Optimized In Silico Modeling of Drug Absorption after Gastric Bypass: The Case of Metformin

Abstract

Bariatric surgery is an effective treatment for severe obesity and related comorbidities, such as type II diabetes. Gastric bypass surgery shortens the length of the intestine, possibly leading to altered drug absorption. Metformin, a first-line treatment for type II diabetes, has permeability-dependent drug absorption, which may be sensitive to intestinal anatomic changes during bypass surgery, including Roux-en-Y gastric bypass (RYGB). Previous computer simulation data indicate increased metformin absorption after RYGB. In this study, we experimentally determined the region-dependent permeability of metformin, using the rat single-pass intestinal perfusion method (SPIP), which we then implemented into GastroPlusTM to assess the contribution of our SPIP data to post-RYGB metformin absorption modeling. Previous simulations allowed a good fit with in vivo literature data on healthy and obese control subjects. However, it was revealed that for post-RYGB drug absorption predictions, simply excluding the duodenum/jejunum is insufficient, as the software underestimates the observed plasma concentrations post-RYGB. By implementing experimentally determined segmental-dependent permeabilities for metformin in the remaining segments post-surgery, GastroPlusTM proved to fit the observed plasma concentration profile, making it a useful tool for predicting drug absorption after gastric bypass. Reliable evaluation of the parameters dictating drug absorption is required for the accurate prediction of overall absorption after bariatric surgery.

Antiallergic Treatment of Bariatric Patients: Potentially Hampered Solubility/Dissolution and Bioavailability of Loratadine, but Not Desloratadine, Post-Bariatric Surgery

“…We believe that a thorough, in-depth mechanistic analysis, , which reveals potential post-surgery problems on one hand, and at the same time provides adequate substitutions to avoid the complexity, will significantly contribute to better pharmacotherapy and overall patient care after bariatric surgery. In this context, the approach applied in this study, where experimental data are implemented in advanced PBPK models, represents a sensible manner to advance our understanding of this complex drug treatment challenge. ,, However, in the absence of clinical data to support the obtained results, the simulation data should be treated with caution. Namely, previous studies on metformin absorption in post-gastric bypass patients highlighted the need for PBPK model adaptations to properly simulate the observed drug plasma concentration profiles after gastric bypass. , To the best of our knowledge, there are currently no available data on loratadine and desloratadine absorption in post-bariatric patients, meaning that some of the mechanisms that may overcome hampered loratadine absorption in the GI tract might be overlooked in the applied PBPK model.…”

“…In this context, the approach applied in this study, where experimental data are implemented in advanced PBPK models, represents a sensible manner to advance our understanding of this complex drug treatment challenge. ,, However, in the absence of clinical data to support the obtained results, the simulation data should be treated with caution. Namely, previous studies on metformin absorption in post-gastric bypass patients highlighted the need for PBPK model adaptations to properly simulate the observed drug plasma concentration profiles after gastric bypass. , To the best of our knowledge, there are currently no available data on loratadine and desloratadine absorption in post-bariatric patients, meaning that some of the mechanisms that may overcome hampered loratadine absorption in the GI tract might be overlooked in the applied PBPK model. Meanwhile, close monitoring of bariatric patients for both drug levels and clinical signs of therapeutic success/failure is absolutely necessary.…”

“…), whereat the system of differential equations is used to calculate the amount of drug dissolved and absorbed from each compartment over time. , Pre-surgery simulations were performed using the default ACAT inputs, except for the percent fluid volumes in the small intestine (23%) and colon (0.5%), which were taken from the literature . The additional ACAT model adjustments for post-bariatric patients included stomach pH value (increased from default pH 1.3 to pH 5.0 for post-LSG patients and pH 7.0 for post-OAGB patients), stomach volume (decreased from default 50 to 10 mL, corresponding to 20% of the pre-surgery gastric volume), and stomach transit time (decreased from default 0.25 to 0.12 h , ). To simulate the bypassed duodenum and jejunum in post-OAGB patients, the volume, length, and transit time for duodenum, jejunum 1, and jejunum 2 were set to zero in this group…”

Managing the Unpredictable: Mechanistic Analysis and Clinical Recommendations for Lamotrigine Treatment after Bariatric Surgery

“…Similar mechanistic analysis should be performed for more drugs [ 38 ], and in vitro, in vivo and in silico models [ 39 ] should support this mechanistic approach, producing more valuable data. The aim of this mechanistic approach is to allow prediction of the pharmacokinetic changes of a given drug before prescribing it to the post-bariatric patient and design a tailored treatment plan, hence choosing the most appropriate drug and dosing regimen.…”

The Complexity of Bariatric Patient’s Pharmacotherapy: Sildenafil Biopharmaceutics and Pharmacokinetics before vs. after Gastric Sleeve/Bypass

“…Physiological parameters describing a healthy human representative in the fasted state were kept at the software default values, except for the % fluid volumes in the small intestine (23%) and colon (0.5%), which were decreased from the default 40% and 10% to 23% and 0.5% [ 31 ], respectively, to account for the much smaller GI volumes in vivo [ 32 , 33 , 34 ]. To account for postbariatric surgery changes in physiological conditions, the ACAT model parameters were manually adjusted, i.e., gastric volume was decreased from default 50 to 10 mL, corresponding to 20% of the presurgery gastric volume [ 35 , 36 ], and gastric transit time was decreased from default 0.25 to 0.12 h [ 37 , 38 ]. The simulations were also performed for bypassed duodenum and jejunum physiology in post-OAGB patients, setting the volume, length, and transit time for the duodenum and jejunum 1 and 2 segments to zero [ 20 , 36 ].…”