FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2010469995> ?p ?o ?g. }

• W2010469995 abstract "Background: MLN2480 is an oral investigational pan-RAF kinase inhibitor currently in Phase I of clinical development. An integrated analysis of clinical PK, nonclinical PK/E and PD/E relationships, and translational PK/PD simulations was performed to help inform selection of dose and schedule for future clinical studies. Methods: Nonclinical PK/E, PK/PD, and PD/E relationships were evaluated at doses of 2 to 37.5 mg/kg QD in the A375 (BRAF mutant) melanoma xenograft model. Tumor PD was characterized by decrease in phosphorylated ERK (pERK) from baseline. A sigmoidal Emax model was fitted to the PK/E data and an inhibitory Emax model to PK/PD data. The PK/E and PK/PD models were used to generate a PD/E relationship, which was characterized by a sigmoidal inhibitory Emax model. Clinical PK was characterized in an ongoing first-in-human (FIH) study and a base population PK model was developed (NONMEM version 7.2). The time course of decrease in tumor pERK was simulated at the clinical maximum tolerated dose (200 mg Q2D) using human population PK parameters and nonclinical PK/PD model parameters corrected for inter-species differences in free fraction. The clinical exposures and simulated PD at 200 mg Q2D were used to provide translational estimates of antitumor activity based on nonclinical PK/E and PD/E relationships. Results: The nonclinical PK/E and PK/PD relationships were characterized by unbound EC50 or IC50 (coefficient of variation [CV]) of 62 ng/mL (20%) and 66 ng/mL (12%), respectively. PD/E analysis indicated that half-maximal tumor growth inhibition (TGI) was associated with a 44% decrease in pERK (CV 7.5%). Clinical PK (n=24) was characterized by rapid absorption (median Tmax 2 hr), low fluctuation at steady-state (mean peak to trough ratio 2.2), and 2.5-fold accumulation after Q2D dosing. Steady-state exposures (AUC0-tau) increased approximately dose-proportionally over 20 to 280 mg Q2D. A one-compartment PK model with first order absorption and elimination adequately described the data (n=26); parameter estimates and interindividual variability (CV%) were 0.73 hr−1 (65%) for Ka, 128 L (35%) for V/F, and 1.6 L/hr (41%) for CL/F. At 200 mg Q2D, time-averaged unbound exposure and predicted decrease in pERK levels were 62 ng/mL and 48%, respectively, translating to 86% and 101% TGI based on the respective nonclinical PK/E and PD/E relationships in the A375 xenograft model. Conclusions: Steady-state exposures at 200 mg Q2D are predicted to result in pERK decreases and antitumor activity associated with tumor stasis in nonclinial models of BRAF mutant melanoma. In ongoing expansion cohorts of an FIH study, tumor PD and antitumor activity are being evaluated in treatment-naive or relapsed/refractory patients with locally advanced or metastatic melanoma, including those with BRAF mutations. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A215. Citation Format: Stephanie Faucette, Jerome Mettetal, Xiaofei Zhou, Jouhara Chouitar, Mayank Patel, Michael Bargfrede, Katherine Galvin, Viviana Bozon, Karthik Venkatakrishnan. Integrated analysis of clinical pharmacokinetics (PK), nonclinical PK/efficacy (E) and pharmacodynamic (PD)/E relationships, and translational PK/PD simulations to guide clinical dose and schedule of MLN2480, an oral investigational pan-RAF kinase inhibitor. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A215." @default.
• W2010469995 created "2016-06-24" @default.
• W2010469995 creator A5003293631 @default.
• W2010469995 creator A5008571021 @default.
• W2010469995 creator A5022752821 @default.
• W2010469995 creator A5030141405 @default.
• W2010469995 creator A5044490765 @default.
• W2010469995 creator A5059923320 @default.
• W2010469995 creator A5070237954 @default.
• W2010469995 creator A5076175695 @default.
• W2010469995 creator A5086497754 @default.
• W2010469995 date "2013-11-01" @default.
• W2010469995 modified "2023-10-18" @default.
• W2010469995 title "Abstract A215: Integrated analysis of clinical pharmacokinetics (PK), nonclinical PK/efficacy (E) and pharmacodynamic (PD)/E relationships, and translational PK/PD simulations to guide clinical dose and schedule of MLN2480, an oral investigational pan-RAF kinase inhibitor." @default.
• W2010469995 doi "https://doi.org/10.1158/1535-7163.targ-13-a215" @default.
• W2010469995 hasPublicationYear "2013" @default.
• W2010469995 type Work @default.
• W2010469995 sameAs 2010469995 @default.
• W2010469995 citedByCount "0" @default.
• W2010469995 crossrefType "proceedings-article" @default.
• W2010469995 hasAuthorship W2010469995A5003293631 @default.
• W2010469995 hasAuthorship W2010469995A5008571021 @default.
• W2010469995 hasAuthorship W2010469995A5022752821 @default.
• W2010469995 hasAuthorship W2010469995A5030141405 @default.
• W2010469995 hasAuthorship W2010469995A5044490765 @default.
• W2010469995 hasAuthorship W2010469995A5059923320 @default.
• W2010469995 hasAuthorship W2010469995A5070237954 @default.
• W2010469995 hasAuthorship W2010469995A5076175695 @default.
• W2010469995 hasAuthorship W2010469995A5086497754 @default.
• W2010469995 hasConcept C111113717 @default.
• W2010469995 hasConcept C112705442 @default.
• W2010469995 hasConcept C2776239304 @default.
• W2010469995 hasConcept C2908647359 @default.
• W2010469995 hasConcept C71924100 @default.
• W2010469995 hasConcept C98274493 @default.
• W2010469995 hasConcept C99454951 @default.
• W2010469995 hasConceptScore W2010469995C111113717 @default.
• W2010469995 hasConceptScore W2010469995C112705442 @default.
• W2010469995 hasConceptScore W2010469995C2776239304 @default.
• W2010469995 hasConceptScore W2010469995C2908647359 @default.
• W2010469995 hasConceptScore W2010469995C71924100 @default.
• W2010469995 hasConceptScore W2010469995C98274493 @default.
• W2010469995 hasConceptScore W2010469995C99454951 @default.
• W2010469995 hasLocation W20104699951 @default.
• W2010469995 hasOpenAccess W2010469995 @default.
• W2010469995 hasPrimaryLocation W20104699951 @default.
• W2010469995 hasRelatedWork W1969971179 @default.
• W2010469995 hasRelatedWork W1972571046 @default.
• W2010469995 hasRelatedWork W2025587649 @default.
• W2010469995 hasRelatedWork W2038785505 @default.
• W2010469995 hasRelatedWork W2046843048 @default.
• W2010469995 hasRelatedWork W2061443461 @default.
• W2010469995 hasRelatedWork W2067125882 @default.
• W2010469995 hasRelatedWork W2080518672 @default.
• W2010469995 hasRelatedWork W2089923741 @default.
• W2010469995 hasRelatedWork W2267692501 @default.
• W2010469995 hasRelatedWork W2281644366 @default.
• W2010469995 hasRelatedWork W2340695156 @default.
• W2010469995 hasRelatedWork W2341616998 @default.
• W2010469995 hasRelatedWork W2481352832 @default.
• W2010469995 hasRelatedWork W2490844072 @default.
• W2010469995 hasRelatedWork W2563744065 @default.
• W2010469995 hasRelatedWork W2785632173 @default.
• W2010469995 hasRelatedWork W2885193200 @default.
• W2010469995 hasRelatedWork W2953630143 @default.
• W2010469995 hasRelatedWork W2992035909 @default.
• W2010469995 isParatext "false" @default.
• W2010469995 isRetracted "false" @default.
• W2010469995 magId "2010469995" @default.
• W2010469995 workType "article" @default.