Evaluation of an In Silico PBPK Post-Bariatric Surgery Model through Simulating Oral Drug Bioavailability of Atorvastatin and Cyclosporine

Abstract

An increasing prevalence of morbid obesity has led to dramatic increases in the number of bariatric surgeries performed. Altered gastrointestinal physiology following surgery can be associated with modified oral drug bioavailability (Foral). In the absence of clinical data, an indication of changes to Foral via systems pharmacology models would be of value in adjusting dose levels after surgery. A previously developed virtual "post-bariatric surgery" population was evaluated through mimicking clinical investigations on cyclosporine and atorvastatin after bariatric surgery. Cyclosporine simulations displayed a reduced fraction absorbed through gut wall (fa) and Foral after surgery, consistent with reported observations. Simulated atorvastatin Foral postsurgery was broadly reflective of observed data with indications of counteracting interplay between reduced fa and an increased fraction escaping gut wall metabolism (FG). Inability to fully recover observed atorvastatin exposure after biliopancreatic diversion with duodenal switch highlights the current gap regarding the knowledge of associated biological changes.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e47; doi:10.1038/psp.2013.23; advance online publication 12 June 2013.

Figure 1

Mean and SD of observed cyclosporin A (CsA) TDx trough levels at steady state pre to post-Roux-en-Y gastric bypass (RYGB) at −6, −3, 0, 3, 6, 9, and 12 months relative to RYGB surgical event (0 months). Time points from −6 to 12 months correspond to dose levels of 1.7, 1.7, 1.8, 2.4, 2.8, 3.2, 3.5 mg/kg/day, respectively (n = 3) administered twice daily. Observed data are compared with simulated 50, 95, and 5% prediction interval, indicated by gray area, of CsA Sandimmune trough levels (n = 10 × 3). (a) Simulated post-RYGB at a small intestinal transit time (SIT) of 3.0 h, (b) log-normalized simulated CsA trough ratio as compared with 0 months (RYGB SIT = 3.0 h), (c) simulated CsA trough levels at RYGB SIT of 5.0 h, (d) log-normalized simulated CsA trough ratio as compared with 0 months (RYGB SIT = 5.0 h).

Figure 2

Observed mean blood concentration of cyclosporine microemulsion (Sandimmune Neoral; Novartis) at steady state 2 h postdosing in controls (n = 10 × 7) and one patient (n = 10 × 1) post-jejunoileal bypass (JIB) as compared with simulated sex- and age-matched controls (n = 300) and post-JIB (n = 800) at a small intestinal transit time of 0.4 h over dose range of 300–1,000 mg, where 5, 50, and 95% prediction intervals are indicated by gray areas.

Figure 3

Simulated 50, 95, and 5% prediction interval (indicated by gray areas) of oral drug exposure of atorvastatin acid in randomized trials of age-, sex-, dose-, and BMI-matched patients pre- to post-Roux-en-Y gastric bypass surgery (small intestinal transit = 3.0 h) as compared with observed data. (a–j) Ten randomized simulated trials consisting of 12 individuals in each trial (n = 10 × 12), as compared with observed (n = 12; open circles). AUC, area under the concentration–time curve.

Figure 4

Simulated 50, 95, and 5% prediction intervals of the ratio of (a) fraction of dose absorbed in the intestine (f_a), and (b) fraction escaping gut wall metabolism (F_G) of atorvastatin acid pre- to post-Roux-en-Y gastric bypass surgery (small intestinal transit = 3.0 h) in 10 individually simulated randomized trials (1–10) consisting of 10 individuals in each pre- and postsurgery (n = 10 × 10).

Figure 5

Spider plot of sensitivity analysis of simulated post/pre-biliopancreatic diversion with duodenal switch (BPD-DS) at a small intestinal transit time (SIT) of 1.2 h; (a) AUC_{0–8 h}, (b) C_max, and (c) t_max ratio, BPD-DS (SIT = 4.2 h); (d) AUC_{0–8 h}, (e) C_max, and (f) t_max ratio, examining the impact of the fold change in physiological parameters: gastric emptying, ileal bile concentration (bile conc.), villous blood flow (Q_villi), enterocytic volume (V_ent) in the remaining postsurgical small intestine, post-BPD-DS gastrointestinal CYP3A content, small intestinal permeability (P_eff), as compared with mean observed ratio pre- to post-BPD-DS. AUC, area under the concentration–time curve; C_max, maximum plasma drug concentration; t_max, time of maximum plasma drug concentration.