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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Modeling and Simulation to Support Phase 2 Dose Selection for RG7652, a Fully Human Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9.

RG7652 is a fully humanized monoclonal antibody targeting human PCSK9, a regulator of serum low density lipoprotein cholesterol (LDLc) levels. RG7652 prevents degradation of the hepatic LDLc receptors by blocking PCSK9 binding and thereby resulting in efficient LDLc uptake by hepatocytes. The pharmacokinetics of RG7652 have been evaluated in healthy subjects after single and multiple […]

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Model-Based Meta-Analysis of the HbA1c Lowering Effect Of PF-04971729, a Sodium Glucose Co-Transporter-2 Inhibitor (SGLT2i), In Comparison to Other SGLT2i And Anti-Diabetic Agents (ADA)

PF-04971729 is a potent, selective SGLT2i in development for treatment of type 2 diabetes mellitus (T2DM). Since there is growing recognition of the need for comparative effectiveness of various ADA, a model was developed to quantify time course of dose vs HbA1c response of PF-04971729 relative to other ADA including SGLT2i, DPP4 inhibitors (DPP4i), GLP-1 […]

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Model-Based Meta-Analysis of the Effect on Body Weight of PF-04971729, a Sodium Glucose Co-Transporter-2 Inhibitor (SGLT2i), in Comparison to other SGLT2i and Anti-Diabetic Agents (ADA)

PF-04971729 is a potent, selective SGLT2i in development for treatment of type 2 diabetes mellitus (T2DM). Since there is growing recognition of the need for comparative effectiveness of various ADA, a model was developed to quantify the time course of dose vs body weight change for PF-04971729 relative to other ADA including SGLT2i, DPP4 inhibitors […]

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The use of clinical trial simulation to support dose selection: application to development of a new treatment for chronic neuropathic pain.

Pregabalin is being evaluated for the treatment of neuropathic pain. Two phase 2 studies were simulated to determine how precisely the dose that caused a one-point reduction in the pain score could be estimated. The likelihood of demonstrating at least a one-point change for each available dose strength was also calculated. A pharmacokinetic-pharmacodynamic (PK/PD) model […]

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A population pharmacokinetic-pharmacodynamic analysis of repeated measures time-to-event pharmacodynamic responses: the antiemetic effect of ondansetron.

This paper presents and illustrates methodology for specifying, estimating, and evaluating a predictive model for repeated measures time-to-event responses. The illustrative example specifies a model of the antiemetic effect vs. concentration relationship for the 5-HT3 antagonist ondansetron in the human ipecac model for emesis. A key part of this model is a time-dependent log hazard […]

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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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Therapeutic benefit of eletriptan compared to sumatriptan for the acute relief of migraine pain–results of a model-based meta-analysis that accounts for encapsulation

A novel model-based meta-analysis was used to quantify the dose-response relationship of sumatriptan and eletriptan for the proportion of patients that achieve migraine pain relief up to 4 h after treatment. The proportion of patients that became pain free was also evaluated. This analysis includes some unique features, allowing comparison of sumatriptan and eletriptan doses […]

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Model-based development of gemcabene, a new lipid-altering agent

The purpose of this study was to evaluate the value of model-based, quantitative decision making during the development of gemcabene, a novel lipid-altering agent. The decisions were driven by a model of the likely clinical profile of gemcabene in comparison with its competitors, such as 3-hydroxymethylglutaryl coenzyme A reductase inhibitors (statins), the cholesterol absorption inhibitor […]

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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 Drug Development: A Rational Approach to Efficiently Accelerate Drug Development

The pharmaceutical industry continues to face significant challenges. Very few compounds that enter development reach the marketplace, and the investment required for each success can surpass $1.8 billion. Despite attempts to improve efficiency and increase productivity, total investment continues to rise whereas the output of new medicines declines. With costs increasing exponentially through each development […]

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Predicted Heart Rate Effect of Inhaled LABA PF-00610355 in volunteers and COPD patients

The aim of this study was to assess the cardiovascular effects of a new inhaled long-acting β-adrenoceptor agonist PF-00610355 in COPD patients. Thirteen thousand and sixty-two heart rate measurements collected in 10 clinical studies from 579 healthy volunteers, asthma and COPD patients were analyzed. The relationship between heart rate profiles and predicted plasma concentration profiles, […]

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Characterizing systemic exposure of inhaled drugs: application to the long-acting β2-agonist PF-00610355

PF-00610355 is an orally inhaled long-acting β2-adrenoreceptor agonist that is being developed for the once-daily treatment of chronic obstructive pulmonary disease (COPD). The pharmacological effect is exerted in the lungs. However, systemic exposure of PF-00610355 is expected to be responsible for certain drug-related adverse effects. This analysis characterizes PF-00610355 using an integrated analysis of systemic […]

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Short-term efficacy reliably predicts long-term clinical benefit in rheumatoid arthritis clinical trials as demonstrated by model-based meta-analysis

The objective of this study was to assess the relationship between short-term and long-term treatment effects measured by the American College of Rheumatology (ACR) 50 responses and to assess the feasibility of predicting 6-month efficacy from short-term data. A rheumatoid arthritis (RA) database was constructed from 68 reported trials. We focused on the relationship between […]

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Pharmacometric Approaches to Guide Dose Selection of the Novel GPR40 Agonist TAK-875 in Subjects With Type 2 Diabetes Mellitus

The G-protein-coupled receptor 40 agonist (GPR40) TAK-875 is being developed as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. Pharmacometric approaches such as model-based exposure-response and meta-analyses were applied to (i) characterize exposure/dose-efficacy responses of TAK-875, (ii) characterize the time course of glycosylated hemoglobin A1c (HbA1c) […]

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Clinical Trial Simulation to Inform Phase 2: Comparison of Concentrated vs. Distributed First-in-Patient Study Designs in Psoriasis

Clinical trial simulation (CTS) and model-based meta-analysis (MBMA) can increase our understanding of small, first-in-patient (FIP) trial design performance to inform Phase 2 decision making. In this work, we compared dose-ranging designs vs. designs testing only placebo and the maximum dose for early decision making in psoriasis. Based on MBMA of monoclonal antibodies in the […]

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Time course of bone mineral density changes with denosumab compared with other drugs in postmenopausal osteoporosis: a dose-response-based meta-analysis

Our objective was to compare the time course of bone mineral density (BMD) changes at the lumbar spine (LS) and total hip (TH) in postmenopausal women during treatment with denosumab, bisphosphonates, selective estrogen receptor modulators, PTH, or calcitonin. Data were extracted from 142 randomized controlled trials for prevention or treatment of postmenopausal osteoporosis representing over […]

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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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