| 1. |
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| 2. |
- Brekkan, Ari, et al.
(författare)
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Sensitivity of Pegfilgrastim Pharmacokinetic and Pharmacodynamic Parameters to Product Differences in Similarity Studies
- 2019
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Ingår i: AAPS Journal. - : Springer. - 1550-7416. ; 21:85
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Tidskriftsartikel (refereegranskat)abstract
- In this work, a previously developed pegfilgrastim (PG) population pharmacokinetic-pharmacodynamic (PKPD) model was used to evaluate potential factors of importance in the assessment of PG PK and PD similarity. Absolute neutrophil count (ANC) was the modelled PD variable. A two-way cross-over study was simulated where a reference PG and a potentially biosimilar test product were administered to healthy volunteers. Differences in delivered dose amounts or potency between the products were simulated. A different baseline absolute neutrophil count (ANC) was also considered. Additionally, the power to conclude PK or PD similarity based on areas under the PG concentration-time curve (AUC) and ANC-time curve (AUEC) were calculated. Delivered dose differences between the products led to a greater than dose proportional differences in AUC but not in AUEC, respectively. A 10% dose difference from a 6 mg dose resulted in 51% and 7% differences in AUC and AUEC, respectively. These differences were more pronounced with low baseline ANC. Potency differences up to 50% were not associated with large differences in either AUCs or AUECs. The power to conclude PK similarity was affected by the simulated dose difference; with a 4% dose difference from 6 mg the power was approximately 29% with 250 subjects. The power to conclude PD similarity was high for all delivered dose differences and sample sizes.
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| 3. |
- Harisubramanyabalaji, Subramani Palanisamy, et al.
(författare)
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Improving Image Classification Robustness Using Predictive Data Augmentation
- 2018
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Ingår i: Computer Safety, Reliability, and Security. - Cham : Springer. - 9783319992280 - 9783319992297 ; , s. 548-561
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Konferensbidrag (refereegranskat)abstract
- Safer autonomous navigation might be challenging if there is a failure in sensing system. Robust classifier algorithm irrespective of camera position, view angles, and environmental condition of an autonomous vehicle including different size & type (Car, Bus, Truck, etc.) can safely regulate the vehicle control. As training data play a crucial role in robust classification of traffic signs, an effective augmentation technique enriching the model capacity to withstand variations in urban environment is required. In this paper, a framework to identify model weakness and targeted augmentation methodology is presented. Based on off-line behavior identification, exact limitation of a Convolutional Neural Network (CNN) model is estimated to augment only those challenge levels necessary for improved classifier robustness. Predictive Augmentation (PA) and Predictive Multiple Augmentation (PMA) methods are proposed to adapt the model based on acquired challenges with a high numerical value of confidence. We validated our framework on two different training datasets and with 5 generated test groups containing varying levels of challenge (simple to extreme). The results show impressive improvement by 5-20% in overall classification accuracy thereby keeping their high confidence.
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| 4. |
- Juul, Rasmus Vestergaard, et al.
(författare)
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A Pharmacokinetic-Pharmacodynamic Model of Morphine Exposure and Subsequent Morphine Consumption in Postoperative Pain
- 2016
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Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 33:5, s. 1093-1103
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Tidskriftsartikel (refereegranskat)abstract
- To characterize the pharmacokinetic-pharmacodynamic (PK-PD) relationship between exposure of morphine and subsequent morphine consumption and to develop simulation tools for model validation. Dose, formulation and time of morphine administration was available from a published study in 63 patients receiving intravenous, oral immediate release or oral controlled release morphine on request after hip surgery. The PK-PD relationship between predicted exposure of morphine and morphine consumption was modeled using repeated time to event (RTTE) modeling in NONMEM. To validate the RTTE model, a visual predictive check method was developed with simulated morphine consumption given the exposure of preceding morphine administration. The probability of requesting morphine was found to be significantly related to the exposure of morphine as well as night/day. Oral controlled release morphine was more effective than intravenous and oral immediate release formulations at equivalent average concentrations. Maximum effect was obtained for 8 h by oral controlled release doses a parts per thousand yenaEuro parts per thousand 15 mg, where probability of requesting a new dose was reduced to 20% for a typical patient. This study demonstrates the first quantitative link between exposure of morphine and subsequent morphine consumption and introduces an efficient visual predictive check approach with simulation of adaptive dosing.
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| 5. |
- Juul, Rasmus Vestergaard, et al.
(författare)
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Analysis of opioid consumption in clinical trials : a simulation based analysis of power of four approaches
- 2017
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Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : SPRINGER/PLENUM PUBLISHERS. - 1567-567X .- 1573-8744. ; 44:4, s. 325-333
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Tidskriftsartikel (refereegranskat)abstract
- Inconsistent trial design and analysis is a key reason that few advances in postoperative pain management have been made from clinical trials analyzing opioid consumption data. This study aimed to compare four different approaches to analyze opioid consumption data. A repeated time-to-event (RTTE) model in NONMEM was used to simulate clinical trials of morphine consumption with and without a hypothetical adjuvant analgesic in doses equivalent to 15-62% reduction in morphine consumption. Trials were simulated with duration of 24-96 h. Monte Carlo simulation and re-estimation were performed to determine sample size required to demonstrate efficacy with 80% power using t test, Mann-Whitney rank sum test, time-to-event (TTE) modeling and RTTE modeling. Precision of efficacy estimates for RTTE models were evaluated in 500 simulations. A sample size of 50 patients was required to detect 37% morphine sparing effect with at least 80% power in a 24 h trial with RTTE modeling whereas the required sample size was 200 for Mann-Whitney, 180 for t-test and 76 for TTE models. Extending the trial duration from 24 to 96 h reduced the required sample size by 3.1 fold with RTTE modeling. Precise estimate of potency was obtained with a RTTE model accounting for both morphine effects and time-varying covariates on opioid consumption. An RTTE analysis approach proved better suited for demonstrating efficacy of opioid sparing analgesics than traditional statistical tests as a lower sample size was required due the ability to account for time-varying factors including PK.
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| 6. |
- Kristoffersson, Anders N., et al.
(författare)
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Inter occasion variability in individual optimal design
- 2015
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Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 42:6, s. 735-750
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Tidskriftsartikel (refereegranskat)abstract
- Inter occasion variability (IOV) is of importance to consider in the development of a design where individual pharmacokinetic or pharmacodynamic parameters are of interest. IOV may adversely affect the precision of maximum a posteriori (MAP) estimated individual parameters, yet the influence of inclusion of IOV in optimal design for estimation of individual parameters has not been investigated. In this work two methods of including IOV in the maximum a posteriori Fisher information matrix (FIMMAP) are evaluated: (i) MAP(occ)-the IOV is included as a fixed effect deviation per occasion and individual, and (ii) POPocc-the IOV is included as an occasion random effect. Sparse sampling schedules were designed for two test models and compared to a scenario where IOV is ignored, either by omitting known IOV (Omit) or by mimicking a situation where unknown IOV has inflated the IIV (Inflate). Accounting for IOV in the FIMMAP markedly affected the designs compared to ignoring IOV and, as evaluated by stochastic simulation and estimation, resulted in superior precision in the individual parameters. In addition MAP(occ) and POPocc accurately predicted precision and shrinkage. For the investigated designs, the MAP(occ) method was on average slightly superior to POPocc and was less computationally intensive.
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| 7. |
- Niebecker, Ronald, et al.
(författare)
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Population pharmacokinetics of edoxaban in patients with symptomatic deep-vein thrombosis and/or pulmonary embolism-the Hokusai-VTE phase 3 study
- 2015
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 80:6, s. 1374-1387
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: This study characterized the population pharmacokinetics of edoxaban in patients with symptomatic deep-vein thrombosis and/or pulmonary embolism in the Hokusai-VTE phase 3 study. The impact of the protocol-specified 50% dose reductions applied to patients with body weight ≤ 60 kg, creatinine clearance (CLcr ) of 30 to 50 ml min(-1) or concomitant P-glycoprotein inhibitor on edoxaban exposure was assessed using simulations.METHODS: The sparse data from Hokusai-VTE, 9531 concentrations collected from 3707 patients, were pooled with data from 13 phase 1 studies. In the analysis, the covariate relationships used for dose reductions were estimated and differences between healthy subjects and patients as well as additional covariate effects of age, race and gender were explored based on statistical and clinical significance.RESULTS: A linear two-compartment model with first order absorption preceded by a lag time best described the data. Allometrically scaled body weight was included on disposition parameters. Apparent clearance was parameterized as non-renal and renal. The latter increased non-linearly with increasing CLcr . Compared with healthy volunteers, inter-compartmental clearance and the CLcr covariate effect were different in patients (+64.6% and +274%). Asian patients had a 22.6% increased apparent central volume of distribution. The effect of co-administration of P-glycoprotein inhibitors seen in phase 1 could not be confirmed in the phase 3 data. Model-based simulations revealed lower exposure in dose-reduced compared with non-dose-reduced patients.CONCLUSIONS: The adopted dose-reduction strategy resulted in reduced exposure compared with non-dose-reduced, thereby overcompensating for covariate effects. The clinical impact of these differences on safety and efficacy remains to be evaluated.
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| 8. |
- Nyberg, Joakim, 1978-, et al.
(författare)
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Edoxaban Exposure-Response Analysis and Clinical Utility Index Assessment in Patients With Symptomatic Deep-Vein Thrombosis or Pulmonary Embolism
- 2016
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Ingår i: CPT. - : Wiley. - 2163-8306. ; 5:4, s. 222-232
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Tidskriftsartikel (refereegranskat)abstract
- Edoxaban exposure-response relationships from the phase III study evaluating edoxaban for prevention and treatment of venous thromboembolism (VTE) in patients with acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) were assessed by parametric time-to-event analysis. Statistical significant exposure-response relationships were recurrent VTE with hazard ratio (HR) based on average edoxaban concentration at steady state (C-av) (HRCav) 50.98 (i.e., change in the HR with every 1 ng/mL increase of C-av); the composite of recurrent DVT and nonfatal PE with HRC(av)50.99; and the composite of recurrent DVT, nonfatal PE, and all-cause mortality HRC(av)50.98, and all death using maximal edoxaban concentration (C-max) with HR (C-max) 50.99. No statistical significant exposure-response relationships were found for clinically relevant bleeding or major adverse cardiovascular event. Results support the recommendation of once-daily edoxaban 60 mg, and a reduced 30 mg dose in patients with moderate renal impairment, body weight <= 60 kg, or use of P-glycoprotein inhibitors verapamil or quinidine.
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| 9. |
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| 10. |
- Nyberg, Joakim, et al.
(författare)
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Methods and software tools for design evaluation for population pharmacokinetics-pharmacodynamics studies
- 2015
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 79:1, s. 6-17
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Tidskriftsartikel (refereegranskat)abstract
- Population Pharmacokinetic (PK)-Pharmacodynamic (PD) (PKPD) models are increasingly used in drug development and in academic research. Hence designing efficient studies is an important task. Following the first theoretical work on optimal design for nonlinear mixed effect models, this research theme has grown rapidly. There are now several different software tools that implement an evaluation of the Fisher information matrix for population PKPD. We compared and evaluated five software tools: PFIM, PkStaMP, PopDes, PopED, and POPT. The comparisons were performed using two models: i) a simple one compartment warfarin PK model; ii) a more complex PKPD model for Pegylated-interferon (peg-interferon) with both concentration and response of viral load of hepatitis C virus (HCV) data. The results of the software were compared in terms of the standard error values of the parameters (SE) predicted from the software and the empirical SE values obtained via replicated clinical trial simulation and estimation. For the warfarin PK model and the peg-interferon PKPD model all software gave similar results. Of interest it was seen, for all software, that the simpler approximation to the Fisher information matrix, using the block diagonal matrix, provided predicted SE values that were closer to the empirical SE values than when the more complicated approximation was used (the full matrix). For most PKPD models, using any of the available software tools will provide meaningful results, avoiding cumbersome simulation and allowing design optimization.
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| 11. |
- Nyberg, Joakim, 1978-, et al.
(författare)
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RETRACTED: Population Kinetics of 0.9% Saline Distribution in Hemorrhaged Awake and Isoflurane-anesthetized Volunteers
- 2019
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Ingår i: Anesthesiology. - : Ovid Technologies (Wolters Kluwer Health). - 0003-3022 .- 1528-1175. ; 131:3, s. 501-511
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Tidskriftsartikel (refereegranskat)abstract
- Background: Population-based, pharmacokinetic modeling can be used to describe variability in fluid distribution and dilution between individuals and across populations. The authors hypothesized that dilution produced by crystalloid infusion after hemorrhage would be larger in anesthetized than in awake subjects and that population kinetic modeling would identify differences in covariates. Methods: Twelve healthy volunteers, seven females and five males, mean age 28 +/- 4.3 yr, underwent a randomized crossover study. Each subject participated in two separate sessions, separated by four weeks, in which they were assigned to an awake or an anesthetized arm. After a baseline period, hemorrhage (7 ml/kg during 20 min) was induced, immediately followed by a 25 ml/kg infusion during 20 min of 0.9% saline. Hemoglobin concentrations, sampled every 5 min for 60 min then every 10 min for an additional 120 min, were used for population kinetic modeling. Covariates, including body weight, sex, and study arm (awake or anesthetized), were tested in the model building. The change in dilution was studied by analyzing area under the curve and maximum plasma dilution. Results: Anesthetized subjects had larger plasma dilution than awake subjects. The analysis showed that females increased area under the curve and maximum plasma dilution by 17% (with 95% CI, 1.08 to 1.38 and 1.07 to 1.39) compared with men, and study arm (anesthetized increased area under the curve by 99% [0.88 to 2.45] and maximum plasma dilution by 35% [0.71 to 1.63]) impacted the plasma dilution whereas a 10-kg increase of body weight resulted in a small change (less than1% [0.93 to 1.20]) in area under the curve and maximum plasma dilution. Mean arterial pressure was lower in subjects while anesthetized (P < 0.001). Conclusions: In awake and anesthetized subjects subjected to controlled hemorrhage, plasma dilution increased with anesthesia, female sex, and lower body weight. Neither study arm nor body weight impact on area under the curve or maximum plasma dilution were statistically significant and therefore no effect can be established.
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| 12. |
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| 13. |
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| 14. |
- Strömberg, Eric, 1987-, et al.
(författare)
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The effect of Fisher information matrix approximation methods in population optimal design calculations
- 2016
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Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 43:6, s. 609-619
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Tidskriftsartikel (refereegranskat)abstract
- With the increasing popularity of optimal design in drug development it is important to understand how the approximations and implementations of the Fisher information matrix (FIM) affect the resulting optimal designs. The aim of this work was to investigate the impact on design performance when using two common approximations to the population model and the full or block-diagonal FIM implementations for optimization of sampling points. Sampling schedules for two example experiments based on population models were optimized using the FO and FOCE approximations and the full and block-diagonal FIM implementations. The number of support points was compared between the designs for each example experiment. The performance of these designs based on simulation/estimations was investigated by computing bias of the parameters as well as through the use of an empirical D-criterion confidence interval. Simulations were performed when the design was computed with the true parameter values as well as with misspecified parameter values. The FOCE approximation and the Full FIM implementation yielded designs with more support points and less clustering of sample points than designs optimized with the FO approximation and the block-diagonal implementation. The D-criterion confidence intervals showed no performance differences between the full and block diagonal FIM optimal designs when assuming true parameter values. However, the FO approximated block-reduced FIM designs had higher bias than the other designs. When assuming parameter misspecification in the design evaluation, the FO Full FIM optimal design was superior to the FO block-diagonal FIM design in both of the examples.
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| 15. |
- Westman, Jonas, 1986-, et al.
(författare)
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Formal Architecture Modeling of Sequential Non-Recursive C Programs
- 2017
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Ingår i: Science of Computer Programming. - : Elsevier. - 0167-6423 .- 1872-7964. ; 146, s. 2-27
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Tidskriftsartikel (refereegranskat)abstract
- To manage the complexity of C programs, architecture models are used as high-level descriptions, allowing developers to understand, assess, and manage the C programs without having to understand the intricate complexity of the code implementations. However, for the architecture models to serve their purpose, they must be accurate representations of the C programs. In order to support creating accurate architecture models, the present paper presents a mapping from the domain of sequential non-recursive C programs to a domain of formal architecture models, each being a hierarchy of components with well-defined interfaces. The hierarchically organized components and their interfaces, which capture both data and function call dependencies, are shown to both enable high-level assessment and analysis of the C program and provide a foundation for organizing and expressing specifications for compositional verification.
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