A.S. Darwich (1), D. Pade (2), K. Rowland-Yeo (2), M. Jamei (2), D.M. Ashcroft (1), A. 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.
Objectives: The invasive nature of bariatric surgery, partially restricting the gastrointestinal (GI) tract, has led to observed changes in oral drug bioavailability (Foral) [1]. This study aimed to develop a mechanistic pharmacokinetic in silico model based on known physiological alterations, applying it to clinically relevant drugs.
Methods: A set of GI and ‘whole body’ physiological parameters were identified based on factors influencing Foral post bariatric surgery, including: GI dimensions, pH, GI drug metabolising enzyme abundances, gastric emptying, small intestinal transit (SIT) and bile delay. Using the Advanced Dissolution, Absorption, Metabolism (ADAM) model in Simcyp® Simulator, the morbidly obese population template [2, 3] was altered to mimic the characteristics of Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG) and biliopancreatic diversion with duodenal switch (BPD-DS) and jejunoileal bypass (JIB). A set of drugs (e.g. simvastatin, atorvastatin, omeprazole, diclofenac, cyclosporine, fluconazole and ciprofloxacin) were simulated over therapeutic dose ranges and varying SIT, comparing pre to post surgery AUC, plasma concentration-time profiles, fa (fraction absorbed in the gut wall) and FG (fraction escaping gut wall metabolism).
Results: Different drugs showed variation in sensitivity to surgery. Simvastatin immediate release (IR) displayed a post/pre surgery AUC ratio of 1.14 (±0.18) following RYGB (SIT=3.0h) at a low therapeutic dose, becoming less apparent at a higher dose, due to an increase in FG counteracted by a reduction in fa. Diclofenac enteric-coated (EC) post/pre surgery AUC ratio displayed a minor reduction following RYGB (SIT=3.0h). Following BPD-DS a more extensive reduction in fa resulted in a lower AUC ratio as compared to RYGB. Post JIB, drugs displayed an extensive reduction in AUC due to a more apparent reduction in fa. Simulated cyclosporine displayed a dose dependent reduction in plasma concentration post JIB (SIT=0.7h) in magnitude of observed data [4]. Simulations post SG did not significantly alter the drug exposure.
Conclusions: Trends in Foral pre to post bariatric surgery seem to be highly dependent on drug specific parameters such as affinity to CYP3A4, solubility and permeability issues, where the extent of these effects will be dependent on the surgery in question. Current limitations in simulating the impact on Foral following bariatric surgery include the lack of clinical and physiological data.
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.
[2] Jamei M, Turner D, Yang J, Neuhoff S, Polak S, Rostami-Hodjegan A, Tucker G. Population-based mechanistic prediction of oral drug absorption. AAPS J 2009; 11: 225-37.
[3] Ghobadi C, Johnson TN, Aarabi M, Almond LM, Allabi AC, Rowland-Yeo K, Jamei M, Rostami-Hodjegan A. Application of a systems approach to the bottom-up assessment of pharmacokinetics in obese patients: expected variations in clearance. Clin Pharmacokinet 2011; 50: 809-22.
[4] Chenhsu RY, Wu Y, Katz D, Rayhill S. Dose-adjusted cyclosporine c2 in a patient with jejunoileal bypass as compared to seven other liver transplant recipients. Ther Drug Monit 2003; 25: 665-70.
Reference: PAGE 21 () Abstr 2323 [www.page-meeting.org/?abstract=2323]
Poster: Absorption and Physiology-Based PK