Dataset Information

Evaluation of an In Silico PBPK Post-Bariatric Surgery Model through Simulating Oral Drug Bioavailability of Atorvastatin and Cyclosporine.

ABSTRACT: An increasing prevalence of morbid obesity has led to dramatic increases in the number of bariatric surgeries performed. Altered gastrointestinal physiology following surgery can be associated with modified oral drug bioavailability (Foral). In the absence of clinical data, an indication of changes to Foral via systems pharmacology models would be of value in adjusting dose levels after surgery. A previously developed virtual "post-bariatric surgery" population was evaluated through mimicking clinical investigations on cyclosporine and atorvastatin after bariatric surgery. Cyclosporine simulations displayed a reduced fraction absorbed through gut wall (fa) and Foral after surgery, consistent with reported observations. Simulated atorvastatin Foral postsurgery was broadly reflective of observed data with indications of counteracting interplay between reduced fa and an increased fraction escaping gut wall metabolism (FG). Inability to fully recover observed atorvastatin exposure after biliopancreatic diversion with duodenal switch highlights the current gap regarding the knowledge of associated biological changes.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e47; doi:10.1038/psp.2013.23; advance online publication 12 June 2013.

SUBMITTER: Darwich AS

PROVIDER: S-EPMC3697036 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Evaluation of an In Silico PBPK Post-Bariatric Surgery Model through Simulating Oral Drug Bioavailability of Atorvastatin and Cyclosporine.

Darwich A S AS Pade D D Rowland-Yeo K K Jamei M M Asberg A A Christensen H H Ashcroft D M DM Rostami-Hodjegan A A

CPT: pharmacometrics & systems pharmacology 20130612

An increasing prevalence of morbid obesity has led to dramatic increases in the number of bariatric surgeries performed. Altered gastrointestinal physiology following surgery can be associated with modified oral drug bioavailability (Foral). In the absence of clinical data, an indication of changes to Foral via systems pharmacology models would be of value in adjusting dose levels after surgery. A previously developed virtual "post-bariatric surgery" population was evaluated through mimicking cl ...[more]

PMID: 23903405

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Project description:Bariatric surgery is often the preferred method to resolve obesity and diabetes, with ∼800,000 cases worldwide yearly and high outcome variability. The ability to predict the long-term body mass index (BMI) change following surgery has important implications for individuals and the health care system in general. Given the tight connection between eating habits, sugar consumption, BMI, and the gut microbiome, we tested whether the microbiome before any treatment is associated with different treatment outcomes, as well as other intakes (high-density lipoproteins [HDL], triglycerides, etc.). A projection of the gut microbiome composition of obese (sampled before and after bariatric surgery) and lean patients into principal components was performed, and the relation between this projection and surgery outcome was studied. The projection revealed three different microbiome profiles belonging to lean, obese, and obese individuals who underwent bariatric surgery, with the postsurgery microbiome more different from the lean microbiome than the obese microbiome. The same projection allowed for a prediction of BMI loss following bariatric surgery, using only the presurgery microbiome. The microbial changes following surgery were an increase in the relative abundance of Proteobacteria and Fusobacteria and a decrease in Firmicutes. The gut microbiome can be decomposed into main components depicting the patient's development and predicting in advance the outcome. Those may be translated into the better clinical management of obese individuals planning to undergo metabolic surgery. IMPORTANCE BMI and diabetes can affect the gut microbiome composition. Bariatric surgery has large variabilities in the outcome. The microbiome was previously shown to be a good predictor for multiple diseases. We analyzed here the gut microbiome before and after bariatric surgery and showed the following. (i) The microbiome before surgery can be used to predict surgery outcomes. (ii) The postsurgery microbiome drifts further away from the lean microbiome than the microbiome of the presurgery obese patients. These results can lead to a microbiome-based presurgery decision whether to perform surgery.

Project description:Atorvastatin, prescribed for the treatment of hypercholesterolemia, demonstrated overwhelming benefits in reducing cardiovascular morbidity and mortality. However, many patients discontinue therapy due to adverse reactions, especially myopathy. The Dutch Pharmacogenetics Working Group (DPWG) recommends an alternative agent to atorvastatin and simvastatin or a dose adjustment depending on other risk factors for statin-induced myopathy in SLCO1B1 rs4149056 CC or TC carriers. In contrast, the Clinical Pharmacogenetics Implementation Consortium (CPIC) published their guideline on simvastatin, but not on atorvastatin. In this work, we aimed to demonstrate the effect of SLCO1B1 phenotype and other variants (e.g., in CYP3A4/5, UGT enzymes or SLC transporters) on atorvastatin pharmacokinetics. For this purpose, a candidate-gene pharmacogenetic study was proposed. The study population comprised 156 healthy volunteers enrolled in atorvastatin bioequivalence clinical trials. The genotyping strategy comprised a total of 60 variants in 15 genes. Women showed higher exposure to atorvastatin compared to men (p = 0.001), however this difference disappeared after dose/weight (DW) correction. The most relevant pharmacogenetic differences were the following: AUC/DW and Cmax /DW based on (a) SLCO1B1 phenotype (p < 0.001 for both) and (b) CYP3A5*3 (p = 0.004 and 0.018, respectively). As secondary findings: SLC22A1 *2/*2 genotype was related to higher Cmax/DW (ANOVA p = 0.030) and SLC22A1 *1/*5 genotype was associated with higher Vd/F (ANOVA p = 0.032) compared to SLC22A1 *1/*1, respectively. Finally, UGT2B7 rs7439366 *1/*1 genotype was associated with higher tmax as compared with the *1/*3 genotype (ANOVA p = 0.024). Based on our results, we suggest that SLCO1B1 is the best predictor for atorvastatin pharmacokinetic variability and that prescription should be adjusted based on it. We suggest that the CPIC should include atorvastatin in their statin-SLCO1B1 guidelines. Interesting and novel results were observed based on CYP3A5 genotype, which should be confirmed with further studies.

Project description:Purpose Physical activity is critical for weight loss maintenance and cardiometabolic disease prevention after metabolic/bariatric surgery (MBS), but few patients meet recommended levels. While difficulties meeting physical activity recommendations are common in the general population, those who have undergone MBS may have unique psychological barriers to activity that impede success, including negative associations with physical activity that are related to a long history with obesity, weight stigma, and physical limitations. This qualitative study aimed to better understand the positive and negative emotional experiences of post-MBS patients with regard to physical activity to inform the development of an emotion-focused intervention to increase physical activity after MBS. Methods Adults who had MBS in the past 2 years completed semi-structured interviews and psychological/behavioral questionnaires. After transcription, a codebook was developed using inductive and deductive methods. Coded data were analyzed using content analysis. Results Participants were 23 adults (78% female). Contexts that contributed to positive emotions during physical activity included an enjoyable type of exercise, social interaction, mindfulness during exercise, and mastery. Contexts that contributed to negative affect were more unique to the MBS population, including all-or-nothing thinking about exercise, using distraction, depression, negative body image, exercising only for weight loss, and the COVID-19 pandemic. Conclusion For most participants, emotional factors were relevant in the decision to be physically active and in their ability to maintain their habits. An intervention that encourages factors that lead to positive affect and addresses factors that lead to negative affect could be effective in increasing physical activity following MBS. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s11695-021-05807-x.

Dataset Information

Evaluation of an In Silico PBPK Post-Bariatric Surgery Model through Simulating Oral Drug Bioavailability of Atorvastatin and Cyclosporine.

Publications

Evaluation of an In Silico PBPK Post-Bariatric Surgery Model through Simulating Oral Drug Bioavailability of Atorvastatin and Cyclosporine.

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