Aaps J
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Randomized Controlled Trial Multicenter Study
Population analyses of efficacy and safety of ABT-594 in subjects with diabetic peripheral neuropathic pain.
ABT-594, a neuronal nicotinic acetylcholine receptor ligand, is 30- to 100-fold more potent than morphine in animal models of nociceptive and neuropathic pain. Efficacy and safety of ABT-594 in subjects with painful diabetic polyneuropathy was evaluated in a phase 2 study. The objective of this work was to use a nonlinear mixed effects model-based approach for characterizing the relationship between dose and response (efficacy and safety) of ABT-594. ⋯ ABT-594 ED(50) values (improvement in 50% of subjects) for improvement in pain scores of ≥1, ≥2, and ≥3 were 50, 215, and 340 μg, respectively, for the average number of days (33) on treatment. The rank order of ED(50) values for AEs was nausea, vomiting, dizziness, headache, and abnormal dreams; nicotine users were less sensitive to AEs. Population pharmacodynamic models developed to characterize the improvement in pain score and incidence of adverse events indicate an approximately twofold separation between the ED(50) values for efficacy and AEs.
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A generic product must meet the standards established by the Food and Drug Administration (FDA) to be approved for marketing in the USA. FDA approves a generic product for marketing if it is proved to be therapeutically equivalent to the reference product. Bioequivalence (BE) between a proposed generic product and its corresponding reference product is one of the major components of therapeutic equivalence. These approvals may be delayed if the BE portion of the submission is determined to be deficient. Many of these BE deficiencies recur commonly and can be avoided. ⋯ Recurring deficiencies are found in a majority of the ANDAs reviewed by FDA's Division of Bioequivalence. The most common deficiencies were the two deficiencies related to dissolution (method and specifications) found in 23.3% of the applications and analytical method validation and/or report found in 16.5% of the applications. The approval of generic drugs would be greatly accelerated if these deficiencies could be avoided.
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Pharmacokinetic-pharmacodynamic (PK-PD) modeling greatly enables quantitative implementation of the "learn and confirm" paradigm across different stages of drug discovery and development. This work describes the successful prospective application of this concept in the discovery and early development of a novel κ-opioid receptor (KOR) antagonist, PF-04455242, where PK-PD understanding from preclinical biomarker responses enabled successful prediction of the clinical response in a proof of mechanism study. Preclinical data obtained in rats included time course measures of the KOR antagonist (PF-04455242), a KOR agonist (spiradoline), and a KOR-mediated biomarker response (prolactin secretion) in plasma. ⋯ This prediction was in good agreement with that estimated via the application of the proposed PK-PD model to the clinical data (i.e., 39.2 ng/mL). These results illustrate the utility of the proposed PK-PD model in supporting the quantitative translation of preclinical studies into an accurate clinical expectation. As such, the proposed PK-PD model is useful for supporting the design, selection, and early development of novel KOR antagonists.
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Recent years have witnessed a growing interest in a field of vaccinology that we have named vaccinomics. The overall idea behind vaccinomics is to identify genetic and other mechanisms and pathways that determine immune responses, and thereby provide new candidate vaccine approaches. Considerable data show that host genetic polymorphisms act as important determinants of innate and adaptive immunity to vaccines. ⋯ The influence of HLA genes, non-HLA, and innate genes in inter-individual variations in immune responses to viral vaccines are examined using population-based gene/SNP association studies. The ability to understand relationships between immune response gene variants and vaccine-specific immunity may assist in designing new vaccines. At the same time, application of state-of-the-art next-generation sequencing technology (and bioinformatics) is desired to provide new genetic information and its relationship to the immune response.
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Analysis of longitudinal ordered categorical efficacy or safety data in clinical trials using mixed models is increasingly performed. However, algorithms available for maximum likelihood estimation using an approximation of the likelihood integral, including LAPLACE approach, may give rise to biased parameter estimates. The SAEM algorithm is an efficient and powerful tool in the analysis of continuous/count mixed models. ⋯ The SAEM algorithm is extended for analysis of longitudinal categorical data. It provides accurate estimates parameters and standard errors. The estimation is fast and stable.