| 1. |
- Alskär, Oskar, et al.
(författare)
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A pharmacokinetic model for the glycation of albumin
- 2012
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Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 39:3, s. 273-282
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Tidskriftsartikel (refereegranskat)abstract
- Glycated haemoglobin (HbA1c) concentrations can be falsely lowered in circumstances when red blood cell (RBC) survival is reduced, e.g. in patients with chronic kidney disease (CKD). Glycated albumin (GA) has been suggested as an alternative marker of glycaemic control in these patients since it is independent of the RBC life span. The primary aim of this work was to develop a pharmacokinetic model that describes the time course of GA. The secondary aim was to assess the performance of GA as marker for glycaemic control in comparison to HbA1c based on simulations. For the second aim, three different scenarios were considered in the simulations: 1) assessment of the effect of large intra-day fluctuations in mean blood glucose on GA concentrations, 2) initiation of antidiabetic treatment on the GA profile, and 3) a hypothetical phase II study for a new antidiabetic compound. The GA model, as well as a previously developed HbA1c model described literature data well. GA concentrations appear to be stable even in the presence of high intra-day fluctuations in mean blood glucose concentrations. Simulation of a decrease in mean blood glucose concentrations resulted in a faster change in GA compared to HbA1c. GA also provided a time to 90 % power of the effect of a hypothetical antidiabetic drug that was 16 days shorter than when using HbA1c. These results indicate that GA could be used as alternative marker to assess blood glucose control in diabetic patients with CKD and also to follow an individual patient over time.
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| 2. |
- Duffull, Stephen B., et al.
(författare)
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Assessing robustness of designs for random effects parameters for nonlinear mixed-effects models
- 2017
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Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 44:6, s. 611-616
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Tidskriftsartikel (refereegranskat)abstract
- Optimal designs for nonlinear models are dependent on the choice of parameter values. Various methods have been proposed to provide designs that are robust to uncertainty in the prior choice of parameter values. These methods are generally based on estimating the expectation of the determinant (or a transformation of the determinant) of the information matrix over the prior distribution of the parameter values. For high dimensional models this can be computationally challenging. For nonlinear mixed-effects models the question arises as to the importance of accounting for uncertainty in the prior value of the variances of the random effects parameters. In this work we explore the influence of the variance of the random effects parameters on the optimal design. We find that the method for approximating the expectation and variance of the likelihood is of potential importance for considering the influence of random effects. The most common approximation to the likelihood, based on a first-order Taylor series approximation, yields designs that are relatively insensitive to the prior value of the variance of the random effects parameters and under these conditions it appears to be sufficient to consider uncertainty on the fixed-effects parameters only.
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| 3. |
- Isbister, Geoffrey K., et al.
(författare)
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Activated charcoal decreases the risk of QT prolongation after citalopram overdose
- 2007
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Ingår i: Annals of Emergency Medicine. - : Elsevier BV. - 0196-0644 .- 1097-6760. ; 50:5, s. 593-600
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Tidskriftsartikel (refereegranskat)abstract
- Study objective: We determine whether single-dose activated charcoal (SDAC) administration after citalopram overdose reduces the proportion of patients developing abnormal QT prolongation. Methods: Data were collected retrospectively for citalopram overdose patients presenting to 8 emergency departments. Demographics, dose, coingested drugs, SDAC administration, and serial ECGs were extracted from medical records. The primary outcome was the proportion of patients who had an observed QT,RR combination at any time above an abnormal threshold, established as a predictor of torsade de pointes. We compared the proportion of patients with QT prolongation who received or did not receive SDAC. These data were analyzed within a Bayesian framework, using probabilities of abnormal QT,RR combinations with and without derived from a previous single-center study. WinBUGS was used to generate posterior estimates and credible intervals of the relative risk by combining the prior probabilities and the study data. Results: SDAC was administered on average 2.1 hours (range, 0.5 to 6.25 hours) after ingestion in 48 of 254 admissions, and abnormal QT,RR combinations occurred in 2 cases (4.2%), compared with 23 of 206 (11.2%) cases not receiving SDAC. There did not appear to be any clinically important difference in age, sex, dose, and cardiotoxic coingestants between the 2 groups. No cases of torsade de pointes occurred. The estimated relative risk of having an abnormal QT,RR combination for SDAC compared to no SDAC was 0.28 (0.06 to 0.70) (median with 2.5% and 97.5% credible limits). The probability that the relative risk was less than 1.0 was 0.99, which can be interpreted as very strong evidence in favor of a beneficial effect of SDAC. The absolute risk difference was estimated as 7.5% and the median number needed to treat as 13.3. Conclusion: SDAC may be effective in reducing the risk of a prolonged QT in patients after citalopram overdose. Current trends toward nonuse of activated charcoal should be evaluated to determine whether patients poisoned by specific agents may benefit from activated charcoal administration.
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| 4. |
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| 6. |
- Korell, Julia, et al.
(författare)
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A population pharmacokinetic model for low-dose methotrexate and its polyglutamated metabolites in red blood cells.
- 2013
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Ingår i: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 52:6, s. 475-85
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Measurement of intracellular concentrations of methotrexate (MTX) and its polyglutamated metabolites (MTXGlu(2-5)) in red blood cells (RBCs) has been suggested as a potential means of monitoring low-dose MTX treatment of rheumatoid arthritis (RA). However, a possible correlation between RBC MTX and MTXGlu2-5 concentrations and clinical outcomes of MTX treatment in RA is debated. A better understanding of the dose-concentration-time relationship of MTX and MTXGlu(2-5) in RBCs by population pharmacokinetic modelling is desirable and will facilitate assessing a potential RBC concentration-effect relationship in the future.AIM: The purpose of this analysis was to describe the pharmacokinetics of MTX and MTXGlu(2-5) in RBCs. Secondary objectives included investigation of deglutamation reactions and the loss of MTX and MTXGlu(2-5) from the RBC.METHODS: A model was developed using NONMEM(®) version 7.2 based on RBC data obtained from 48 patients with RA receiving once-weekly low-dose MTX treatment. This model was linked to a fixed two-compartment model that was used to describe the pharmacokinetics of MTX in the plasma. A series of five compartments were used to describe the intracellular pharmacokinetics of MTX and MTXGlu(2-5) in RBCs. Biologically plausible covariates were tested for a significant effect on MTX plasma clearance and the intracellular volume of distribution of all MTX species in RBCs ([Formula: see text]). The developed model was used to test hypotheses related to the enzymatic deglutamation of MTXGlu(2-5) and potential loss of MTXGlu(2-5) from RBCs.RESULTS: The final RBC pharmacokinetic model required the intracellular volumes of distribution for the parent and metabolites to be set to the value estimated for the parent drug MTX alone, and the rate constants describing the polyglutamation steps were fixed at literature values. Significant covariates included effect of body surface area-adjusted estimated glomerular filtration rate on renal plasma clearance and effect of allometrically scaled total body weight with a fixed exponent of 0.75 on non-renal plasma clearance of MTX. The only significant covariate with an effect on [Formula: see text] was mean corpuscular volume (MCV). The model supported single deglutamation steps and a single mechanism of MTX and MTXGlu(2-5) loss from RBCs.CONCLUSIONS: The developed model enabled acceptable description of the intracellular kinetics of MTX and MTXGlu(2-5) in RBCs. In the future it can form the basis of a full pharmacokinetic-pharmacodynamic model to assess the time-RBC concentration-effect relationship of low-dose MTX treatment in RA.
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| 7. |
- Korell, Julia, et al.
(författare)
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A semi-mechanistic red blood cell survival model provides some insight into red blood cell destruction mechanisms
- 2013
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Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 40:4, s. 469-478
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Tidskriftsartikel (refereegranskat)abstract
- Most mathematical models developed for the survival of haematological cell populations, in particular red blood cells (RBCs), follow the principle of parsimony. They focus on the predominant destruction mechanism of age-related cell death (senescence) and do not account for within subject variability in the RBC lifespan. However, assessment of the underlying physiological destruction mechanisms can be of interest in pathological conditions that affect RBC survival, for example sickle cell anaemia or anaemia of chronic kidney disease. We have previously proposed a semi-mechanistic RBC survival model which accounts for four different types of RBC destruction mechanisms. In this work, it is shown that the proposed model in combination with informative RBC survival data is able to provide a deeper insight into RBC destruction mechanisms. The proposed model was applied in a non-linear mixed effect modelling framework to biotin derived RBC survival data available from literature. Three mechanisms were estimable based on the available data of twelve subjects, including random destruction, senescence and destruction due to delayed failure. It was possible to identify three subjects with a decreased RBC survival in the study population. These three subjects all showed differences in the contribution of the estimated destruction mechanisms: an increased random destruction, versus an accelerated senescence, versus a combination of both.
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| 8. |
- Korell, Julia, et al.
(författare)
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Comparison of intracellular methotrexate kinetics in red blood cells with the kinetics in other cell types
- 2014
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 77:3, s. 493-497
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Tidskriftsartikel (refereegranskat)abstract
- AimTo assess the similarities in intracellular pharmacokinetics (PK) of methotrexate (MTX) in red blood cells (RBCs) and other cell lines. MethodsThree previously published PK models for intracellular MTX and MTX polyglutamate (MTXGlu(2-5)) concentrations were used: (i) a model for the kinetics in RBCs, (ii) a model for the kinetics in human breast cancer cells (HBCCs) and (iii) a model for the kinetics in various white blood cell (WBC) lines. All three models were used to simulate the response in a typical individual receiving 10mg oral MTX once weekly and the predicted steady-state concentrations (C-ss) and time to C-ss (t(ss)) were compared. ResultsThe HBCC model showed a lower C-ss for MTXGlu(2 and 3) and higher C-ss for MTXGlu(4 and 5) compared with the RBC PK model, while t(ss) and overall intracellular MTX exposure appeared similar. The WBC PK model showed much lower C-ss for the parent MTXGlu(1) and of t(ss) for all MTXGlu(n), as well as a much lower cumulative C-ss for MTXGlu(2-7) for the majority of the WBC cell lines. ConclusionRBC kinetics of MTX differ from the kinetics in other cell types such as WBCs and HBCCs to a variable degree. It is possible that similarly diverse profiles may exist across other cell lines, including those on the causal path in rheumatoid arthritis. Hence, there may not necessarily be a clear link between RBC MTX concentrations and disease control in rheumatoid arthritis.
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| 9. |
- Li, Jingyun, et al.
(författare)
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A general model for cell death and biomarker release from injured tissues
- 2021
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Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer. - 1567-567X .- 1573-8744. ; 48, s. 69-82
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Tidskriftsartikel (refereegranskat)abstract
- Cellular response to insults may result in the initiation of different cell death processes. For many cases the cell death process will result in an acute release of cellular material that in some circumstances provides valuable information about the process (i.e. may represent a biomarker). The characteristics of the biomarker release is often informative and plays critical roles in clinical practice and toxicology research. The aim of this study is to develop a general, semi-mechanistic model to describe cell turnover and biomarker release by injured tissue that can be used for estimation in pharmacokinetic and (toxicokinetic)-pharmacodynamic studies. The model included three components: (1) natural tissue turnover, (2) biomarker release from cell death and its movement from the cell through the tissue into the blood, (3) different target insult mechanisms of cell death. We applied the general model to biomarker release profiles for four different cell insult causes. Our model simulations showed good agreements with reported data under both delayed release and rapid release cases. Additionally, we illustrate the use of the model to provide different biomarker profiles. We also provided details on interpreting parameters and their values for other researchers to customize its use. In conclusion, our general model provides a basic structure to study the kinetic behaviour of biomarker release and disposition after cellular insult.
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| 10. |
- Pan, Shan, et al.
(författare)
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Assessment of the Relationship Between Methotrexate Polyglutamates in Red Blood Cells and Clinical Response in Patients Commencing Methotrexate for Rheumatoid Arthritis
- 2014
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Ingår i: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 53:12, s. 1161-1170
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Tidskriftsartikel (refereegranskat)abstract
- Therapeutic drug monitoring in patients with rheumatoid arthritis (RA) receiving methotrexate (MTX, MTXGlu(1)) has not been established. In this study, we aim to explore the relationship between red blood cell (RBC) concentrations of MTX and its polyglutamate metabolites (MTXGlu (n) ; n = 2, 3, 4, 5) and clinical response in RA patients commencing MTX. The binding activity of MTXGlu (n) to three putative enzymes involved in the MTX mechanism of action-dihydrofolate reductase, thymidylate synthase, and 5-aminoimidazole-4-carboxamide ribonucleotide transformylase-was simulated. RBC MTXGlu (n) concentrations that gave the highest inhibition activity across all three enzymes were linked with the disease activity score DAS28-3v (C-reactive protein [CRP]). A population pharmacokinetic-pharmacodynamic model was developed to describe the relationship between RBC MTX polyglutamate concentrations and clinical response in 12 RA patients commencing MTX. The highest inhibition activity was with RBC MTXGlu(3-5). These polyglutamates were further evaluated for their relationship with DAS28-3v (CRP). Three of the 12 patients had a high DAS28-3v (CRP) at baseline (mean = 6.1) and showed a delayed response to MTX treatment. The remaining nine patients with a lower DAS28-3v (CRP) baseline (mean = 3.6) showed an immediate response. The developed MTX pharmacokinetic-pharmacodynamic model provided an acceptable description of the observed DAS28-3v (CRP) across all patients. The developed model describes a longitudinal relationship between RBC MTXGlu(3-5) concentrations and DAS28-3v (CRP) in patients with RA commencing MTX. Further work is required to determine whether measurement of RBC MTX polyglutamates might be useful for dose individualisation in patients with RA.
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| 11. |
- Shivva, Vittal, et al.
(författare)
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Parameterisation affects identifiability of population models
- 2014
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Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 41:1, s. 81-86
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Tidskriftsartikel (refereegranskat)abstract
- Identifiability is an important aspect of model development. In this work, using a simple one compartment population pharmacokinetic model, we show that identifiability of the variances of the random effects parameters are affected by the parameterisation of the fixed effects parameters.
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