Adam S. Darwich (1), Devendra Pade (2), Karen Rowland-Yeo (2), Masoud Jamei (2), Anders Åsberg (3), Hege Christensen (3), Darren M. Ashcroft (1), Amin Rostami-Hodjegan (1,2)
(1) Centre of Applied Pharmacokinetic Research, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, UK, (2) Simcyp Ltd, Blades Enterprise Centre, Sheffield, UK, (3) Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway.
Objectives: The prevalence of bariatric surgery has increased dramatically over the last decade. Bariatric surgery leads to changes in the gastrointestinal physiology which affect oral drug bioavailability (Foral). Due to sparse clinical data, a “bottom-up” approach using in vitro-in vivo extrapolation (IVIVE) in conjunction with systems pharmacology may be valuable in predicting trends in oral drug exposure post surgery [1].
Methods: Post bariatric surgery population models were created using the ‘Advanced Dissolution Absorption and Metabolism (ADAM) model’ within the Simcyp Simulator (v10). General application was demonstrated on a set of drugs and validity demonstrated for cyclosporine and atorvastatin acid where clinical data post bariatric surgery were available [2].
Results: Overall, simulated trends in Foral were drug and surgery specific. The oral exposure of cyclosporine post surgery was reduced due to a lower fraction absorbed (fa) and the reduced peak plasma concentrations were consistent with the reported clinical observations. Simulated oral drug exposure of atorvastatin acid post Roux-en-Y gastric bypass surgery was also reflective of the observed data with indications of counteracting interplay between a reduced fa and increased fraction that escapes gut wall metabolism (FG). Observed exposure profiles with regards to tmax of atorvastatin acid post biliopancreatic diversion with duodenal switch were not fully recovered by simulations.
Conclusions: Trends in oral drug bioavailability pre to post bariatric surgery seem to be highly dependent on drug specific parameters such as affinity to CYP3A, solubility, permeability and surgery specific systems alterations. The potential of a systems pharmacology physiologically-based pharmacokinetic modelling approach was demonstrated, allowing a framework for optimisation of oral drug therapy post bariatric surgery. Inability to fully recover observed changes in tmax in certain scenarios suggests that additional systems parameters, which are currently unknown, may play a vital role.
References:
[1] Darwich AS, Henderson K, Burgin A, Ward N, Whittam J, Ammori BJ, Ashcroft DM, Rostami-Hodjegan A. Trends in oral drug bioavailability following bariatric surgery: Examining the variable extent of impact on exposure of different drug classes. Br J Clin Pharmacol. 2012; 74(5):774-87.
[2] Darwich AS, Pade D, Ammori BJ, Jamei M, Ashcroft DM, Rostami-Hodjegan A. 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. J Pharm Pharmacol. 2012; 64(7):1008-24.
Reference: PAGE 22 () Abstr 2856 [www.page-meeting.org/?abstract=2856]
Poster: Absorption and Physiology-Based PK