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- Bonate, Peter L., et al.
(författare)
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Training the next generation of pharmacometric modelers : a multisector perspective
- 2023
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Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Nature. - 1567-567X .- 1573-8744. ; 51:1, s. 5-31
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Tidskriftsartikel (refereegranskat)abstract
- The current demand for pharmacometricians outmatches the supply provided by academic institutions and considerable investments are made to develop the competencies of these scientists on-the-job. Even with the observed increase in academic programs related to pharmacometrics, this need is unlikely to change in the foreseeable future, as the demand and scope of pharmacometrics applications keep expanding. Further, the field of pharmacometrics is changing. The field largely started when Lewis Sheiner and Stuart Beal published their seminal papers on population pharmacokinetics in the late 1970’s and early 1980’s and has continued to grow in impact and use since its inception. Physiological-based pharmacokinetics and systems pharmacology have grown rapidly in scope and impact in the last decade and machine learning is just on the horizon. While all these methodologies are categorized as pharmacometrics, no one person can be an expert in everything. So how do you train future pharmacometricians? Leading experts in academia, industry, contract research organizations, clinical medicine, and regulatory gave their opinions on how to best train future pharmacometricians. Their opinions were collected and synthesized to create some general recommendations.
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| 3. |
- Kjellsson, Maria C., et al.
(författare)
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Modeling sleep data for a new drug in development using Markov mixed-effects models
- 2011
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Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 28:10, s. 2610-2627
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Tidskriftsartikel (refereegranskat)abstract
- To characterize the time-course of sleep in insomnia patients as well as placebo and concentration-effect relationships of two hypnotic compounds, PD 0200390 and zolpidem, using an accelerated model-building strategy based on mixed-effects Markov models. Data were obtained in a phase II study with the drugs. Sleep stages were recorded during eight hours of sleep for two nights per treatment for the five treatments. First-order Markov models were developed for one transition at a time in a sequential manner; first a baseline model, followed by placebo and lastly the drug models. To accelerate the process, predefined models were selected based on a priori knowledge of sleep, including inter-subject and inter-occasion variability. Baseline sleep was described using piece-wise linear models, depending on time of night and duration of sleep stage. Placebo affected light sleep stages; drugs also affected slow-wave sleep. Administering PD 0200390 30 min earlier than standard dosing was shown through simulations to reduce latency to persistent sleep by 40%. The proposed accelerated model-building strategy resulted in a model well describing sleep patterns of insomnia patients with and without treatments.
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| 4. |
- Kornprobst, Jacques, et al.
(författare)
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Boris Choubert: Unrecognized visionarygeologist, pioneer of the global tectonics.
- 2018
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Ingår i: BSGF - Earth Science Bulletin. - : EDP Sciences. - 0037-9409 .- 1777-5817. ; 189:2, s. 1-15
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Tidskriftsartikel (refereegranskat)abstract
- This work is a review of Boris Choubert’s paper (1935), which was published in French under the rather devalorizing title: “Research on the Genesis of Palaeozoic and Precambrian Belts.” Despite its innovative content, this article had no impact either at the time of its publication or even later. It begins with the construction of a remarkable fit of the circum-Atlantic continents. This was based on the 1.000 meters isobath instead of the shoreline. Thirty years before Bullard et al. (1965), it demonstrated in an indisputable way the reality of the continents motion on the surface of the Earth. Therefore, Choubert designated Wegener’s “continental drift” as the main cause of tectonics. Even going beyond Wegener’s theory, he argued that this mechanism was efficient well before the formation of the Triassic Pangæa, during the whole Palaeozoic to result in the building of the Caledonian and Hercynian mountains. Although he was still encumbered by the vocabulary of the time regarding geosynclines, Boris Choubert described tectonics based on the horizontal mobility of the Precambrian continental blocks. Oddly enough, he did not apply this model to the Precambrian structures, which he attributed to the effects of the Earth’s rotation on the continental crust during its solidification. At the time of its publication, this paper was a very important step towards understanding global tectonics. Unfortunately, Choubert’s contemporaries did not generally recognize its significance.
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| 6. |
- Ueckert, Sebastian, 1983-, et al.
(författare)
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Challenges and potential of optimal design in late phase clinical trials through application in Alzheimer’s disease
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Optimal design is a methodology that can be a valuable tool for the planning of clinical studies. Current applications however, are largely limited to early phases of the drug development process. The increasing complexity in late phase trials is a major reason why optimal design is not applied at these stages. This work uses the example of Alzheimer's disease to investigate challenges and potential of applying optimal design in late phase clinical trials.Information from several sources was used to construct a disease progression model for Alzheimer's disease. The resulting model was used to optimize the study design of an Alzheimer's trial for three distinct metrics: maximal information, minimal number of samples and maximal power to detect a drug effect. Challenges encountered and addressed during the implementation included covariates, dropout and clinical constraints.Depending on the optimization criterion used, the optimal designs had 35% a higher efficiency, needed 33% fewer samples to obtain the same amount of information or required 70% fewer individuals to achieve 80% power compared to the reference design.Optimal design can improve the design and therefore reduce the costs of late phase trials. Several tools and techniques have been identified to address the main challenges connected to this application.
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| 7. |
- Ueckert, Sebastian, 1983-, et al.
(författare)
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Improved Utilization of ADAS-cog Assessment Data through Item Response Theory based Pharmacometric Modeling
- 2014
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Ingår i: Pharmaceutical research. - : Springer. - 0724-8741 .- 1573-904X. ; 31:8, s. 2152-2165
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Tidskriftsartikel (refereegranskat)abstract
- PurposeThis work investigates improved utilization of ADAS-cog data (the primaryoutcome in Alzheimer's disease (AD) trials of mild and moderate AD) by combiningpharmacometric modeling and item response theory (IRT).MethodsA baseline IRT model characterizing the ADAS-cog was built based on datafrom 2744 individuals. Pharmacometric methods were used to extend the baseline IRTmodel to describe longitudinal ADAS-cog scores from an 18-month clinical study with322 patients. Sensitivity of the ADAS-cog items in different patient populations as wellas the power to detect a drug effect in relation to total score base methods wereassessed with IRT based models.ResultsIRT analysis was able to describe both total and item level baseline ADAS-cogdata. Longitudinal data were also well described. Differences in the informationcontent of the item level components could be quantitatively characterized and rankedfor mild cognitively impairment and mild AD populations. Based on clinical trialsimulations with a theoretical drug effect, the IRT method demonstrated a significantlyhigher power to detect drug effect compared to the traditional method of analysis.ConclusionA combined framework of IRT and pharmacometric modeling permits amore effective and precise analysis than total score based methods and thereforeincreases the value of ADAS-cog data.
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| 10. |
- Glasbey, JC, et al.
(författare)
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- 2021
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swepub:Mat__t
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