Population pharmacokinetic analysis of axitinib in healthy volunteers.

Axitinib is a potent and selective second generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3 approved for second line treatment of advanced renal cell carcinoma. The objectives of this analysis were to assess plasma pharmacokinetics and identify covariates that may explain variability in axitinib disposition following single dose administration in healthy […]

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Axitinib in metastatic renal cell carcinoma: results of a pharmacokinetic and pharmacodynamic analysis.

Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, approved for second-line therapy for advanced renal cell carcinoma (RCC). Axitinib population pharmacokinetic and pharmacokinetic/pharmacodynamic relationships were evaluated. Using nonlinear mixed effects modeling with pooled data from 383 healthy volunteers, 181 patients with metastatic RCC, and 26 patients […]

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Population pharmacokinetic modeling of motesanib and its active metabolite, M4, in cancer patients.

Motesanib is a small molecule and potent multikinase inhibitor with antiangiogenic and antitumor activity. Population pharmacokinetic (POPPK) modeling of motesanib and M4, an active metabolite, was performed to assess sources of variability in cancer patients. The analysis included data collected from 451 patients from 8 clinical trials with oral doses of motesanib ranging from 25 […]

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Population pharmacokinetic/pharmacodynamic modeling of tumor growth kinetics in medullary thyroid cancer patients receiving cabozantinib.

Nonlinear mixed effects models were developed to describe the relationship between cabozantinib exposure and target lesion tumor size in a phase III study of patients with progressive metastatic medullary thyroid cancer. These models used cabozantinib exposure estimates from a previously published population pharmacokinetic model for cabozantinib in cancer patients that was updated with data from […]

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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 […]

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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 […]

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Pharmacokinetics of melagatran and the effect on ex vivo coagulation time in orthopaedic surgery patients receiving subcutaneous melagatran and oral ximelagatran: a population model analysis

Ximelagatran, an oral direct thrombin inhibitor, is rapidly bioconverted to melagatran, its active form. The objective of this population analysis was to characterise the pharmacokinetics of melagatran and its effect on activated partial thromboplastin time (APTT), an ex vivo measure of coagulation time, in orthopaedic surgery patients sequentially receiving subcutaneous melagatran and oral ximelagatran as […]

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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 = […]

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Model-based meta-analysis for quantifying Paclitaxel dose response in cancer patients

Model-based meta-analysis of dose response is a sophisticated method to guide dose and regimen selection. In this report, the effects of paclitaxel dose and regimen (weekly or every 3 weeks) on the efficacy and safety in cancer patients were quantified by model-based meta-analysis of 29 monotherapy trials. Logistic regression models were developed to assess the […]

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Therapeutic index of anticoagulants for prevention of venous thromboembolism following orthopedic surgery: a dose-response meta-analysis

Information on the comparative effectiveness of drugs is crucial for drug development decisions, in addition to being needed by regulators, prescribers, and payers. We have carried out a dose-response meta-analysis of three end points each for efficacy and bleeding for various anticoagulants evaluated for the prevention of venous thromboembolism (VTE) following orthopedic surgery to assess […]

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Detection of lymph node metastases by gadolinium-enhanced magnetic resonance imaging: systematic review and meta-analysis

Gadolinium-based contrast agents are used with magnetic resonance imaging (MRI) to highlight tumor vascularity in organs. They are also widely used for primary tumor visualization. We conducted a systematic review and meta-analysis of the existing evidence of the accuracy of gadolinium-enhanced MRI for staging lymph node metastases. We systematically searched the MEDLINE, Cochrane, CANCERLIT, and […]

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Systematic review: diagnostic accuracy of clinical decision rules for venous thromboembolism in elderly

Physicians committed to the care of elderly patients are challenged with the diagnosis of venous thromboembolism (VTE: deep venous thrombosis and pulmonary embolism) due to a higher incidence, co-morbidities masking signs and symptoms and burdening referrals. Clinical decision rules (CDRs) have been developed and implemented for VTE. Yet, until now, no study has evaluated the […]

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Excluding venous thromboembolism using point of care D-dimer tests in outpatients: a diagnostic meta-analysis

This article is a review the evidence on the diagnostic accuracy of the currently available point of care D-dimer tests for excluding venous thromboembolism. We conducted a systematic review of research on the accuracy of point of care D-dimer tests, using bivariate regression to examine sources of variation and to estimate sensitivity and specificity. Studies […]

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Quantitative Systems Pharmacology Brings Value to Drug Development

Quantitative systems pharmacology (QSP) sits at the interface between pharmacometric modeling and simulation, and systems biology. It uses mathematics to describe biological processes. While pharmacokinetics describes what the body does to the drug, pharmacodynamics quantifies what the drug does to the body; the pharmacological response. QSP is a mechanistic modeling approach and an emerging technology, which mathematically integrates pharmacokinetics, pharmacological response and disease progress/modulation.

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