The Complexity of Bariatric Patient's Pharmacotherapy: Sildenafil Biopharmaceutics and Pharmacokinetics before vs. after Gastric Sleeve/Bypass

Abstract

Postbariatric altered gastrointestinal (GI) anatomy/physiology may significantly harm oral drug absorption and overall bioavailability. In this work, sildenafil, the first phosphodiesterase-5 (PDE5) inhibitor, was investigated for impaired postbariatric solubility/dissolution and absorption; this research question is of particular relevance since erectile dysfunction (ED) is associated with higher body mass index (BMI). Sildenafil solubility was determined both in vitro and ex vivo, using pre- vs. postsurgery gastric contents aspirated from patients. Dissolution tests were done in conditions mimicking the stomach before surgery, after sleeve gastrectomy (post-SG, pH 5), and after one anastomosis gastric bypass (post-OAGB, pH 7). Finally, these data were included in physiologically based pharmacokinetic (PBPK) modelling (GastroPlus^®) to simulate sildenafil PK before vs. after surgery. pH-dependent solubility was demonstrated with low solubility (0.3 mg/mL) at pH 7 vs. high solubility at pH 1-5, which was also confirmed ex vivo with much lower solubility values in postbariatric gastric samples. Hampered dissolution of all sildenafil doses was obtained under post-OAGB conditions compared with complete (100%) dissolution under both presurgery and post-SG conditions. PBPK simulations revealed delayed sildenafil absorption in postbariatric patients (increased t_max) and reduced C_max, especially in post-OAGB patients, relative to a presurgery state. Hence, the effect of bariatric surgery on sildenafil PK is unpredictable and may depend on the specific bariatric procedure. This mechanistically based analysis suggests a potentially undesirable delayed onset of action of sildenafil following gastric bypass surgery.

Keywords: bariatric surgery; delayed onset; erectile dysfunction; ex vivo solubility; gastric pH; oral absorption; phosphodiesterase-5 inhibitors; physiologically based pharmacokinetic modeling; postbariatric dissolution.

Figure 1

Sildenafil in vitro solubility as a function of pH ((left) panel) and ex vivo solubility in gastric fluid aspirated from three patients before ((left) column; mean pH 2.0) vs. after ((right) column; mean pH 7.0) bariatric surgery. The red dashed line represents the solubility threshold for complete postbariatric dose dissolution. Data presented as mean (SD); n = 4 for each pH; n = 3 for each experimental group.

Figure 2

Sildenafil in vitro dissolution of commercially available Viagra^® tablets of 25 mg ((left) panel), 50 mg ((middle) panel) and 100 mg ((right) panel). The 250 mL at pH 1 medium (blue circles) represents presurgery stomach state, 50 mL at pH 5 medium (green squares) represents post-SG conditions, and 50 mL at pH 7 medium (red triangles) represents post-OAGB gastric scenario. Average (SD); n = 4 for each experimental group.

Figure 3

The predicted plasma concentration time profiles under presurgery, post-SG, and post-OAGB states for sildenafil 25 mg ((left) panel), 50 mg ((middle) panel), and 100 mg ((right) panel). Square markers represent the mean values observed in human studies (50 mg, Nichols et al.; 100 mg, Alwhaibi et al.) [41,49].

Figure 4

The predicted in vivo dissolution ((left) panel) and the predicted GI tract regional absorption ((right) panel) profiles under presurgery, post-SG, and post-OAGB states for sildenafil 100 mg tablets.