) for inhibition of HER2 phosphorylation throughout the 12-hour dosing interval. In patients, tumor levels were 6- and 10-fold higher with QD and BID dosing, respectively, compared to plasma trough levels. The relationship between tumor and plasma concentration was complex, indicating multiple determinants. HER receptor phosphorylation varied depending upon lapatinib tumor concentrations, suggestive of changes in the repertoire of HER homo- and heterodimers.
conclusionPlasma lapatinib concentrations underestimated tumor drug levels, suggesting that optimal dosing should be focused on the site of action to avoid to inappropriate dose escalation. Larger clinical trials are required to determine optimal dose and schedule to achieve tumor concentrations that maximally inhibit HER receptors.
trial registrationCLINICAL
trial registrationNCT00359190.
Indexed as
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.