A Dutch Survey on Medication Adjustments after Metabolic and Bariatric Surgery: Experiences of Bariatric Surgeons, Internists, Pharmacists, and General Practitioners

Background: As metabolic and bariatric surgery (MBS) can alter the pharmacokinetics of drugs, post-bariatric surgery patients may require medication adjustments and monitoring. To improve pharmacotherapy in these patients, we aimed to understand the beliefs, attitudes, knowledge, and concerns of healthcare professionals who treat these patients. Methods: A survey by means of an online questionnaire was divided into six sections. It was sent to bariatric surgeons, internists, pharmacists, and general practitioners in the Netherlands. Results: Out of 229 returned surveys, 222 were included. Virtually all respondents (98%) expected MBS to influence the effect of medication. Both reduced efficacy (23%) and more adverse events or medication-related complications (21%) were recognized. Two-thirds of the respondents felt competent to prescribe or to provide advice regarding medication in post-bariatric surgery patients. Most of the respondents (95%) believed that other healthcare professionals should be aware of the contraindication “bariatric surgery”. Of the respondents, 37% indicated that they were not aware of the medication advice incorporated in the electronic health record systems. Almost half of the respondents (48%) indicated that they documented changes in drug effects. Most respondents answered that these ought to be registered in the pharmacovigilance database or national registry. Conclusions: The majority of prescribers and pharmacists believe that patients will receive better pharmacotherapy if healthcare professionals take MBS into account. However, not all prescribers think they are competent to act adequately. To improve this, information on changed drug effects after MBS should be more widely shared among healthcare professionals via resources that are easily accessible. Graphical Abstract: (Figure presented.

Impact of Bariatric Surgery in the Short and Long Term: A Need for Time-Dependent Dosing of Drugs

Sparse information is available on pharmacokinetic changes of drugs over time after bariatric surgery. By reviewing the literature on the short- and long-term pharmacokinetic changes of drugs, several patterns were identified for 39 drugs. No relevant pharmacokinetic changes were identified for roughly a third of the drugs. Of the remaining drugs, levels were variable and partly unpredictable shortly after the surgery. In the long term, most of the drug levels remain altered, but in some cases they returned to preoperative values. Based on the changes and the efficacy-safety balance of each drug, clinicians may need to perform additional clinical monitoring for specific drugs, including measuring drug levels. This review provides suggestions for clinicians and pharmacists for specific time-dependent drug dosing advice

Clinical trial simulation to optimize trial design for fludarabine dosing strategies in allogeneic hematopoietic cell transplantation

Optimal fludarabine exposure has been associated with improved treatment outcome in allogeneic hematopoietic cell transplantation, suggesting potential benefit of individualized dosing. A randomized controlled trial (RCT) comparing alternative fludarabine dosing strategies to current practice may be warranted, but should be sufficiently powered for a relevant end point, while still feasible to enroll. To find the optimal design, we simulated RCTs comparing current practice (160 mg/m 2) to either covariate-based or therapeutic drug monitoring (TDM)-guided dosing with potential outcomes being nonrelapse mortality (NRM), graft failure, or relapse, and ultimately overall survival (covering all three aforementioned outcomes). The inclusion in each treatment arm (n) required to achieve 80% power was calculated for all combinations of end points and dosing comparisons. The trial requiring the lowest n for sufficient power compared TDM-guided dosing to current practice with NRM as primary outcome (n = 70, NRM decreasing from 21% to 5.7%). We conclude that a superiority trial is feasible

Utilization of data below the analytical limit of quantitation in pharmacokinetic analysis and modeling: promoting interdisciplinary debate

Traditionally, bioanalytical laboratories do not report actual concentrations for samples with results below the LOQ (BLQ) in pharmacokinetic studies. BLQ values are outside the method calibration range established during validation and no data are available to support the reliability of these values. However, ignoring BLQ data can contribute to bias and imprecision in model-based pharmacokinetic analyses. From this perspective, routine use of BLQ data would be advantageous. We would like to initiate an interdisciplinary debate on this important topic by summarizing the current concepts and use of BLQ data by regulators, pharmacometricians and bioanalysts. Through introducing the limit of detection and evaluating its variability, BLQ data could be released and utilized appropriately for pharmacokinetic research

The influence of body composition on the systemic exposure of paclitaxel in esophageal cancer patients

Changes in body composition are associated with chemotherapy-related toxicities and effectiveness of treatment. It is hypothesized that the pharmacokinetics (PK) of chemotherapeutics may depend on body composition. The effects of body composition on the variability of paclitaxel PK were studied in patients with esophageal cancer. Skeletal muscle index (SMI), visceral adipose tissue (VAT), and skeletal muscle density (SMD) were measured at the third lumbar vertebra on computed tomography (CT) scans performed before treatment. Paclitaxel PK data were collected from a prospective study performed between May 2004 and January 2014. Non-linear mixed-effects modeling was used to fit paclitaxel PK profiles and evaluate the covariates body surface area (BSA), SMI, VAT, and SMD using a significance threshold of p < 0.001. Paclitaxel was administered to 184 patients in a dose range of 50 to 175 mg/m2 . Median BSA was 1.98 m2 (range of 1.4 to 2.8 m2 ). SMI, VAT, and SMD were not superior to BSA in predicting paclitaxel PK. The additive value of SMI, VAT, and SMD to BSA was also negligible. We did not find evidence that paclitaxel dosing could be further optimized by correcting for SMI, VAT, or SMD

Sex differences in cardiovascular complications and mortality in hospital patients with covid-19: registry based observational study

Objective To assess whether the risk of cardiovascular complications of covid-19 differ between the sexes and to determine whether any sex differences in risk are reduced in individuals with pre-existing cardiovascular disease. Design Registry based observational study. Setting 74 hospitals across 13 countries (eight European) participating in CAPACITY-COVID (Cardiac complicAtions in Patients With SARS Corona vIrus 2 regisTrY), from March 2020 to May 2021 Participants All adults (aged ≥18 years), predominantly European, admitted to hospital with highly suspected covid-19 disease or covid-19 disease confirmed by positive laboratory test results (n=11 167 patients). Main outcome measures Any cardiovascular complication during admission to hospital. Secondary outcomes were in-hospital mortality and individual cardiovascular complications with ≥20 events for each sex. Logistic regression was used to examine sex differences in the risk of cardiovascular outcomes, overall and grouped by pre-existing cardiovascular disease. Results Of 11 167 adults (median age 68 years, 40% female participants) included, 3423 (36% of whom were female participants) had pre-existing cardiovascular disease. In both sexes, the most common cardiovascular complications were supraventricular tachycardias (4% of female participants, 6% of male participants), pulmonary embolism (3% and 5%), and heart failure (decompensated or de novo) (2% in both sexes). After adjusting for age, ethnic group, pre-existing cardiovascular disease, and risk factors for cardiovascular disease, female individuals were less likely than male individuals to have a cardiovascular complication (odds ratio 0.72, 95% confidence interval 0.64 to 0.80) or die (0.65, 0.59 to 0.72). Differences between the sexes were not modified by pre-existing cardiovascular disease; for the primary outcome, the female-to-male ratio of the odds ratio in those without, compared with those with, pre-existing cardiovascular disease was 0.84 (0.67 to 1.07). Conclusions In patients admitted to hospital for covid-19, female participants were less likely than male participants to have a cardiovascular complication. The differences between the sexes could not be attributed to the lower prevalence of pre-existing cardiovascular disease in female individuals. The reasons for this advantage in female individuals requires further research

Patients with bariatric surgery: Urgent need for accurate registration of the contraindication to enable safe pharmacotherapy in hospital and primary care

Purpose: To enable the use of automatic clinical decision support for pharmacotherapy in patients with bariatric surgery, it is necessary to register the contraindication “bariatric surgery” in the hospital, general practitioner (GP), and community pharmacy electronic health record systems. The aim of this research was to quantify the correct registration of this contraindication in hospital, GP, and community pharmacy records. Furthermore, we investigated whether the registration status in primary care was dependent on the registration status in the hospital. Methods: From patients who underwent bariatric procedures performed in the Albert Schweitzer Hospital (Dordrecht, the Netherlands) between 2018 and 2021, the percentage of registered contraindications in hospital medical records was assessed. Due to feasibility reasons, a subset of the patients’ data was created for assessing the percentage of registered contraindications in GP and community pharmacy records. Results: Out of 664 patients who underwent bariatric surgery, the contraindication bariatric surgery was registered in 69.1% of the cases. Out of 552 patients, 28.3% and 25.1% were correctly registered in GP and community pharmacy records, respectively. There was no correlation between registration status in the hospital EHR and registration status in GP practices or community pharmacies. Conclusions: The percentage of correct registration of bariatric surgery in hospital, GP, and community pharmacies is low. To avoid doctors prescribing and pharmacists dispensing drugs to post-bariatric patients without knowing that they have undergone this procedure, better registration of the contraindication is required to enable optimal use of clinical decision support systems for the pharmacotherapy of patients after bariatric surgery

Simultaneous quantification of busulfan, clofarabine and F-ARA-A using isotope labelled standards and standard addition in plasma by LC–MS/MS for exposure monitoring in hematopoietic cell transplantation conditioning

In allogeneic hematopoietic cell transplantation (HCT) it has been shown that over- or underexposure to conditioning agents have an impact on patient outcomes. Conditioning regimens combining busulfan (Bu) and fludarabine (Flu) with or without clofarabine (Clo) are gaining interest worldwide in HCT. To evaluate and possibly adjust full conditioning exposure a simultaneous analysis of Bu, F-ARA-A (active metabolite of Flu) and Clo in one analytical run would be of great interest. However, this is a chromatographical challenge due to the large structural differences of Bu compared to F-ARA-A and Clo. Furthermore, for the bioanalysis of drugs it is common to use stable isotope labelled standards (SILS). However, when SILS are unavailable (in case of Clo and F-ARA-A) or very expensive, standard addition may serve as an alternative to correct for recovery and matrix effects. This study describes a fast analytical method for the simultaneous analysing of Bu, Clo and F-ARA-A with liquid chromatography-tandem mass spectrometry (LC–MS/MS) including standard addition methodology using 604 spiked samples. First, the analytical method was validated in accordance with European Medicines Agency guidelines. The lower limits of quantification (LLOQ) were for Bu 10 μg/L and for Clo and F-ARA-A 1 μg/L, respectively. Variation coefficients of LLOQ were within 20% and for low medium and high controls were all within 15%. Comparison of Bu, Clo and F-ARA-A standard addition results correspond with those obtained with calibration standards in calf serum. In addition for Bu, results obtained by this study were compared with historical data analysed within TDM. In conclusion, an efficient method for the simultaneous quantification of Bu, Clo and F-ARA-A in plasma was developed. In addition, a robust and cost-effective method to correct for matrix interference by standard addition was established

Excellent T-cell reconstitution and survival provided ATG exposure is low or absent after pediatric cord blood transplantation

Successful immune reconstitution (IR) is associated with improved outcomes following pediatric cord blood transplantation (CBT). Usage and timing of anti-thymocyte globulin (ATG), introduced to the conditioning to prevent graft-versus-host-disease and graft failure, negatively influences T-cell IR. We studied the relation between ATG exposure, IR and clinical outcomes. All pediatric patients receiving a first CBT between 2004-2015 at the University Medical Center Utrecht were included. ATG-exposure measures were determined with a validated PK-model. Main outcome of interest was early CD4+ IR, defined as CD4+ T-cell counts over 50x10(6)/L twice within 100 days after CBT. Other outcomes of interest included event free survival (EFS). Cox proportional-hazard and Fine-Gray competing-risk models were used. A total of 137 patients, median age of 7.4 years (range 0.2-22.7), were included, of whom 82% received ATG. Area under the curve (AUC) of ATG after infusion of the CB transplant predicted successful CD4+ IR. Adjusted probability on CD4+ IR was reduced with 26% for every 10 points increase in AUC after CBT (hazard ratio (HR) 0.974, p<0.0001). Chances on EFS were higher in patients with successful CD4+ IR (HR 0.26, p<0.0001) and lower ATG exposure after CBT (HR 1.005, p=0.0071). This study stresses the importance of early CD4+ IR after CBT, which can be achieved by reducing the exposure to ATG after CBT. Individualized dosing of ATG to reach optimal exposure, or in selected patients omission of ATG, may contribute to improved outcomes in pediatric CBT