| 1. |
- Abrantes, João A., et al.
(författare)
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Bayesian Forecasting Utilizing Bleeding Information to Support Dose Individualization of Factor VIII
- 2019
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Ingår i: CPT. - : Wiley. - 2163-8306. ; 8:12, s. 894-903
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Tidskriftsartikel (refereegranskat)abstract
- Bayesian forecasting for dose individualization of prophylactic factor VIII replacement therapy using pharmacokinetic samples is challenged by large interindividual variability in the bleeding risk. A pharmacokinetic‐repeated time‐to‐event model‐based forecasting approach was developed to contrast the ability to predict the future occurrence of bleeds based on individual (i) pharmacokinetic, (ii) bleeding, and (iii) pharmacokinetic, bleeding and covariate information using observed data from the Long‐Term Efficacy Open‐Label Program in Severe Hemophilia A Disease (LEOPOLD) clinical trials (172 severe hemophilia A patients taking prophylactic treatment). The predictive performance assessed by the area under receiver operating characteristic (ROC) curves was 0.67 (95% confidence interval (CI), 0.65–0.69), 0.78 (95% CI, 0.76–0.80), and 0.79 (95% CI, 0.77–0.81) for patients ≥ 12 years when using pharmacokinetics, bleeds, and all data, respectively, suggesting that individual bleed information adds value to the optimization of prophylactic dosing regimens in severe hemophilia A. Further steps to optimize the proposed tool for factor VIII dose adaptation in the clinic are required.
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| 2. |
- Almquist, Joachim, et al.
(författare)
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Model-Based Analysis Reveals a Sustained and Dose-Dependent Acceleration of Wound Healing by VEGF-A mRNA (AZD8601)
- 2020
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Ingår i: CPT. - : WILEY. - 2163-8306. ; 9:7, s. 384-394
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Tidskriftsartikel (refereegranskat)abstract
- Intradermal delivery of AZD8601, an mRNA designed to produce vascular endothelial growth factor A (VEGF-A), has previously been shown to accelerate cutaneous wound healing in a murine diabetic model. Here, we develop population pharmacokinetic and pharmacodynamic models aiming to quantify the effect of AZD8601 injections on the dynamics of wound healing. A dataset of 584 open wound area measurements from 131 mice was integrated from 3 independent studies encompassing different doses, dosing timepoints, and number of doses. Evaluation of several candidate models showed that wound healing acceleration is not likely driven directly by time-dependent VEGF-A concentration. Instead, we found that administration of AZD8601 induced a sustained acceleration of wound healing depending on the accumulated dose, with a dose producing 50% of the maximal effect of 92 mu g. Simulations with this model showed that a single dose of 200 mu g AZD8601 can reduce the time to reach 50% wound healing by up to 5 days.
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| 3. |
- Almquist, Joachim, 1980, et al.
(författare)
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Unraveling the Pharmacokinetic Interaction of Ticagrelor and MEDI2452 (Ticagrelor Antidote) by Mathematical Modeling
- 2016
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Ingår i: CPT: Pharmacometrics and Systems Pharmacology. - : Wiley. - 2163-8306. ; 5:6, s. 313-323
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Tidskriftsartikel (refereegranskat)abstract
- The investigational ticagrelor-neutralizing antibody fragment, MEDI2452, is developed to rapidly and specifically reverse the antiplatelet effects of ticagrelor. However, the dynamic interaction of ticagrelor, the ticagrelor active metabolite (TAM), and MEDI2452, makes pharmacokinetic (PK) analysis nontrivial and mathematical modeling becomes essential to unravel the complex behavior of this system. We propose a mechanistic PK model, including a special observation model for post-sampling equilibration, which is validated and refined using mouse in vivo data from four studies of combined ticagrelor-MEDI2452 treatment. Model predictions of free ticagrelor and TAM plasma concentrations are subsequently used to drive a pharmacodynamic (PD) model that successfully describes platelet aggregation data. Furthermore, the model indicates that MEDI2452-bound ticagrelor is primarily eliminated together with MEDI2452 in the kidneys, and not recycled to the plasma, thereby providing a possible scenario for the extrapolation to humans. We anticipate the modeling work to improve PK and PD understanding, experimental design, and translational confidence.
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| 4. |
- Alskär, Oskar, et al.
(författare)
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Model-Based Interspecies Scaling of Glucose Homeostasis
- 2017
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Ingår i: CPT. - : John Wiley & Sons. - 2163-8306. ; 6:11, s. 778-786
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Tidskriftsartikel (refereegranskat)abstract
- Being able to scale preclinical pharmacodynamic response to clinical would be beneficial in drug development. In this work, the integrated glucose insulin (IGI) model, developed on clinical intravenous glucose tolerance test (IVGTT) data, describing dynamic glucose and insulin concentrations during glucose tolerance tests, was scaled to describe data from similar tests performed in healthy rats, mice, dogs, pigs, and humans. Several approaches to scaling the dynamic glucose and insulin were investigated. The theoretical allometric exponents of 0.75 and 1, for clearances and volumes, respectively, could describe the data well with some species-specific adaptations: dogs and pigs showed slower first phase insulin secretion than expected from the scaling, pigs also showed more rapid insulin dependent glucose elimination, and rodents showed differences in glucose effectiveness. The resulting scaled IGI model was shown to accurately predict external preclinical IVGTT data and may be useful in facilitating translations of preclinical research into the clinic.
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| 5. |
- Baaz, Marcus, 1993, et al.
(författare)
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Model-based prediction of progression-free survival for combination therapies in oncology
- 2023
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Ingår i: Cpt-Pharmacometrics & Systems Pharmacology. - 2163-8306. ; 12:9, s. 1227-37
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Tidskriftsartikel (refereegranskat)abstract
- Progression-free survival (PFS) is an important clinical metric for comparing and evaluating similar treatments for the same disease within oncology. After the completion of a clinical trial, a descriptive analysis of the patients' PFS is often performed post hoc using the Kaplan-Meier estimator. However, to perform predictions, more sophisticated quantitative methods are needed. Tumor growth inhibition models are commonly used to describe and predict the dynamics of preclinical and clinical tumor size data. Moreover, frameworks also exist for describing the probability of different types of events, such as tumor metastasis or patient dropout. Combining these two types of models into a so-called joint model enables model-based prediction of PFS. In this paper, we have constructed a joint model from clinical data comparing the efficacy of FOLFOX against FOLFOX + panitumumab in patients with metastatic colorectal cancer. The nonlinear mixed effects framework was used to quantify interindividual variability (IIV). The model describes tumor size and PFS data well, and showed good predictive capabilities using truncated as well as external data. A machine-learning guided analysis was performed to reduce unexplained IIV by incorporating patient covariates. The model-based approach illustrated in this paper could be useful to help design clinical trials or to determine new promising drug candidates for combination therapy trials.
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| 6. |
- Bauer, Robert J., et al.
(författare)
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Tutorial for $DESIGN in NONMEM : Clinical trial evaluation and optimization
- 2021
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Ingår i: CPT. - : John Wiley & Sons. - 2163-8306. ; 10:12, s. 1452-1465
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Tidskriftsartikel (refereegranskat)abstract
- This NONMEM tutorial shows how to evaluate and optimize clinical trial designs, using algorithms developed in design software, such as PopED and PFIM 4.0. Parameter precision and model parameter estimability is obtained by assessing the Fisher Information Matrix (FIM), providing expected model parameter uncertainty. Model parameter identifiability may be uncovered by very large standard errors or inability to invert an FIM. Because evaluation of FIM is more efficient than clinical trial simulation, more designs can be investigated, and the design of a clinical trial can be optimized. This tutorial provides simple and complex pharmacokinetic/pharmacodynamic examples on obtaining optimal sample times, doses, or best division of subjects among design groups. Robust design techniques accounting for likely variability among subjects are also shown. A design evaluator and optimizer within NONMEM allows any control stream first developed for trial design exploration to be subsequently used for estimation of parameters of simulated or clinical data, without transferring the model to another software. Conversely, a model developed in NONMEM could be used for design optimization. In addition, the $DESIGN feature can be used on any model file and dataset combination to retrospectively evaluate the model parameter uncertainty one would expect given that the model generated the data, particularly if outliers of the actual data prevent a reasonable assessment of the variance-covariance. The NONMEM trial design feature is suitable for standard continuous data, whereas more elaborate trial designs or with noncontinuous data-types can still be accomplished in optimal design dedicated software like PopED and PFIM.
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| 7. |
- Boger, Elin, et al.
(författare)
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A Partial Differential Equation Approach to Inhalation Physiologically Based Pharmacokinetic Modeling
- 2018
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Ingår i: CPT: Pharmacometrics and Systems Pharmacology. - : Wiley. - 2163-8306. ; 7:10, s. 638-646
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Tidskriftsartikel (refereegranskat)abstract
- CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics. The heterogeneous nature of the lungs and the range of processes affecting pulmonary drug disposition make prediction of inhaled drugs challenging. These predictions are critical, as the local exposure cannot be measured and current inhalation physiologically based pharmacokinetic (PBPK) models do not capture all necessary features. Utilizing partial differential equations, we present an inhalation PBPK model to describe the heterogeneity in both lung physiology and particle size. The model mechanistically describes important processes, such as deposition, mucociliary clearance, and dissolution. In addition, simplifications are introduced to reduce computational cost without loss of accuracy. Three case studies exemplify how the model can enhance our understanding of pulmonary drug disposition. Specific findings include that most small airways can be targeted by inhalation, and overdosing may eradicate the advantage of inhalation. The presented model can guide the design of inhaled molecules, formulations, as well as clinical trials, providing opportunities to explore regional targeting.
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| 8. |
- Boger, E., et al.
(författare)
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Systems Pharmacology Approach for Prediction of Pulmonary and Systemic Pharmacokinetics and Receptor Occupancy of Inhaled Drugs
- 2016
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Ingår i: CPT. - : Wiley. - 2163-8306. ; 5:4, s. 201-210
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Tidskriftsartikel (refereegranskat)abstract
- Pulmonary drug disposition after inhalation is complex involving mechanisms, such as regional drug deposition, dissolution, and mucociliary clearance. This study aimed to develop a systems pharmacology approach to mechanistically describe lung disposition in rats and thereby provide an integrated understanding of the system. When drug-and formulation-specific properties for the poorly soluble drug fluticasone propionate were fed into the model, it proved predictive of the pharmacokinetics and receptor occupancy after intravenous administration and nose-only inhalation. As the model clearly distinguishes among drug-specific, formulation-specific, and system-specific properties, it was possible to identify key determinants of pulmonary selectivity of receptor occupancy of inhaled drugs: slow particle dissolution and slow drug-receptor dissociation. Hence, it enables assessment of factors for lung targeting, including molecular properties, formulation, as well as the physiology of the animal species, thereby providing a general framework for rational drug design and facilitated translation of lung targeting from animal to man.
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| 9. |
- Brussee, Janneke M., et al.
(författare)
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First-Pass CYP3A-Mediated Metabolism of Midazolam in the Gut Wall and Liver in Preterm Neonates
- 2018
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Ingår i: CPT. - : WILEY. - 2163-8306. ; 7:6, s. 374-383
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Tidskriftsartikel (refereegranskat)abstract
- To predict first-pass and systemic cytochrome P450 (CYP) 3A-mediated metabolism of midazolam in preterm neonates, a physiological population pharmacokinetic model was developed describing intestinal and hepatic midazolam clearance in preterm infants. On the basis of midazolam and 1-OH-midazolam concentrations from 37 preterm neonates (gestational age 26-34 weeks) receiving midazolam orally and/or via a 30-minute intravenous infusion, intrinsic clearance in the gut wall and liver were found to be very low, with lower values in the gut wall (0.0196 and 6.7 L/h, respectively). This results in a highly variable and high total oral bioavailability of 92.1% (range, 67-95%) in preterm neonates, whereas this is around 30% in adults. This approach in which intestinal and hepatic clearance were separately estimated shows that the high bioavailability in preterm neonates is explained by, likely age-related, low CYP3A activity in the liver and even lower CYP3A activity in the gut wall.
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| 10. |
- Bukkems, Laura, et al.
(författare)
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Relationship between factor VIII levels and bleeding for rFVIII-SingleChain in severe hemophilia A : A repeated time-to-event analysis
- 2023
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Ingår i: CPT. - : Wiley-Blackwell. - 2163-8306. ; 12:5, s. 706-718
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Tidskriftsartikel (refereegranskat)abstract
- Publications on the exposure-effect relationships of factor concentrates for hemophilia treatment are limited, whereas such analyses give insight on treatment efficacy. Our objective was to examine the relationship between the dose, factor VIII (FVIII) levels and bleeding for rFVIII-SingleChain (lonoctocog alfa, Afstyla). Data from persons with severe hemophilia A on rFVIII-SingleChain prophylaxis from three clinical trials were combined. The published rFVIII-SingleChain population pharmacokinetic (PK) model was evaluated and expanded. The probability of bleeding was described with a parametric repeated time-to-event (RTTE) model. Data included 2080 bleeds, 2545 chromogenic stage assay, and 3052 one-stage assay FVIII levels from 241 persons (median age 19 years) followed for median 1090 days. The majority of the bleeds occurred in joints (65%) and the main bleeding reason was trauma (44%). The probability of bleeding decreased during follow-up and a FVIII level of 8.9 IU/dL (95% confidence interval: 6.9-10.9) decreased the bleeding hazard by 50% compared to a situation without FVIII in plasma. Variability in bleeding hazard between persons with similar FVIII levels was large, and the pre-study annual bleeding rate explained part of this variability. When a FVIII trough level of 1 or 3 IU/dL is targeted during prophylaxis, simulations predicted two (90% prediction interval [PI]: 0-17) or one (90% PI: 0-11) bleeds per year, respectively. In conclusion, the developed PK-RTTE model adequately described the relationship between dose, FVIII levels and bleeds for rFVIII-SingleChain. The obtained estimates were in agreement with those published for the FVIII concentrates BAY 81-8973 (octocog alfa) and BAY 94-9027 (damoctocog alfa pegol), indicating similar efficacy to reduce bleeding.
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