Drug disposition before and after gastric bypass: fenofibrate and posaconazole

Abstract

Aims: Roux-en-Y gastric bypass (RYGB) alters the anatomical structure of the gastrointestinal tract, which can result in alterations in drug disposition. The aim of the present study was to evaluate the oral disposition of two compounds belonging to the Biopharmaceutical Classification System Class II - fenofibrate (bile salt-dependent solubility) and posaconazole (gastric pH-dependent dissolution) - before and after RYGB in the same individuals.

Methods: A single-dose pharmacokinetic study with two model compounds - namely, 67 mg fenofibrate (Lipanthyl®) and 400 mg posaconazole (Noxafil®) - was performed in 12 volunteers pre- and post-RYGB. After oral administration, blood samples were collected at different time points up to 48 h after administration. Plasma concentrations were determined by high-performance liquid chromatography in order to calculate the area under the concentration-time curve up to 48 h (AUC_{0-48 h} ), the peak plasma concentration (C_max) and the time to reach peak concentration (T_max ).

Results: After administration of fenofibrate, no relevant differences in AUC_{0-48 h} , C_max and T_max between the pre- and postoperative setting were observed. The geometric mean of the ratio of AUC_{0-48 h} post/pre-RYGB for fenofibrate was 1.10 [95% confidence interval (CI) 0.87, 1.40; P = 0.40]. For posaconazole, an important decrease in AUC_{0-48 h} and C_max following RYGB was shown; the geometric mean of the AUC_{0-48 h} post/pre-RYGB ratio was 0.68 (95% CI 0.48, 0.96; P = 0.03) and the geometric mean of the C_max pre/post-RYGB ratio was 0.60 (95% CI 0.39, 0.94; P = 0.03). The decreased exposure of posaconazole could be explained by the increased gastric pH and accelerated gastric emptying of fluids post-RYGB. No difference for T_max was observed.

Conclusions: The disposition of fenofibrate was not altered after RYGB, whereas the oral disposition of posaconazole was significantly decreased following RYGB.

Keywords: Roux-en-Y gastric bypass; absorption; bariatric surgery; fenofibrate; pharmacokinetics; posaconazole.

Figure 1

Observed plasma concentration–time profiles of fenofibrate over 48 h after oral administration, shown as mean concentration ± standard error of the mean. Preoperative, Postoperative

Figure 2

Observed plasma concentration–time profiles of posaconazole over 48 h after oral administration, shown as mean concentration ± standard error of the mean. Preoperative, Postoperative