| 1. |
- Darwich, Adam S., et al.
(författare)
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IMI - Oral biopharmaceutics tools project - Evaluation of bottom-up PBPK prediction success part 3 : Identifying gaps in system parameters by analysing In Silico performance across different compound classes
- 2017
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 96, s. 626-642
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Tidskriftsartikel (refereegranskat)abstract
- Three Physiologically Based Pharmacokinetic software packages (GI-Sim, Simcyp (R) Simulator, and GastroPlus (TM)) were evaluated as part of the Innovative Medicine Initiative Oral Biopharmaceutics Tools project (OrBiTo) during a blinded "bottom-up" anticipation of human pharmacokinetics. After data analysis of the predicted vs. measured pharmacokinetics parameters, it was found that oral bioavailability (F-oral) was underpredicted for compounds with low permeability, suggesting improper estimates of intestinal surface area, colonic absorption and/or lack of intestinal transporter information. Foralwas also underpredicted for acidic compounds, suggesting overestimation of impact of ionisation on permeation, lack of information on intestinal transporters, or underestimation of solubilisation of weak acids due to less than optimal intestinal model pH settings or underestimation of bile micelle contribution. F-oral was overpredicted for weak bases, suggesting inadequate models for precipitation or lack of in vitro precipitation information to build informed models. Relative bioavailability was underpredicted for both high logP compounds as well as poorly water-soluble compounds, suggesting inadequate models for solubility/dissolution, underperforming bile enhancement models and/or lack of biorelevant solubility measurements. These results indicate areas for improvement in model software, modelling approaches, and generation of applicable input data. However, caution is required when interpreting the impact of drug-specific properties in this exercise, as the availability of input parameters was heterogeneous and highly variable, and the modellers generally used the data "as is" in this blinded bottom-up prediction approach.
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| 2. |
- Eriksson, Johanna, et al.
(författare)
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Pulmonary Dissolution of Poorly Soluble Compounds Studied in an ex Vivo Rat Lung Model
- 2019
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 16:7, s. 3053-3064
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Tidskriftsartikel (refereegranskat)abstract
- Many inhaled drugs are poorly water soluble, and the dissolution rate is often the rate-limiting step in the overall absorption process. To improve understanding of pulmonary drug dissolution, four poorly soluble inhalation compounds (AZD5423 (a developmental nonsteroidal glucocorticoid), budesonide, fluticasone furoate (FF), and fluticasone propionate (FP)) were administered as suspensions or dry powders to the well-established isolated perfused 4 rat lung (IPL) model. Two particle size distributions (d50 = 1.2 mu m and d50 = 2.8 mu m) were investigated for AZD5423. The pulmonary absorption rates of the drugs from the suspensions and dry powders were compared with historical absorption data for solutions to improve understanding of the effects of dissolution on the overall pulmonary absorption process for poorly soluble inhaled drugs. A physiologically based biopharmaceutical in silico model was used to analyze the experimental IPL data and to estimate a dissolution parameter (K-ex vivo). A similar in silico approach was applied to in vitro dissolution data from the literature to obtain an in vitro dissolution parameter (Kin vitro). When FF, FP, and the larger particles of AZD5423 were administered as suspensions, drug dissolution was the rate-limiting step in the overall absorption process. However, this was not the case for budesonide, which has the highest aqueous solubility (61 mu M), and the smaller particles of AZD5423, probably because of the increased surface area available for dissolution (d50 = 1.2 mu m). The estimated dissolution parameters were ranked in accordance with the solubility of the drugs, and there was good agreement between k(ex vivo) and k(in vitro). The dry powders of all the compounds were absorbed more slowly than the suspensions, indicating that wetting is an important parameter for the dissolution of dry powders. A wetting factor was introduced to the in silico model to explain the difference in absorption profiles between the suspensions and dry powders where AZD5423 had the poorest wettability followed by FP and FF. The IPL model in combination with an in silico model is a useful tool for investigating pulmonary dissolution and improving understanding of dissolution-related parameters for poorly soluble inhaled compounds.
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| 3. |
- Eriksson, Johanna, et al.
(författare)
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Pulmonary drug absorption and systemic exposure in human : Predictions using physiologically based biopharmaceutics modeling
- 2020
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : ELSEVIER. - 0939-6411 .- 1873-3441. ; 156, s. 191-202
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Tidskriftsartikel (refereegranskat)abstract
- Systemic exposure of inhaled drugs is used to estimate the local lung exposure and assess systemic side effects for drugs with local pharmacological targets. Predicting systemic exposure is therefore central for successful development of drugs intended to be inhaled. Currently, these predictions are based mainly on data from in vitro experiments, but the accuracy of these predictions might be improved if they were based on data with higher physiological relevance. In this study, systemic exposure was simulated by applying biopharmaceutics input parameters from isolated perfused rat lung (IPL) data to a lung model developed in MoBi (R) as an extension to the full physiologically-based pharmacokinetic (PBPK) model in PK-Sim (R). These simulations were performed for a set of APIs with a variety of physicochemical properties and formulation types. Simulations based on rat IPL data were also compared to simulations based on in vitro data. The predictive performances of the simulations were evaluated by comparing simulated plasma concentration-time profiles to clinical observations after pulmonary administration. Simulations using IPL-based input parameters predicted systemic exposure well, with predicted AUCs within two-fold of the observed value for nine out of ten drug compounds/formulations, and predicted Cmax values within two-fold for eight out of ten drug compounds/formulations. Simulations using input parameters based on IPL data performed generally better than simulations based on in vitro input parameters. These results suggest that the developed model in combination with IPL data can be used to predict human lung absorption for compounds with different physicochemical properties and types of inhalation formulations.
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| 4. |
- Margolskee, Alison, et al.
(författare)
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IMI - Oral biopharmaceutics tools project - Evaluation of bottom-up PBPK prediction success part 2 : An introduction to the simulation exercise and overview of results
- 2017
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 96, s. 610-625
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Tidskriftsartikel (refereegranskat)abstract
- Orally administered drugs are subject to a number of barriers impacting bioavailability (F-oral), causing challenges during drug and formulation development. Physiologically-based pharmacokinetic (PBPK) modelling can help during drug and formulation development by providing quantitative predictions through a systems approach. The performance of three available PBPK software packages (GI-Sim, Simcyp (R), and GastroPlus (TM)) were evaluated by comparing simulated and observed pharmacokinetic (PK) parameters. Since the availability of input parameters was heterogeneous and highly variable, caution is required when interpreting the results of this exercise. Additionally, this prospective simulation exercise may not be representative of prospective modelling in industry, as API information was limited to sparse details. 43 active pharmaceutical ingredients (APIs) from the OrBiTo database were selected for the exercise. Over 4000 simulation output files were generated, representing over 2550 study arm-institution-software combinations and approximately 600 human clinical study arms simulated with overlap. 84% of the simulated study arms represented administration of immediate release formulations, 11% prolonged or delayed release, and 5% intravenous (i.v.). Higher percentages of i.v. predicted area under the curve (AUC) were within two-fold of observed (52.9%) compared to per oral (p.o.) (37.2%), however, F-oral and relative AUC (F-rel) between p.o. formulations and solutions were generally well predicted (64.7% and 75.0%). Predictive performance declined progressing from i.v. to solution and immediate release tablet, indicating the compounding error with each layer of complexity. Overall performance was comparable to previous large-scale evaluations. A general overprediction of AUC was observed with average fold error (AFE) of 1.56 over all simulations. AFE ranged from 0.0361 to 64.0 across the 43 APIs, with 25 showing overpredictions. Discrepancies between software packages were observed for a few APIs, the largest being 606, 171, and 81.7-fold differences in AFE between SimCYP and GI-Sim, however average performance was relatively consistent across the three software platforms.
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| 5. |
- Sjögren, Erik, et al.
(författare)
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In Silico Modeling of Gastrointestinal Drug Absorption : Predictive Performance of Three Physiologically Based Absorption Models
- 2016
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 13:6, s. 1763-1778
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Tidskriftsartikel (refereegranskat)abstract
- Gastrointestinal (GI) drug absorption is a complex process determined by formulation, physicochemical and biopharmaceutical factors, and GI physiology. Physiologically based in silico absorption models have emerged as a widely used and promising supplement to traditional in vitro assays and preclinical in vivo studies. However, there remains a lack of comparative studies between different models. The aim of this study was to explore the strengths and limitations of the in silico absorption models Simcyp 13.1, GastroPlus 8.0, and GI-Sim 4.1, with respect to their performance in predicting human intestinal drug absorption. This was achieved by adopting an a priori modeling approach and using well-defined input data for 12 drugs associated with incomplete GI absorption and related challenges in predicting the extent of absorption. This approach better mimics the real situation during formulation development where predictive in silico models would be beneficial. Plasma concentration-time profiles for 44 oral drug administrations were calculated by convolution of model predicted absorption-time profiles and reported pharmacokinetic parameters. Model performance was evaluated by comparing the predicted plasma concentration-time profiles, C-max, t(max), and exposure (AUC) with observations from clinical studies. The overall prediction accuracies for AUC, given as the absolute average fold error (AAFE) values, were 2.2, 1.6, and 1.3 for Simcyp, GastroPlus, and GI-Sim, respectively. The corresponding AAFE values for C-max were 2.2, 1.6, and 1.3, respectively, and those for t(max) were 1.7, 1.5, and 1.4, respectively. Simcyp was associated with underprediction of AUC and C-max; the accuracy decreased with decreasing predicted J(abs). A tendency for underprediction was also observed for GastroPlus, but there was no correlation with predicted f(abs). There were no obvious trends for over- or underprediction for GI-Sim. The models performed similarly in capturing dependencies on dose and particle size. In conclusion, it was shown that all three software packages are useful to guide formulation development. However, as a consequence of the high fraction of inaccurate predictions (prediction error >2-fold) and the clear trend toward decreased accuracy with decreased predicted f(abs) observed with Simcyp, the results indicate that GI-Sim and GastroPlus perform better than Simcyp in predicting the intestinal absorption of the incompletely absorbed drugs when a higher degree of accuracy is needed. In addition, this study suggests that modeling and simulation research groups should perform systematic model evaluations using their own input data to maximize confidence in model performance and output.
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| 6. |
- Sjögren, Erik, et al.
(författare)
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Reply to "Comment on 'In Silico Modeling of Gastrointestinal Drug Absorption : Predictive Performance of Three Physiologically Based Absorption Models'"
- 2017
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 14:1, s. 340-343
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Tidskriftsartikel (refereegranskat)abstract
- This is a reply to the comment on "In Silico Modeling of Gastrointestinal Drug Absorption: Predictive Performance of Three Physiologically Based Absorption Models" by Turner and other Simcyp associates. In the reply we address the major concerns raised by Turner et al. regarding the methodology to compare the predictive performance of the different absorption models and at the same time ensure that the systemic pharmacokinetic input was exactly the same for the different models; the selection of the human effective permeability value of fexofenadine; the adoption of model default values and settings; and how supersaturation/precipitation was handled. In addition, we also further discuss aspects related to differences in in silk() models and the potential implications of such differences. Our original report should be viewed as the starting point in a thorough and transparent review of absorption prediction models with the overall aim of improving their application as validated tools for bridging studies of active pharmaceutical ingredients from various sources and origins in a regulatory context. With this reply we encourage other independent investigators to perform further model evaluations of commercial as well as other existing or recently implemented models. This will boost the overall progression of physiologically based biopharmaceutical models for predicting and simulating intestinal drug absorption both in research and development and in a regulatory context.
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| 7. |
- Ödesjö, Helena, et al.
(författare)
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Adherence to lipid-lowering guidelines for secondary prevention and potential reduction in CVD events in Swedish primary care: a cross-sectional study
- 2020
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Ingår i: Bmj Open. - : BMJ. - 2044-6055. ; 10:10
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Tidskriftsartikel (refereegranskat)abstract
- Objectives The protective effect of lipid-lowering treatment for secondary prevention after coronary heart disease (CHD) has been well documented. Current guidelines recommend a target level for low-density lipoprotein cholesterol (LDL-C) of <= 1.8 mmol/L. The aim was to describe lipid-lowering treatment patterns and to provide an estimate of the potential reductions in cardiovascular disease (CVD) events with improved adherence to guidelines. Design Cross-sectional. Setting Primary care in a large Swedish region. Participants 37 120 patients with CHD in a Swedish regional primary care quality register (QregPV), by 31 December 2015. Primary and secondary outcome measures Proportion of patients on statin treatment and proportion of patients achieving LDL-C <= 1.8 mmol/L. Estimated number of CVD events calculated for (1) current treatment, (2) improved treatment and (3) lowered LDL-C, based on applying rate reductions from meta-analyses of randomised trials to the potentially undertreated population. Risk estimation modelling was based on 52 042 patients in the same register on January 2011 followed for 5 years. Results Of 37 120 patients, 18% reached LDL-C <= 1.8 mmol/L and 32% were not on statin treatment. Based on individual risks, the estimated number of CVD events in the study group over 5 years was 9209/37 120. If all patients without a statin or with less potent statin treatment were given atorvastatin 80 mg, an estimated reduction of CVD events by 14% (7901 vs 9209) was seen. If all patients achieved LDL-C <= 1.8 mmol/L, the number of events was estimated to be reduced by 18% (7577 vs 9209). Conclusion One-third of patients with CHD in primary care were not on lipid-lowering treatment. Based on the assumption that included patients would react to statin therapy the same way as the patients in randomised trials, improved adherence to treatment guidelines could lead to a substantial reduction in new CVD events.
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| 8. |
- Ödesjö, Helena, et al.
(författare)
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Pay for performance associated with increased volume of medication reviews but not with less inappropriate use of medications among the elderly - an observational study
- 2017
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Ingår i: Scandinavian Journal of Primary Health Care. - : Informa UK Limited. - 0281-3432 .- 1502-7724. ; 35:3, s. 271-278
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Tidskriftsartikel (refereegranskat)abstract
- Objective: A pay for performance programme was introduced in 2009 by a Swedish county with 1.6 million inhabitants. A process measure with payment linked to coding for medication reviews among the elderly was adopted. We assessed the association with inappropriate medication for five years after baseline. Design and setting: Observational study that compared medication for elderly patients enrolled at primary care units that coded for a high or low volume of medication reviews. Patients: 144,222 individuals at 196 primary care centres, age 75 or older. Main outcome measures: Percentage of patients receiving inappropriate drugs or polypharmacy during five years at primary care units with various levels of reported medication reviews. Results: The proportion of patients with a registered medication review had increased from 3.2% to 44.1% after five years. The high-coding units performed better for most indicators but had already done so at baseline. Primary care units with the lowest payment for coding for medication reviews improved just as well in terms of inappropriate drugs as units with the highest payment - from 13.0 to 8.5%, compared to 11.6 to 7.4% and from 13.6 to 7.2% vs 11.8 to 6.5% for polypharmacy. Conclusions: Payment linked to coding for medication reviews was associated with an increase in the percentage of patients for whom a medication review had been registered. However, the impact of payment on quality improvement is uncertain, given that units with the lowest payment for medication reviews improved equally well as units with the highest payment.
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| 9. |
- Ödesjö, Helena, et al.
(författare)
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Short-term effects of a pay-for-performance programme for diabetes in a primary care setting: an observational study
- 2015
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Ingår i: Scandinavian Journal of Primary Health Care. - : Informa UK Limited. - 0281-3432 .- 1502-7724. ; 33:4, s. 291-297
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Tidskriftsartikel (refereegranskat)abstract
- Objective A pay-for-performance (P4P) programme for primary care was introduced in 2011 by a Swedish county (with 1.6 million inhabitants). Effects on register entry practice and comparability of data for patients with diabetes mellitus were assessed.Design and setting Observational study analysing short-term outcomes before and after introduction of a P4P programme in the study county as compared with a reference county.Subjects A total of 84 053 patients reported to the National Diabetes Register by 349 primary care units.Main outcome measures Completeness of data, level and target achievement of glycated haemoglobin (HbA1c), blood pressure (BP), and LDL cholesterol (LDL).Results In the study county, newly recruited patients who were entered during the incentive programme were less well controlled than existing patients in the register - they had higher HbA1c (54.9 [54.5-55.4] vs. 53.7 [53.6-53.9] mmol/mol), BP, and LDL. The percentage of patients with entry of BP, HbA1c, LDL, albuminuria, and smoking increased in the study county but not in the reference county (+26.3% vs -1.5%). In the study county, with an incentive for BP<130/80mmHg, BP data entry behaviour was altered with an increased preference for sub-target BP values and a decline in zero end-digit readings (38.3% vs. 33.7%, p<0.001).Conclusion P4P led to increased register entry, increased completeness of data, and altered BP entry behaviour. Analysis of newly added patients and data shows that missing patients and data can cause performance to be overestimated. Potential effects on reporting quality should be considered when designing payment programmes.
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| 10. |
- Ödesjö, Helena, et al.
(författare)
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Visit patterns at primary care centres and individual blood pressure level - a cross-sectional study
- 2019
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Ingår i: Scandinavian Journal of Primary Health Care. - : Informa UK Limited. - 0281-3432 .- 1502-7724. ; 37:1, s. 53-59
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Hypertension is a major cause of cardiovascular disease. Nevertheless, blood pressure (BP) is often inadequately treated. We studied visit patterns at primary health care centres (PHCCs) and their relation to individual BP control. Design and setting: Cross-sectional register-based study on all patients with hypertension who visited 188 PHCCs in a Swedish region. Patients: A total of 88,945 patients with uncomplicated hypertension age 40-79. Main outcome measures: Odds ratio (OR) for the individual patient to achieve the BP target of <= 140/90 mmHg. Results: Overall, 63% of patients had BP <= 140/90 mmHg (48% BP < 140/90). The PHCC that the patient was enrolled at and, as part of that, more nurse visits at PHCC level was associated with BP control, adjusted OR 1,10 (95% CI 1.01 to 1.21). Patients visiting PHCCs with the highest proportion of visits with nurses had an even higher chance of achieving the BP target, OR 1.19 (95% CI 1.07 to 1.32). Conclusions: In a Swedish population of patients with hypertension, about half do not achieve recommended treatment goals. Organisation of PHCC and team care are known as factors influencing BP control. Our results suggests that a larger focus on PHCC organisation including nurse based care could improve hypertension care.
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