| 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. |
- Claesson, Jonas, et al.
(author)
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Intestinal circulation, oxygenation and metabolism is not affected by oleic acid lung injury.
- 2005
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In: Clinical Physiology and Functional Imaging. - 1475-0961 .- 1475-097X. ; 25:6, s. 357-363
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Journal article (peer-reviewed)abstract
- This study was performed to establish a platform for further studies on effects of ventilatory treatment modalities on the intestines during mechanical ventilation of acute lung injury (ALI). We tested the hypotheses that oleic acid (OA) infusion causes changes in intestinal circulation, oxygenation and metabolism, and that OA is distributed to tissues outside the lung. This was performed as an experimental, prospective and controlled study in an university animal research laboratory. Thirteen juvenile anaesthetized pigs were used in the main study, where seven were given an intravenous infusion of 0.1 ml kg(-1) OA and six served as control (surgery only). In a separate study, four animals were given an intravenous infusion of 0.1 ml kg(-1) (3)H-labelled OA. We measured systemic and mesenteric (portal venous blood flow, jejunal mucosal perfusion) haemodynamic parameters, mesenteric oxygenation (jejunal tissue oxygen tension) and systemic cytokines (tumour necrosis factor-alpha and interleukin-6). We calculated mesenteric lactate flux and mesenteric oxygen delivery, uptake and extraction ratio. In the animals given 3H-OA, we measured 3H-OA in different tissues (lungs, heart, liver, kidney, stomach, jejunum, colon and arterial blood). We found that OA given intravenously is distributed in small amounts to the intestines. This intestinal exposure to OA does not cause intestinal injury when evaluating mesenteric blood flow, metabolism or oxygenation. OA infusion induced a moderate increase in mean pulmonary arterial pressure and a decrease in PaO2/Fraction inspired O2 (P/F) ratio, giving evidence of severe lung injury. Consequently, the OA lung injury model is suitable for studies on intestinal effects of ventilatory treatment modalities during mechanical ventilation of ALI.
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| 6. |
- Claesson, Jonas, et al.
(author)
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Negative mesenteric effects of lung recruitment maneuvers in oleic acid lung injury are transient and short lasting.
- 2007
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In: Critical Care Medicine. - 0090-3493 .- 1530-0293. ; 35:1, s. 230-238
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To test the hypothesis that repeated recruitment maneuvers (RMs) have sustained negative effects on mesenteric circulation, metabolism, and oxygenation 60 mins after RMs in pigs with oleic acid lung injury. Further, we aimed to test the hypothesis that an infusion of prostacyclin (PC) at 33 ng.kg.min would attenuate such possible negative mesenteric effects. DESIGN: Randomized, experimental, controlled study. SETTING: University hospital animal laboratory. SUBJECTS: A total of 31 anesthetized, fluid-resuscitated pigs with oleic acid lung injury. INTERVENTIONS: Animals were randomized to one of the following four groups: a control group (n = 7) that received no intervention, recruitment group (n = 8) that underwent the RM sequence, a prostacyclin group (n = 8) that received an infusion of PC, and a recruitment-prostacyclin group (n = 8) that received an infusion of PC and concomitant RM sequence. MEASUREMENTS AND MAIN RESULTS: We measured systemic and mesenteric hemodynamic variables, jejunal mucosal perfusion, mesenteric lactate flux, jejunal tissue oxygen tension, and mesenteric oxygen delivery, uptake, and extraction ratio. Five minutes after RMs, mesenteric oxygen extraction ratio and mesenteric lactate flux were more prominently increased in the recruitment group, giving evidence of worsened mesenteric conditions after RMs. These signs of worsened conditions were further supported by more decreased jejunal tissue oxygen tension and portal vein oxygen saturation in the recruitment group. PC preserved mesenteric oxygenation, as indicated by less of a decrease in portal vein oxygen saturation at the time corresponding to 5 mins after RM and less of a decrease in mesenteric oxygen delivery at the time corresponding to 15 mins after RM. PC preserved mesenteric oxygenation as indicated by less of a decrease in portal vein oxygen saturation at 5 mins after RM and an attenuated increase in mesenteric oxygen extraction ratio at 5 mins after RM. There was a trend toward worsened jejunal mucosal perfusion, although not significant. CONCLUSIONS: In an oleic acid lung injury model, three repeated RMs did not improve systemic oxygenation or lung mechanics. Negative effects on mesenteric oxygenation and metabolism were transient and short lasting. The intestinal effects of PC during RMs were minor and opposing, showing preserved oxygenation but a trend toward worsened mucosal perfusion.
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| 7. |
- Fröjse, R, et al.
(author)
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Local metabolic effects of dopexamine on the intestine during mesenteric hypoperfusion.
- 2004
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In: Shock. - : Ovid Technologies (Wolters Kluwer Health). - 1073-2322 .- 1540-0514. ; 21:3, s. 241-7
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Journal article (peer-reviewed)abstract
- This self-controlled experimental study was designed to test the hypothesis that dopexamine, a synthetic catecholamine that activates dopaminergic (DA-1) and beta2-adrenergic receptors, improves oxygenation in the jejunal mucosa during intestinal hypotension. In six normoventilated barbiturate-anesthetized pigs, controlled reductions in superior mesenteric arterial pressure (PSMA) was obtained by an adjustable clamp around the artery. Dopexamine infusions (0.5 and 1.0 microg.kg(-1).min(-1)) were administered at a freely variable PSMA (i.e., with the perivascular clamp fully open) and at a PSMA of 50 mmHg and 30 mmHg. We continuously measured superior mesenteric venous blood flow (QMES; transit-time ultrasonic flowmetry), jejunal mucosal perfusion (laser Doppler flowmetry), and tissue oxygen tension (PO2TISSUE; microoximetry). Jejunal luminal microdialysate of lactate, pyruvate, and glucose were measured every 5 min. Measurements of mucosal PCO2 (air tonometry), together with blood sampling and end-tidal PCO2 measurements, enabled calculations of pHi and PCO2 gap. Dopexamine reduced mesenteric vascular resistance and increased QMES at a PSMA of 50 mmHg and 30 mmHg. At a PSMA of 30 mmHg, dopexamine increased mesenteric oxygen delivery but did not influence mesenteric oxygen uptake or extraction. In this situation, dopexamine had no beneficial effect on jejunal mucosal blood flow. On the contrary, dopexamine increased mesenteric net lactate production and PCO2 gap, whereas PO2TISSUE and pHi decreased. Jejunal luminal microdialysate data demonstrated an increased lactate concentration and a pattern of decreased glucose concentration and increased luminal lactate-pyruvate ratio. These negative metabolic effects of dopexamine should be taken into account in situations of low perfusion pressures.
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