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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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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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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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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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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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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Model-based meta-analysis for comparative efficacy and safety: application in drug development and beyond

High development cost, low development success, cost-disciplined health-care policies, and intense competition demand an efficient drug development process. New compounds need to bring value to patients by being safe, efficacious, and cost-effective as compared with existing treatment options. Model-based meta-analysis (MBMA) facilitates integration and utilization of summary-level efficacy and safety data, providing a quantitative framework […]

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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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A dose-response meta-analysis for quantifying relative efficacy of biologics in rheumatoid arthritis

We present a dose-response meta-analysis to quantify relative efficacy of biologic disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA). There is a strong rationale for this analysis because, although multiple biologics are available, information on head-to-head comparisons is limited. Data on the percentage of patients attaining American College of Rheumatology (ACR) 20, 50, […]

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A model-based dose-response meta-analysis of ocular hypotensive agents as a drug development tool to evaluate new therapies in glaucoma

PURPOSE: To characterize dose and response for intraocular pressure (IOP) reduction and incidence of hyperemia using a model-based meta-analysis of IOP-lowering monotherapy studies to evaluate new ocular antihypertensive therapies for glaucoma. METHODS: Published randomized controlled trials, regulatory documents, and sponsor reports of IOP-lowering monotherapies were used to develop dose-response models to characterize efficacy (IOP change […]

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