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.
OBJECTIVE
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).


RESULTS
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.
Centre of Applied Pharmacokinetic Research, School of Pharmacy and Pharmaceutical Sciences School, University of Manchester, Manchester, UK.
Adam S
AS
Darwich
Devendra
D
Pade
Basil J
BJ
Ammori
Masoud
M
Jamei
Darren M
DM
Ashcroft
Amin
A
Rostami-Hodjegan
D000284:Administration, Oral; D050110:Bariatric Surgery; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D002939:Ciprofloxacin / Q000493:pharmacokinetics; D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004008:Diclofenac / Q000493:pharmacokinetics; D015725:Fluconazole / Q000493:pharmacokinetics; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D008954:Models, Biological; D009767:Obesity, Morbid / Q000188:drug therapy* / Q000601:surgery; D009853:Omeprazole / Q000493:pharmacokinetics; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D019821:Simvastatin / Q000493:pharmacokinetics; D012995:Solubility
D004364:Pharmaceutical Preparations; D004008:Diclofenac; D002939:Ciprofloxacin; D015725:Fluconazole; D019821:Simvastatin; D051544:Cytochrome P-450 CYP3A; D009853:Omeprazole