| 1. |
- Adams, Yvonne, et al.
(författare)
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3D blood-brain barrier-organoids as a model for Lyme neuroborreliosis highlighting genospecies dependent organotropism
- 2023
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Ingår i: ISCIENCE. - : CELL PRESS. - 2589-0042. ; 26:1
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Tidskriftsartikel (refereegranskat)abstract
- Lyme neuroborreliosis (LNB), a tick-borne infection caused by spirochetes within the Borrelia burgdorferi sensu lato (s.L.) complex, is among the most prevalent bacterial central nervous system (CNS) infections in Europe and the US. Here we have screened a panel of low- passage B. burgdorferi s.l. isolates using a novel, human-derived 3D blood-brain barrier (BBB)-organoid model. We show that human-derived BBB-organoids support the entry of Borrelia spirochetes, leading to swelling of the organoids and a loss of their structural integrity. The use of the BBB-organoid model highlights the organotropism between B. burgdorferi s.l. genospecies and their ability to cross the BBB contributing to CNS infection.
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| 2. |
- Friberg, Lena E., et al.
(författare)
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Model of Chemotherapy-Induced Myelosuppression With Parameter Consistency Across Drugs
- 2002
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Ingår i: Journal of Clinical Oncology. - 0732-183X .- 1527-7755. ; 20:24, s. 4713-4721
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To develop a semimechanistic pharmacokinetic-pharmacodynamic model describing chemotherapy-induced myelosuppression through drug-specific parameters and system-related parameters, which are common to all drugs. PATIENTS AND METHODS: Patient leukocyte and neutrophil data after administration of docetaxel, paclitaxel, and etoposide were used to develop the model, which was also applied to myelosuppression data from 2'-deoxy-2'-methylidenecytidine (DMDC), irinotecan (CPT-11), and vinflunine administrations. The model consisted of a proliferating compartment that was sensitive to drugs, three transit compartments that represented maturation, and a compartment of circulating blood cells. Three system-related parameters were estimated: baseline, mean transit time, and a feedback parameter. Drug concentration-time profiles affected the proliferation of sensitive cells by either an inhibitory linear model or an inhibitory E(max) model. To evaluate the model, system-related parameters were fixed to the same values for all drugs, which were based on the results from the estimations, and only drug-specific parameters were estimated. All modeling was performed using NONMEM software. RESULTS: For all investigated drugs, the model successfully described myelosuppression. Consecutive courses and different schedules of administration were also well characterized. Similar system-related parameter estimates were obtained for the different drugs and also for leukocytes compared with neutrophils. In addition, when system-related parameters were fixed, the model well characterized chemotherapy-induced myelosuppression for the different drugs. CONCLUSION: This model predicted myelosuppression after administration of one of several different chemotherapeutic drugs. In addition, with fixed system-related parameters to proposed values, and only drug-related parameters estimated, myelosuppression can be predicted. We propose that this model can be a useful tool in the development of anticancer drugs and therapies.
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| 3. |
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| 4. |
- Henningsson, Anja, 1973-
(författare)
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Mechanism-Based Pharmacokinetic and Pharmacodynamic Modelling of Paclitaxel
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Paclitaxel (Taxol®) is now widely used against breast, ovarian and non-small-cell lung cancer. Anticancer agents generally have narrow therapeutic indices, often with myelosuppression (mainly neutropenia) as dose-limiting side effect. A further complicating factor is that paclitaxel when given as Taxol® has a nonlinear pharmacokinetic (PK) behaviour in plasma. Identifying risk groups more sensitive to chemotherapy due to either a PK or pharmacodynamic (PD) interindividual variability is of importance. The aim of the thesis was to develop predictive mechanism-based PK and PD models applicable for paclitaxel. PK and PK/PD models were developed for patient data from studies with relatively frequent sampling or sparse sampling schedules. Population analyses were performed using the software NONMEM. A pharmacokinetic model describing unbound, total plasma and blood concentrations of paclitaxel from known binding mechanisms was developed and validated. The nonlinear PK in plasma could to a large extent be explained by the micelle forming vehicle Cremophor EL (CrEL) and the unbound drug showed linear PK. Besides a binding component directly proportional to concentrations of CrEL, the model included both linear and nonlinear binding components in plasma and blood. Further, relations between the PK parameters and different demographic factors, including polymorphisms in the cytochrome P450s involved in paclitaxel metabolism, were investigated. A semi-physiological PD model for chemotherapy-induced myelosuppression was developed and applied to different anticancer drugs. The model included a self-renewal for proliferating cells, transit compartments describing the delay in observed myelosuppression and a feedback parameter reflecting the effect on the bone marrow from growth factors that can result in an overshoot in white blood cells. The system-related parameters estimated showed consistency across drugs and the difference in the drug-related parameter reflected the relative bone marrow toxicity of the drugs. Relations between demographic factors and the PD parameters were identified. The developed mechanism-based models promote a better understanding of paclitaxel PK and PD and may be used as tools in dosing individualisation and in development of dosing strategies for new administration forms and new drugs in the same area.
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| 5. |
- Henningsson, Anja, et al.
(författare)
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Mechanism-based pharmacokinetic model for paclitaxel
- 2001
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Ingår i: Journal of Clinical Oncology. - 0732-183X .- 1527-7755. ; 19:20, s. 4065-4073
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE To create a model based on known mechanisms of paclitaxel distribution that could describe the pharmacokinetics (PK) of total and unbound plasma concentrations, as well as blood concentrations. In addition, to investigate the relationship between exposure, based on unbound and total concentrations, and neutropenia. PATIENTS AND METHODS Paclitaxel and Cremophor EL (CrEL) concentrations were obtained from 23 female and three male patients (50 courses in total) with different cancer types that received paclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ) (135 to 225 mg/m(2)) as 3- or 24-hour intravenous infusions. Seven of the patients received combination therapy with doxorubicin or cisplatin. The population PK model was built to fit three types of data simultaneously: unbound, total plasma, and blood concentrations. The area under the curve, threshold, and general models were used to relate neutrophil survival fraction from 19 patients (29 courses in total) to exposure based on unbound and total plasma concentration, respectively. RESULTS The PK model included a linear three-compartment model for unbound concentration, binding directly proportional to CrEL, linear and nonlinear binding to plasma proteins, and linear and nonlinear binding to blood cells. The threshold model best described the PK/pharmacodynamic (PD) relationship for total concentration. No distinction could be made between the models for unbound drug. CONCLUSION Earlier PK models for paclitaxel have been empirical. This study shows that a mechanistic model can be used to describe the nonlinear PK of paclitaxel. There is an indication that the PK/PD relationship is not the same for unbound and total plasma concentrations.
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| 6. |
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| 7. |
- Henningsson, Anja, et al.
(författare)
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Population pharmacokinetic modelling of unbound and total plasma concentrations of paclitaxel in cancer patients
- 2003
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Ingår i: European Journal of Cancer. - 0959-8049 .- 1879-0852. ; 39:8, s. 1105-1114
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to validate and further develop a mechanism-based population pharmacokinetic model for paclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ, USA) based on the knowledge of Cremophor EL (CrEL) micelle entrapment and to evaluate the exposure/toxicity relationships. Paclitaxel (total and unbound) and CrEL concentrations were obtained according to a sparse sampling scheme with on average only 3.5 samples per course from 45 patients with solid tumours who received 3-hour infusions of paclitaxel (final dose range 112-233 mg/m(2)). The present data were predicted well by the mechanism-based model. In addition, bilirubin and body size were found to be significant as covariates. A change in body surface area (BSA) of 0.1 m(2) typically caused a change in clearance (CL) of 22.3 l/h and an increase in bilirubin of 10 microM typically caused a decrease in CL of 41 l/h. Toxicity was best described by a threshold model. In conclusion, even with a sparse sampling scheme, the same mechanism-based binding components as in the previously developed model could be identified. Once the CrEL and total paclitaxel plasma concentrations are known, the unbound concentrations, which are more closely related to the haematological toxicity, can be predicted.
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| 8. |
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| 9. |
- Jönsson, Siv, et al.
(författare)
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Role of modelling and simulation : a European regulatory perspective
- 2012
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Ingår i: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 51:2, s. 69-76
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Tidskriftsartikel (refereegranskat)abstract
- Modelling and simulation (M&S) of clinical data, e.g. pharmacokinetic, pharmacodynamic and clinical endpoints, is a useful approach for more efficient interpretation of collected data and for extrapolation of knowledge to the entire target population. This type of documentation is included in the majority of marketing authorization applications for new medicinal products. This article summarizes the current status of regulatory review with respect to the role of M&S in Europe from the perspective of the Swedish Medical Products Agency. At present, regulatory bodies in Europe encourage the application of the M&S approach during drug development. However, there is a lack of consensus and transparent guidance documents. The main regulatory usage is in the evaluation of dose choices in sub-populations and as support for the dosing regimen in general. The regulatory review of conestat alfa illustrates how the dose recommendation was revised during the approval procedure based on M&S information. A survey of marketing authorization applications for new medicinal products approved in 2010 revealed that the use of the information gained from M&S documentation varies with respect to both regulatory review and the applicants' presentation of the data in the submitted dossier. Increased utilization and broadened application of M&S is anticipated in pharmaceutical development, where one area of focus is medicines for paediatric patients. Accordingly, the regulatory agencies will need to increase their capability to assess and utilize this type of information, and an interactive process among regulatory agencies is warranted to provide more unified regulatory assessment and guidance. Moreover, applicants are encouraged to expand on the usage of exposure-response models to map the systemic exposure range that yields safe and efficacious treatment and to improve the presentation of the gained knowledge in summary documents of the marketing authorization applications.
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