| 1. |
- Bergstrand, Martin, 1977-, et al.
(author)
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A semi-mechanistic model for characterization of regional absorption properties and prospective prediction of plasma concentrations following administration of new modified release formulations
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Journal article (other academic/artistic)abstract
- Methods to study in vivo gastro intestinal (GI) transit and/or regional absorption of pharmaceuticals are available and increasingly used in drug development. A modelling approach to utilize the information generated in such studies for prospective predictions of absorption from newly developed modified release formulations was outlined and tested for the investigational drug AZD0837. This work was a natural extension to the companion article “A semi-mechanistic model to link in vitro and in vivo drug release for modified release formulations”. The drug release model governed the amount of substance released in distinct GI regions over time. GI distribution of released drug substance, region specific rate and extent of absorption and the influence of concomitant food intake were estimated with the model. The model was informed by data from a magnetic marker monitoring study and an intubation study with local administration in colon. Disposition estimates were further supported by observations following administration of oral solution and intravenous infusion of AZD0837. Distinctly different absorption properties were characterized for different GI regions. Bioavailability over the gut-wall was estimated to be high for substance released in the stomach and absorbed in duodenum (70%) compared to substance released and absorbed in the small intestine (25%). Bioavailability was once again higher in colon (70%) but on the other hand considerably slower than in the earlier parts of the GI tract. The established model was largely successful in predicting plasma concentration following administration of three newly developed formulations for which no clinical data had been applied during model building.
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| 2. |
- Bergstrand, Martin, 1977-, et al.
(author)
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A semi-mechanistic model to link in vitro and in vivo drug release for modified release formulations
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Journal article (other academic/artistic)abstract
- In vivo prediction of drug release based on in vitro experiments is important for the development of new modified release (MR) formulations. Most efforts to improve such predictions have focused on altering the in vitro experiments to more resemble the in vivo conditions. A novel approach is evaluated in the present article where a computer model is established and used to link results from standard static in vitro experiment to in vivo predictions. A nonlinear mixed-effects model describing the in vitro drug release for 6 closely related hydrophilic matrix based MR formulations across different experimental conditions (pH, rotation speed and ionic strength) was developed. This model was applied to in vivo observations of drug release and tablet gastro intestinal (GI) position assessed with Magnetic Marker Monitoring (MMM). By combining the MMM observations with literature information on pH and ionic strength along the GI tract, the mechanical stress in different parts of the GI tract could be estimated in units equivalent to rotation speed in the in vitro set-up (USP 2 apparatus). The mechanical stress in the upper stomach was estimated to be 94 rpm and 134 rpm in the lower stomach. For the small intestine and colon the estimates of mechanical stress was 93 and 38 rpm respectively. Predictions of in vivo drug release including expected between subject/tablet variability could be made for other newly developed formulations based on the drug release model combined with a model describing tablet GI transit. This exemplifies a modeling approach that can be utilized to predict in vivo behavior from standard in vitro experiments and support formulation development and quality control of MR formulations.
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| 3. |
- Bergstrand, Martin, 1977-, et al.
(author)
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A semi-mechanistic modeling strategy for characterization of regional absorption properties and prospective prediction of plasma concentrations following administration of new modified release formulations
- 2012
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In: Pharmaceutical research. - : Springer Science+Business Media B.V.. - 0724-8741 .- 1573-904X. ; 29:2, s. 574-584
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Journal article (peer-reviewed)abstract
- PURPOSE To outline and test a new modeling approach for prospective predictions of absorption from newly developed modified release formulations based on in vivo studies of gastro intestinal (GI) transit, drug release and regional absorption for the investigational drug AZD0837. METHODS This work was a natural extension to the companion article "A semi-mechanistic model to link in vitro and in vivo drug release for modified release formulations". The drug release model governed the amount of substance released in distinct GI regions over time. GI distribution of released drug substance, region specific rate and extent of absorption and the influence of food intake were estimated. The model was informed by magnetic marker monitoring data and data from an intubation study with local administration in colon. RESULTS Distinctly different absorption properties were characterized for different GI regions. Bioavailability over the gut-wall was estimated to be high in duodenum (70%) compared to the small intestine (25%). Colon was primarily characterized by a very slow rate of absorption. CONCLUSIONS The established model was largely successful in predicting plasma concentration following administration of three newly developed formulations for which no clinical data had been applied during model building.
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| 4. |
- Bergstrand, Martin, 1977-, et al.
(author)
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A Semi-mechanistic Modeling Strategy to Link In Vitro and In Vivo Drug Release for Modified Release Formulations
- 2012
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In: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 29:3, s. 695-706
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Journal article (peer-reviewed)abstract
- PURPOSE: To develop a semi-mechanistic model linking in vitro to in vivo drug release. METHODS: A nonlinear mixed-effects model describing the in vitro drug release for 6 hydrophilic matrix based modified release formulations across different experimental conditions (pH, rotation speed and ionic strength) was developed. It was applied to in vivo observations of drug release and tablet gastro intestinal (GI) position assessed with magnetic marker monitoring (MMM). By combining the MMM observations with literature information on pH and ionic strength along the GI tract, the mechanical stress in different parts of the GI tract could be estimated in units equivalent to rotation speed in the in vitro USP 2 apparatus. RESULTS: The mechanical stress in the upper and lower stomach was estimated to 94 and 134 rpm, respectively. For the small intestine and colon the estimates of mechanical stress was 93 and 38 rpm. Predictions of in vivo drug release including between subject/tablet variability was made for other newly developed formulations based on the drug release model and a model describing tablet GI transit. CONCLUSION: The paper outlines a modeling approach for predicting in vivo behavior from standard in vitro experiments and support formulation development and quality control.
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| 5. |
- Bergstrand, Martin, et al.
(author)
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Mechanistic modeling of a magnetic marker monitoring study linking gastrointestinal tablet transit, in vivo drug release, and pharmacokinetics
- 2009
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In: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 86:1, s. 77-83
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Journal article (peer-reviewed)abstract
- Magnetic marker monitoring (MMM) is a new technique for visualizing transit and disintegration of solid oral dosage forms through the gastrointestinal (GI) tract. The aim of this work was to develop a modeling approach for gaining information from MMM studies using data from a food interaction study with felodipine extended-release (ER) formulation. The interrelationship between tablet location in the GI tract, in vivo drug release, and felodipine disposition was modeled. A Markov model was developed to describe the tablet's movement through the GI tract. Tablet location within the GI tract significantly affected drug release and absorption through the gut wall. Food intake decreased the probability of tablet transition from the stomach, decreased the rate with which released felodipine left the stomach, and increased the fraction absorbed across the gut wall. In conclusion, the combined information of tablet location in the GI tract, in vivo drug release, and plasma concentration can be utilized in a mechanistically informative way with integrated modeling of data from MMM studies.
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| 6. |
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| 7. |
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| 8. |
- Lindberg, Hans, et al.
(author)
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Devaluation Expectations : The Swedish Krona 1982-1991
- 1991
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Reports (other academic/artistic)abstract
- Devaluation expectations for the Swedish krona are estimated for the period 1982-1991 with several methods. First the "simplest test" is applied under either only the minimal assumption of "no positive minimum profit" or the additional assumption of uncovered interest parity. Then a more precise method suggested by Bertola and Svensson is used, in which expected rates of depreciation within the exchange rate band, estimated in several ways, are subtracted from interest rate differentials. Finally, estimated devaluations expectations are to some extent explained by a few macrovariables and parliament elections.
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| 9. |
- Rosenhall, Ulf, et al.
(author)
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Self-assessed hearing problems in Sweden: a demographic study.
- 1999
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In: Audiology : official organ of the International Society of Audiology. - : Informa UK Limited. - 0020-6091. ; 38:6, s. 328-34
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Journal article (peer-reviewed)abstract
- A study of self-assessed hearing problems was performed comprising 48,680 Swedish inhabitants aged 16-84 years. The participants of the survey responded to personal interviews during the period 1986-1993. One of the questions in the interview concerned difficulties of hearing in background noise. The total prevalence of the reported hearing problems was 10.7 per cent, varying from 2.4 per cent in the youngest age group to 30 per cent in the oldest. Men reported difficulties in hearing more often than women, except in the youngest age group. Hearing problems were more often reported by manual workers, unemployed and by those who had taken early retirement, than by non-manual employees and the self-employed. Regional differences regarding hearing problems were observed. The prevalence of self-reported problems was lowest in metropolitan Stockholm (7.9 per cent) and increased in the following order: other major cities (9.4 per cent), other cities (10.5 per cent), small population centres (12.5 per cent), agricultural areas (13.5 per cent) and sparsely populated forest areas (15 per cent). In summary, a number of factors related to ageing, socioeconomic status and domicile were related to self-assessed difficulties hearing a conversation. These factors obviously include determinants such as genetics, health status, gender-related differences, exposure to noise and possible conditioning effects of low-level noise exposure.
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| 10. |
- Selegård, Linnéa, et al.
(author)
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Bifunctional gadolinium decorated ZnO nanocrystals integrating both enhanced MR signal and bright fluorescence
- 2013
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Other publication (other academic/artistic)abstract
- Gadolinium decorated ZnO nanoparticles simultaneously possess both fluorescent and MR enhancement properties. These ZnO nanoparticles are crystalline and shielded by an amorphous gadolinium acetate matrix. Interestingly, the Gd-acetate decoration enhances the fluorescence emission of the ZnO nanoparticles. The quantum yield does increase for samples with high Gd/Zn relative ratios and these samples do also show a higher colloidal stability.In addition, these nanoparticles show an enhanced relaxivity value per Gd atom (r119.9mM1s-1) compared to results earlier reported both on Gd alloyed ZnO nanoparticles and pure Gd2O3 nanoparticles. This improvement is considered to be due to the close proximity of Gd atoms and surrounding water molecules. A comprehensive study of the quantum yield and the relaxivity, as a function of composition, enable us to identify the ultimate design/composition of gadolinium decorated ZnO nanoparticles for optimum fluorescence and MR enhancement properties.
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