Midazolam pharmacokinetics following semi-simultaneous oral and intravenous administration in morbidly obese patients before and 1 year after bariatric surgery
Margreke JE Brill (1,2), Anne van Rongen (1,2), Aletta PI Houwink (3), Bert van Ramshorst (4), Eric J Hazebroek(4), Eric PA van Dongen (3), Catherijne AJ Knibbe (1,2)
(1) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands. (2) Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands. (3) Department of Anaesthesiology and Intensive Care, St. Antonius Hospital, Nieuwegein, The Netherlands. (4) Department of Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands.
Objectives: Gastric bypass/sleeve surgery is considered the most successful treatment for morbid obesity (body mass index, BMI >40 kg/m2). As both surgery induced weight loss and gastro-intestinal alterations may influence a drugs pharmacokinetics, we aimed to quantify the influence of bariatric surgery on oral and intravenous pharmacokinetics of CYP3A substrate midazolam in patients before and 1 year post bariatric surgery.
Methods: Twenty morbidly obese patients [144.4 kg (112-186 kg)] participated before gastric bypass/sleeve surgery and 18 patients [-44.5 kg (21-58 kg)] returned 52 ± 2 weeks after surgery. On both occasions, patients received 7.5 mg oral and 5 mg i.v. midazolam separated by 160 ± 50 minutes and 21-23 blood samples were collected until 9-11 h post oral dose. Population pharmacokinetic modeling was performed using NONMEM 7.2.
Results: Midazolam concentrations of both groups were best described by a three-compartment model with equalized peripheral volumes and a transit compartment model for absorption with transit rates set equal to the absorption rate. Post bariatric surgery, population mean (RSE%) midazolam absorption rate and clearance were higher compared to before bariatric surgery [0.40 (11%) vs. 0.17 (10%) min-1 (p<0.01) and 0.68 (5%) vs. 0.49 (11%) L/min (p<0.01), respectively] and peripheral volume of distribution was lower [51 (11%) vs. 84 (13%) L (p<0.01)]. Bioavailability and central volume of distribution were similar to before surgery [0.54 (8%) and 51(14%) L, respectively].
Conclusions: Oral and i.v. midazolam pharmacokinetics in post gastric bypass/sleeve patients revealed higher oral absorption rate and clearance compared to before bariatric surgery, while the peripheral volume of distribution was lower and bioavailability was unaltered.