Bariatric surgery is a common applied surgical intervention in individuals with obesity to achieve weight-loss, to reduce comorbidities and improve overall survival. However, commonly performed techniques are associated with physiological changes in the gastrointestinal tract that may lead to changes in oral drug disposition. Furthermore, recommended dietary restrictions after bariatric surgery might influence drug disposition and due to prophylactic prescribed drugs interactions might occur. Also, in the years after bariatric surgery, patients will lose weight. These alterations can influence oral drug disposition of oral antineoplastic drugs and, subsequently influence outcomes of breast cancer treatment. The purpose of this review is to provide an overview of the available evidence on the effect of bariatric surgery on the pharmacokinetics of oral antineoplastic drug used in breast cancer treatment. We performed a comprehensive analysis of published pharmacokinetic and pharmacodynamics data. Subsequently we provide, where possible, recommendations on preferences within therapeutic classes and provide recommendations when prescribing oral antineoplastic drugs for breast cancer. Due to the limited availability of clinical evidence on oral drug disposition and subsequently outcomes in this population, our advice is to monitor patients extensively for efficacy but also for safety before and after surgery.

Background and Purpose: Realistic models predicting hepatobiliary processes in health and disease are lacking. We therefore aimed to develop a physiologically relevant human liver model consisting of normothermic machine perfusion (NMP) of explanted diseased human livers that can be used to investigate hepatic first-pass, clearance, biliary excretion and drug-drug interactions. Experimental approach: Eleven livers were included in the study, seven with a cirrhotic and four with a non-cirrhotic disease background. After explantation of the diseased liver, the liver artery and portal vein were reconstructed followed by NMP. After 120 minutes of perfusion, a drug cocktail (rosuvastatin, digoxin, metformin and furosemide) was administered to the portal vein and 120 minutes later, a second bolus of the drug cocktail was co-administered with drug inhibitors to study relevant drug-drug interactions. Key results: The explanted livers showed good viability and functionality after explantation and 360 minutes of NMP. Hepatic first-pass and clearance of rosuvastatin and digoxin showed to be the most affected by cirrhosis with an increase in Cmax of 10.03 and 2.89 times, respectively, compared to non-cirrhotic livers. No major differences were observed for metformin and furosemide. Drug-drug interaction of rosuvastatin or digoxin with inhibitors were more pronounced in non-cirrhotic livers compared to cirrhotic livers. Conclusions and Implications: Our results demonstrated that explanted cirrhotic and non-cirrhotic livers were suitable for NMP and we demonstrated the applicability to study hepatic first pass, clearance, biliary excretion and drug-drug interaction. This model can be applied in a variety of research settings for hepatology, transplantation and pharmacology

Bariatric or weight-loss surgery is a popular option for weight reduction. Depending on the surgical procedure, gastric changes like decreased transit time and volume and increased pH, decreased absorption surface in the small intestine, decreased exposure to bile acids and enterohepatic circulation, and decreased gastrointestinal transit time may be expected. In the years after bariatric surgery, patients will also substantially lose weight. As a result of these changes, the absorption, distribution, metabolism, and/or elimination of drugs may be altered. The purpose of this article is to report the general influence of bariatric surgery on oral drug absorption, and to provide guidance for dosing of commonly used or high-risk drugs in this special population. Upon oral drug administration, the time to maximum concentration is often earlier and this concentration may be higher with less consistent effects on trough concentrations and exposure. Additionally, prescription of liquid formulations to bariatric patients is supported by some reports, even though the high sugar load of these suspensions may be of concern. Studies on extended release medications result in an unaltered exposure for a substantial number of drugs. Also, studies evaluating the influence of timing after surgery show dynamic absorption profiles. Although for this group a specific advice can be proposed for many drugs, we conclude that there is insufficient evidence for general advices for oral drug therapy after bariatric surgery implying that a risk assessment on a case-by-case basis is required for each drug.

Aim In critically ill mechanically ventilated children, midazolam is used first line for sedation, however its sedative effects have been difficult to quantify for which novel quantification methods are still required. In this analysis, we use parametric time-to-event (PTTE) analysis to quantify the effects of midazolam in critically ill children. Methods For the PTTE analysis, data was analyzed from a published sedation interruption study in mechanically ventilated critically ill children. In this study, blinded midazolam or placebo infusions were administered during the sedation interruption phase until, based on COMFORT-B and NISS scores, patients became undersedated and unblinded midazolam was restarted. Using NONMEM® v.7.4.3.,the restart of unblinded midazolam was analysed as a clinical event, followed by internal and external validation. Results Data contained 138 events from 79 individuals (37 blinded midazolam; 42 blinded placebo). In the PTTE model, a constant function best described the baseline hazard. The use of midazolam reduced the hazard for restart of unblinded midazolam due to undersedation by 51%. In the blinded midazolam group, time to midazolam restart was 26 h versus 58 h in patients with low versus high disease severity upon admission (PRISM II <10 versus > 21), respectively. For blinded placebo these times were 14 h and 33 h, respectively. The model performed well in an external validation with 42 individuals. Conclusion The PTTE analysis effectively quantified the effect of midazolam and the influence of disease severity on sedation in mechanically ventilated critically ill children and provides a valuable tool to quantify sedative efficacy