Population Pharmacokinetics and Exposure-response of Trametinib, a MEK Inhibitor, in Patients with BRAF V600 Mutation-positive Melanoma

The purpose of this study was to characterize the pharmacokinetics of oral trametinib, a first in class MEK inhibitor, identify covariates, and describe the relationship between exposure and clinical effects in patients with BRAF V600 metastatic melanoma. Trametinib concentrations obtained in three clinical studies were included in the population pharmacokinetic analysis. Trametinib 2 mg once daily was … Continued

Onartuzumab with or without Bevacizumab in Combination with Weekly Paclitaxel Does Not Prolong QTc or Adversely Affect Other ECG Parameters in Patients with Locally Recurrent or Metastatic Triple-negative Breast Cancer

The purpose of this study was to examine the potential effect of onartuzumab, when administered with or without bevacizumab in combination with weekly paclitaxel, on the corrected QT interval (QTc) and other electrocardiogram (ECG) parameters, was investigated in a randomized, phase 2 study OAM4861g of first- or second-line therapy in patients with locally recurrent or … Continued

Exposure-response Analysis of Pertuzumab in HER2-positive Metastatic Breast Cancer: Absence of Effect on QTc Prolongation and Other ECG Parameters

The phase III trial of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel for first-line treatment of HER2-positive metastatic breast cancer included a substudy to determine whether pertuzumab affected the corrected QT (QTc) interval or other electrocardiogram parameters. Triplicate 12-lead electrocardiogram measurements and serum samples were collected before (-30 and -15 min) … Continued

Physiologically-based Pharmacokinetic Models for Everolimus and Sorafenib in Mice

Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved as an immunosuppressant and for second-line therapy of hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). Sorafenib is a multikinase inhibitor used as first-line therapy in HCC and RCC. This study assessed the pharmacokinetics (PK) of everolimus and sorafenib alone and in combination in plasma … Continued

Synergistic Interactions between Sorafenib and Everolimus in Pancreatic Cancer Xenografts in Mice

Molecular targeting of cellular signaling pathways is a promising approach in cancer therapy, but often fails to achieve sustained benefit because of the activation of collateral cancer cell survival and proliferation pathways. We tested the hypothesis that a combination of targeted agents that inhibit compensatory pathways would be more effective than single agents in controlling … Continued

Exposure-response Relationship of AMG 386 in Combination with Weekly Paclitaxel in Recurrent Ovarian Cancer and Its Implication for Dose Selection

The purpose of this study was to characterize exposure–response relationships of AMG 386 in a phase 2 study in advanced ovarian cancer for the facilitation of dose selection in future studies. A population pharmacokinetic model of AMG 386 (N = 141) was developed and applied in an exposure–response analysis using data from patients (N = … Continued

Evaluation of Combined Bevacizumab and Intraperitoneal Carboplatin or Paclitaxel Therapy in a Mouse Model of Ovarian Cancer

The purpose of this was to evaluate the pharmacokinetics of bevacizumab following IP and IV administration, and to investigate combined bevacizumab therapy (IP or IV) with IP paclitaxel or carboplatin in a mouse model of ovarian cancer. Bevacizumab pharmacokinetics were investigated following IV or IP dosing, and mice bearing peritoneal A2780 xenografts were treated with … Continued

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