Development of a Permeability-limited Model of the Human Brain and Cerebrospinal Fluid (CSF) to Integrate Known Physiological and Biological Knowledge: Estimating Time Varying CSF Drug Concentrations and Their Variability Using In Vitro Data

A 4-compartment permeability-limited brain (4Brain) model consisting of brain blood, brain mass, cranial and spinal cerebrospinal fluid (CSF) compartments has been developed and incorporated into a whole body physiologically-based pharmacokinetic (PBPK) model within the Simcyp Simulator. The model assumptions, structure, governing equations and system parameters are described. The model in particular considers the anatomy and […]

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Pharmacokinetics of Tramadol and O-Desmethyltramadol Enantiomers Following Administration of Extended-Release Tablets to Elderly and Young Subjects.

Tramadol is frequently used in geriatric patients; however, pharmacokinetic (PK) publications on tramadol and O-desmethyltramadol (ODM) in elderly patients are rare. Our objective was to characterize the PK of tramadol and ODM, including absorption processes and covariates for tramadol, in elderly and young subjects after single-dose administration of 200-mg extended-release tablets. We conducted a PK […]

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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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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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Placebo response changes depending on the neuropathic pain syndrome: results of a systematic review and meta-analysis

The purpose of this study was to compare placebo responses in neuropathic pain syndromes through systematic literature review and meta-analysis. We used randomized placebo-controlled trials assessing pain intensity or pain relief in any neuropathic pain syndrome published since 1995 with +AD4-/+AD0-5days follow-up. We measured placebo response as measured by pain intensity and responder rates (proportion reporting +AD4-/+AD0-50+ACU- pain […]

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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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Meta-analysis of thoracic epidural anesthesia versus general anesthesia for cardiac surgery

A combination of general anesthesia (GA) with thoracic epidural anesthesia (TEA) may have a beneficial effect on clinical outcomes after cardiac surgery. We have performed a meta-analysis to compare mortality and cardiac, respiratory, and neurologic complications in patients undergoing cardiac surgery with GA alone or a combination of GA with TEA. Randomized studies comparing outcomes […]

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Learning from Failure: Leveraging Biosimulation for Pediatric Drug Development Success

The high rate of trial failures, increasing regulatory demands, and ethical imperatives all require a reexamination of the current approach to pediatric drug development. Biosimulation is a proven approach that will help optimize trial design and inform the drug label. This approach can support global regulatory strategies that increase the likelihood of success for pediatric drug development programs.

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Can QSP Save Lives? Lessons from the Bial Trial Debacle

One of the biggest challenges for the pharmaceutical industry is the high rate of drug attrition in Phase 2 clinical trials, which wastes significant amounts of money and time. The major reasons for this attrition are that either candidate drugs do not show efficacy or have unexpected toxicity, in turn implying that we did not fully understand the complexity of the biology the candidate drugs were designed to modulate.

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