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| 2. |
- Hovd, M., et al.
(author)
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Neither Gastric Bypass Surgery Nor Diet-Induced Weight-Loss Affect OATP1B1 Activity as Measured by Rosuvastatin Oral Clearance
- 2023
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In: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 62:5, s. 725-735
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Journal article (peer-reviewed)abstract
- IntroductionRosuvastatin pharmacokinetics is mainly dependent on the activity of hepatic uptake transporter OATP1B1. In this study, we aimed to investigate and disentangle the effect of Roux-en-Y gastric bypass (RYGB) and weight loss on oral clearance (CL/F) of rosuvastatin as a measure of OATP1B1-activity.MethodsPatients with severe obesity preparing for RYGB (n = 40) or diet-induced weight loss (n = 40) were included and followed for 2 years, with four 24-hour pharmacokinetic investigations. Both groups underwent a 3-week low-energy diet (LED; < 1200 kcal/day), followed by RYGB or a 6-week very-low-energy diet (VLED; < 800 kcal/day).ResultsA total of 80 patients were included in the RYGB group (40 patients) and diet-group (40 patients). The weight loss was similar between the groups following LED and RYGB. The LED induced a similar (mean [95% CI]) decrease in CL/F in both intervention groups (RYGB: 16% [0, 31], diet: 23% [8, 38]), but neither induced VLED resulted in any further changes in CL/F. At Year 2, CL/F had increased by 21% from baseline in the RYGB group, while it was unaltered in the diet group. Patients expressing the reduced function SLCO1B1 variants (c.521TC/CC) showed similar changes in CL/F over time compared with patients expressing the wild-type variant.ConclusionsNeither body weight, weight loss nor RYGB per se seem to affect OATP1B1 activity to a clinically relevant degree. Overall, the observed changes in rosuvastatin pharmacokinetics were minor, and unlikely to be of clinical relevance.
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| 3. |
- Krogstad, V., et al.
(author)
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Correlation of Body Weight and Composition With Hepatic Activities of Cytochrome P450 Enzymes
- 2021
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In: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 110:1, s. 432-437
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Journal article (peer-reviewed)abstract
- Obesity is associated with comorbidities of which pharmacological treatment is needed. Physiological changes associated with obesity may influence the pharmacokinetics of drugs, but the effect of body weight on drug metabolism capacity remains uncertain. The aim of this study was to investigate ex vivo activities of hepatic drug metabolizing CYP enzymes in patients covering a wide range of body weight. Liver biopsies from 36 individuals with a body mass index (BMI) ranging from 18 to 63 kg/m(2) were obtained. Individual hepatic microsomes were prepared and activities of CYP3A, CYP2B6, CYP2C8, CYP2D6, CYP2C9, CYP2C19 and CYP1A2 were determined. The unbound intrinsic clearance (C-Lint,C-u) values for CYP3A correlated negatively with body weight (r = -0.43, p < 0.01), waist circumference (r = -0.47, p < 0.01), hip circumference (r = -0.51, p < 0.01), fat percent (r = -0.41, p < 0.05), fat mass (r = -0.48, p < 0.01) and BMI (r = -0.46, p < 0.01). Linear regression analysis showed that C-Lint,C-u values for CYP3A decreased with 5% with each 10% increase in body weight (r(2) = 0.12, beta = -0.558, p < 0.05). There were no correlations between body weight measures and CLint,u values for the other CYP enzymes investigated. These results indicate reduced hepatic metabolizing capacity of CYP3A substrates in patients with increasing body weight. (C) 2020 The Authors. Published by Elsevier Inc.
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| 4. |
- Kvitne, K. E., et al.
(author)
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Correlations between 4 beta-hydroxycholesterol and hepatic and intestinal CYP3A4: protein expression, microsomal ex vivo activity, and in vivo activity in patients with a wide body weight range
- 2022
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In: European Journal of Clinical Pharmacology. - : Springer Science and Business Media LLC. - 0031-6970 .- 1432-1041. ; 78:8, s. 1289-1299
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Journal article (peer-reviewed)abstract
- Purpose Variability in cytochrome P450 3A4 (CYP3A4) metabolism is mainly caused by non-genetic factors, hence providing a need for accurate phenotype biomarkers. Although 4 beta-hydroxycholesterol (4 beta OHC) is a promising endogenous CYP3A4 biomarker, additional investigations are required to evaluate its ability to predict CYP3A4 activity. This study investigated the correlations between 4 beta OHC concentrations and hepatic and intestinal CYP3A4 protein expression and ex vivo microsomal activity in paired liver and jejunum samples, as well as in vivo CYP3A4 phenotyping (midazolam) in patients with a wide body weight range. Methods The patients (n = 96; 78 with obesity and 18 normal or overweight individuals) were included from the COCKTAIL-study (NCT02386917). Plasma samples for analysis of 4 beta OHC and midazolam concentrations, and liver (n = 56) and jejunal (n = 38) biopsies were obtained. The biopsies for determination of CYP3A4 protein concentration and microsomal activity were obtained during gastric bypass or cholecystectomy. In vivo CYP3A4 phenotyping was performed using semi-simultaneous oral (1.5 mg) and intravenous (1.0 mg) midazolam. Results 4 beta OHC concentrations were positively correlated with hepatic microsomal CYP3A4 activity (rho = 0.53, p < 0.001), and hepatic CYP3A4 concentrations (rho = 0.30, p = 0.027), but not with intestinal CYP3A4 concentrations (rho = 0.18, p = 0.28) or intestinal microsomal CYP3A4 activity (rho = 0.15, p = 0.53). 4 beta OHC concentrations correlated weakly with midazolam absolute bioavailability (rho = - 0.23, p = 0.027) and apparent oral clearance (rho = 0.28, p = 0.008), but not with systemic clearance (rho = - 0.03, p = 0.81). Conclusion These findings suggest that 4 beta OHC concentrations reflect hepatic, but not intestinal, CYP3A4 activity. Further studies should investigate the potential value of 4 beta OHC as an endogenous biomarker for individual dose requirements of intravenously administered CYP3A4 substrate drugs.
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| 5. |
- Kvitne, K. E., et al.
(author)
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Short- and long-term effects of body weight, calorie restriction and gastric bypass on CYP1A2, CYP2C19 and CYP2C9 activity
- 2022
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In: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 88:9, s. 4121-4133
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Journal article (peer-reviewed)abstract
- Aim Roux-en-Y gastric bypass (RYGB) may influence drug disposition due to surgery-induced gastrointestinal alterations and/or subsequent weight loss. The objective was to compare short- and long-term effects of RYGB and diet on the metabolic ratios of paraxanthine/caffeine (cytochrome P450 [CYP] 1A2 activity), 5-hydroxyomeprazole/omeprazole (CYP2C19 activity) and losartan/losartan carboxylic acid (CYP2C9 activity), and cross-sectionally compare these CYP-activities with normal-to-overweight controls. Methods This trial included patients with severe obesity preparing for RYGB (n = 40) or diet-induced (n = 41) weight loss, and controls (n = 18). Both weight loss groups underwent a 3-week low-energy diet (<1200 kcal/day, weeks 0-3) followed by a 6-week very-low-energy diet or RYGB (both <800 kcal/day, weeks 3-9). Follow-up time was 2 years, with four pharmacokinetic investigations. Results Mean +/- SD weight loss from baseline was similar in the RYGB-group (13 +/- 2.4%) and the diet group (10.5 +/- 3.9%) at week 9, but differed at year 2 (RYGB -30 +/- 6.9%, diet -3.1 +/- 6.3%). From weeks 0 to 3, mean (95% confidence interval [CI]) CYP2C19 activity similarly increased in both groups (RYGB 43% [16, 55], diet 48% [22, 60]). Mean CYP2C19 activity increased by 30% (2.6, 43) after RYGB (weeks 3-9), but not in the diet-group (between-group difference -0.30 [-0.63, 0.03]). CYP2C19 activity remained elevated in the RYGB group at year 2. Baseline CYP2C19 activity was 2.7-fold higher in controls compared with patients with obesity, whereas no difference was observed in CYP1A2 and CYP2C9 activities. Conclusion Our findings suggest that CYP2C19 activity is lower in patients with obesity and increases following weight loss. This may be clinically relevant for drug dosing. No clinically significant effect on CYP1A2 and CYP2C9 activities was observed.
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| 6. |
- Kvitne, K. E., et al.
(author)
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Short- and long-term effects of body weight loss following calorie restriction and gastric bypass on CYP3A-activity - a non-randomized three-armed controlled trial
- 2022
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In: Cts-Clinical and Translational Science. - : Wiley. - 1752-8054 .- 1752-8062. ; 15:1, s. 221-233
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Journal article (peer-reviewed)abstract
- It remains uncertain whether pharmacokinetic changes following Roux-en-Y gastric bypass (RYGB) can be attributed to surgery-induced gastrointestinal alterations per se and/or the subsequent weight loss. The aim was to compare short- and long-term effects of RYGB and calorie restriction on CYP3A-activity, and cross-sectionally compare CYP3A-activity with normal weight to overweight controls using midazolam as probe drug. This three-armed controlled trial included patients with severe obesity preparing for RYGB (n = 41) or diet-induced (n = 41) weight-loss, and controls (n = 18). Both weight-loss groups underwent a 3-week low-energy-diet (<1200 kcal/day) followed by a 6-week very-low-energy-diet or RYGB (both <800 kcal/day). Patients were followed for 2 years, with four pharmacokinetic investigations using semisimultaneous oral and intravenous dosing to determine changes in midazolam absolute bioavailability and clearance, within and between groups. The RYGB and diet groups showed similar weight-loss at week 9 (13 +/- 2.4% vs. 11 +/- 3.6%), but differed substantially after 2 years (-30 +/- 7.0% vs. -3.1 +/- 6.3%). At baseline, mean absolute bioavailability and clearance of midazolam were similar in the RYGB and diet groups, but higher compared with controls. On average, absolute bioavailability was unaltered at week 9, but decreased by 40 +/- 7.5% in the RYGB group and 32 +/- 6.1% in the diet group at year 2 compared with baseline, with no between-group difference. No difference in clearance was observed over time, nor between groups. In conclusion, neither RYGB per se nor weight loss impacted absolute bioavailability or clearance of midazolam short term. Long term, absolute bioavailability was similarly decreased in both groups despite different weight loss, suggesting that the recovered CYP3A-activity is not only dependent on weight-loss through RYGB.
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| 12. |
- Jansson-Lofmark, R., et al.
(author)
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Does In Vitro Potency Predict Clinically Efficacious Concentrations?
- 2020
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In: Clinical Pharmacology and Therapeutics. - : Wiley. - 0009-9236 .- 1532-6535. ; 108:2, s. 298-305
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Journal article (peer-reviewed)abstract
- The in vitro affinity of a compound for its target is an important feature in drug discovery, but what remains is how predictive in vitro properties are of in vivo therapeutic drug exposure. We assessed the relationship between in vitro potency and clinically efficacious concentrations for marketed small molecule drugs (n = 164) and how they may differ depending on therapeutic indication, mode of action, receptor type, target localization, and function. Approximately 70% of compounds had a therapeutic unbound plasma exposure lower than in vitro potency; the median ratio of exposure in relation to in vitro potency was 0.32, and 80% had ratios within the range of 0.007 to 8.7. We identified differences in the in vivo-to-in vitro potency ratio between indications, mode of action, target type, and matrix localization, and whether or not the drugs had active metabolites. The in vitro-assay variability contributions appeared to be the smallest; within the same drug target and mode of action the within-variability was slightly broader; but both were substantially less compared with the overall distribution of ratios. These data suggest that in vitro potency conditions, estimated in vivo potency, required level of receptor occupancy, and target turnover are key components for further understanding the link between clinical drug exposure and in vitro potency.
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| 14. |
- Lindblad, A, et al.
(author)
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Would physician-assisted suicide jeopardize trust in the medical services? An empirical study of attitudes among the general public in Sweden
- 2009
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In: Scandinavian journal of public health. - : SAGE Publications. - 1403-4948 .- 1651-1905. ; 37:3, s. 260-264
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Journal article (peer-reviewed)abstract
- Aim: To investigate the attitudes among the Swedish population towards physician-assisted suicide, with special regard to the possible effects on trust in the medical services of physician-assisted suicide being allowed. Design: A postal questionnaire about physician-assisted suicide under certain conditions and its possible influence on trust in the medical services was distributed to 1206 randomly selected individuals living in the county of Stockholm. Two reminders were distributed, followed by a short version of the questionnaire containing only the question about the attitude towards physician-assisted suicide. Results: The total response rate was 51%, a short-version reminder adding another 7%. Of all participants, 73% were in favour of physician-assisted suicide, 12% were against, and 15% were undecided. They believed that their trust in the medical services would increase (38%) or not be influenced at all (45%) if physician-assisted suicide were to be allowed. However, 75% of those who were against physician-assisted suicide believed that their trust would decrease. As compared to those reporting high trust in medical services (n = 492), those with low trust (n = 97) stated that their trust would increase, 36% (confidence interval (CI) = 35—37%) vs. 49% (95% CI = 39—59%). Thirty-three per cent (95% CI = 28—38%) of the younger respondents (<50 years), and 43% (95% CI = 37—49%) of the older respondents believed that their trust would increase. Conclusions: We found no evidence for the assumption that trust in the medical services would be unambiguously jeopardized if physician-assisted suicide were to be legalized. Only among the minority who opposed physician-assisted suicide did a majority of respondents report that their trust would decrease.
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| 17. |
- Lofmark, R, et al.
(author)
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From cure to palliation: Staff communication, documentation, and transfer of patient
- 2005
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In: Journal of Palliative Medicine. - : Mary Ann Liebert Inc. - 1096-6218 .- 1557-7740. ; 8:6, s. 1105-1109
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Journal article (peer-reviewed)abstract
- In the transition from curative treatment to palliative care of a general end-of-life patient population, the internal communication of the acute care staff seems to be less than optimal. The communication had reference to the dialogue within the staff both before and after the decision to concentrate on palliative care, and possible transfer of the patient. This survey of Swedish nurses and physicians showed that most of 780 respondents wanted more internal communication, and a more individualized procedure of decision-making. All staff should be informed about the decision made but full agreement was not seen as realistic. The largest difference of opinion between nurses and physicians concerned the involvement of nurses in the decision-making about the transition. A uniform documentation of the decision to transfer care focus was the ideal. Approximately every fourth patient in acute care is transferred to receive palliative care. Only approximately half of the respondents had any training in palliative care and the majority wanted more training. There seems to be a need for more palliative care training, perhaps somewhat different for each speciality. Furthermore, a common language to enable nurses and physicians to communicate more easily may improve the transition process.
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| 20. |
- Lofmark, R, et al.
(author)
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Palliative care training: a survey of physicians in Australia and Europe
- 2006
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In: Journal of palliative care. - : SAGE Publications. - 0825-8597 .- 2369-5293. ; 22:2, s. 105-110
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Journal article (peer-reviewed)abstract
- The purpose of this paper is to present data about the level and background characteristics of physicians’ training in palliative care in Australia (AU), Belgium (BE), Denmark (DK), Italy (IT), the Netherlands (NL), Sweden (SE) and Switzerland (CH) (n=16,486). The response rate to an anonymous questionnaire differed between countries (39%-68%). In most countries approximately half of all responding physicians had any formal training in palliative care (median: 3–10 days). Exceptions were NL (78%) and IT (35%). The most common type of training was a postgraduate course. Physicians in nursing home medicine (only in NL), geriatrics, oncology (not in NL), and general practice had the most training. In all seven countries, physicians with such training discussed options for palliative care and options to forgo life-sustaining treatment more often with their patients than did physicians without. Irrespective of earlier palliative care training, 87%-98% of the physicians wanted extended training.
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| 23. |
- Sokolov, V., et al.
(author)
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Comparative quantitative systems pharmacology modeling of anti-PCSK9 therapeutic modalities in hypercholesterolemia S
- 2019
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In: Journal of Lipid Research. - 0022-2275. ; 60:9, s. 1610-1621
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Journal article (peer-reviewed)abstract
- Since the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) as an attractive target in the treatment of hypercholesterolemia, multiple anti-PCSK9 therapeutic modalities have been pursued in drug development. The objective of this research is to set the stage for the quantitative benchmarking of two anti-PCSK9 pharmacological modality classes, monoclonal antibodies (mAbs) and small interfering RNA (siRNA). To this end, we developed an integrative mathematical model of lipoprotein homeostasis describing the dynamic interplay between PCSK9, LDL-cholesterol (LDL-C), VLDL-cholesterol, HDL-cholesterol (HDL-C), apoB, lipoprotein a [Lp(a)], and triglycerides (TGs). We demonstrate that LDL-C decreased proportionally to PCSK9 reduction for both mAb and siRNA modalities. At marketed doses, however, treatment with mAbs resulted in an additional similar to 20% LDL-C reduction compared with siRNA. We further used the model as an evaluation tool and determined that no quantitative differences were observed in HDL-C, Lp(a), TG, or apoB responses, suggesting that the disruption of PCSK9 synthesis would provide no additional effects on lipoprotein-related biomarkers in the patient segment investigated. Predictive model simulations further indicate that siRNA therapies may reach reductions in LDL-C levels comparable to those achieved with mAbs if the current threshold of 80% PCSK9 inhibition via siRNA could be overcome.
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| 24. |
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