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.

Forecasting oral absorption across biopharmaceutics classification system classes with physiologically based pharmacokinetic models

“…Appropriate implementation of PBPK models and the interpretation of results from modelling and simulation studies can thus reduce both the time and cost required for the development of a suitable drug product . Retrospective simulations of pharmacokinetic profiles have already been published by several authors . However, prospective prediction of the complete pharmacokinetic profile in humans using preclinical data, which would be a quantum leap for the pharmaceutical industry, remains a challenge.…”

Modelling the Absorption of Metformin with Patients Post Gastric Bypass Surgery

“…To mimic this condition, the transit times and the length of duodenum and jejunum compartments in ACAT model were set to zero. Data suggest that the transit time of small intestine is increased [4,24,26], Quigley et al found that the small intestinal transit time is increased by 35% following 50% resections of dogs small instinet and by 29% following 75% of the resections [27]. Therefore, the transit time of the ileum was increased by 32% especially that the RYGB resections, to some extent, is variable.…”

“…He reviewed many studies, which used PBPK module, to realize how physiological factors such as age, gender, race, weight, height, disease, genetic polymorphism, pregnancy, and organ impairments influence the PK of drugs that administered to each populations in these conditions [40]. One of recent study has also evaluated using PBPK modeling, using the Simcyp Simulator TM software, as a tool in examining the impact of physiological changes in obesity surgery [4]. The study used cyclosporine and atorvastatin as models drugs to predict the drugs absorption after RYBG and biliopancreatic diversion biliopancreatic diversion with duodenal switch, respectively .The study concluded that PBPK has a potential to predict the oral drug bioavailability in the absence of clinical data [4].…”

“…One of recent study has also evaluated using PBPK modeling, using the Simcyp Simulator TM software, as a tool in examining the impact of physiological changes in obesity surgery [4]. The study used cyclosporine and atorvastatin as models drugs to predict the drugs absorption after RYBG and biliopancreatic diversion biliopancreatic diversion with duodenal switch, respectively .The study concluded that PBPK has a potential to predict the oral drug bioavailability in the absence of clinical data [4]. The current study supports this finding and showed the importance of using computer simulations as a valuable tool to simulate the impact and mechanistic background of the physiological changes on drugs absorption.…”

“…Roux-en-Y gastric bypass (RYGB) is a popular operation as it claimed to be the most effective and safest procedure to decrease the body weight in obese patients [3] (Figure 1). Currently there are no specific guidelines for adjusting the dose of drugs administered to post gastric bypass surgery patients, and the effect of the surgery on a drugs' bioavailability is not very clear [4]. Literature reports that the observed drug absorption patterns after gastric bypass surgery are sometimes unexpected.…”