A mechanistic pharmacokinetic model to assess modified oral drug bioavailability post bariatric surgery in morbidly obese patients: interplay between CYP3A gut wall metabolism, permeability and dissolution

Abstract

Objectives  Due to the multi-factorial physiological implications of bariatric surgery, attempts to explain trends in oral bioavailability following bariatric surgery using singular attributes of drugs or simplified categorisations such as the biopharmaceutics classification system have been unsuccessful. So we have attempted to use mechanistic models to assess changes to bioavailability of model drugs.

Methods  Pharmacokinetic post bariatric surgery models were created for Roux-en-Y gastric bypass, biliopancreatic diversion with duodenal switch, sleeve gastrectomy and jejunoileal bypass, through altering the ‘Advanced Dissolution Absorption and Metabolism’ (ADAM) model incorporated into the Simcyp® Simulator. Post to pre surgical simulations were carried out for five drugs with varying characteristics regarding their gut wall metabolism, dissolution and permeability (simvastatin, omeprazole, diclofenac, fluconazole and ciprofloxacin).

Key findings  The trends in oral bioavailability pre to post surgery were found to be dependent on a combination of drug parameters, including solubility, permeability and gastrointestinal metabolism as well as the surgical procedure carried out.

Conclusions  In the absence of clinical studies, the ability to project the direction and the magnitude of changes in bioavailability of drug therapy, using evidence-based mechanistic pharmacokinetic in silico models would be of significant value in guiding prescribers to make the necessary adjustments to dosage regimens for an increasing population of patients who are undergoing bariatric surgery.