The Pharmacokinetics of the CYP3A Substrate Midazolam in Morbidly Obese Patients Before and One Year After Bariatric Surgery

Abstract

Purpose: Bariatric surgery is nowadays commonly applied as treatment for morbid obesity (BMI > 40 kg/m(2)). As information about the effects of this procedure on a drug's pharmacokinetics is limited, we aimed to evaluate the pharmacokinetics of CYP3A probe substrate midazolam after oral and intravenous administration in a cohort of morbidly obese patients that was studied before and 1 year post bariatric surgery.

Methods: Twenty morbidly obese patients (aged 26-58 years) undergoing bariatric surgery participated in the study of which 18 patients returned 1 year after surgery. At both occasions, patients received 7.5 mg oral and 5 mg intravenous midazolam separated by 160 ± 48 min. Per patient and occasion, a mean of 22 blood samples were collected. Midazolam concentrations were analyzed using population pharmacokinetic modeling.

Results: One year after bariatric surgery, systemic clearance of midazolam was higher [0.65 (7%) versus 0.39 (11%) L/min, mean ± RSE (P < 0.01), respectively] and mean oral transit time (MTT) was faster [23 (20%) versus 51 (15%) minutes (P < 0.01)], while oral bioavailability was unchanged (0.54 (9%)). Central and peripheral volumes of distribution were overall lower (P < 0.05).

Conclusions: In this cohort study in morbidly obese patients, systemic clearance was 1.7 times higher 1 year after bariatric surgery, which may potentially result from an increase in hepatic CYP3A activity per unit of liver weight. Although MTT was found to be faster, oral bioavailability remained unchanged, which considering the increased systemic clearance implies an increase in the fraction escaping intestinal first pass metabolism.

Keywords: CYP3A; bariatric surgery; midazolam; pharmacokinetics.

Fig. 1

Midazolam concentration versus time after oral dose profiles upon a 7.5 mg oral midazolam dose and a 5 mg intravenous dose separated by 160 ± 48 min in 20 morbidly obese patients before (black lines) and 1 year after surgery (grey dotted lines). Two patients were unable to participate 1 year after surgery.

Fig. 2

Observed versus individual predicted midazolam concentrations (a), observed versus population predicted midazolam concentrations (b), conditional weighted residuals (CWRES) versus time (c) and population predicted midazolam concentrations (d) of the final model for 20 morbidly obese patients (black dots, occasion 1) of which 18 returned 1 year post surgery for a second study visit (grey dots, occasion 2). The dashed line represents the line of identity (x = y).

Fig. 3

Population mean (black line) and 90% interval (grey area) of midazolam concentrations versus time after a 5 mg intravenous dose (a), a 2.5 mg/h continuous infusion (b) and a 7.5 mg oral dose (c) in morbidly obese patients before bariatric surgery (black solid line) and after bariatric surgery (black dotted line).

Fig. 4

Empirical bayes estimates (black dots) and population mean estimates (black lines) of midazolam clearance (a) and oral bioavailability (b) of the final pharmacokinetic model in 20 morbidly obese patients (black closed dots) and 18 bariatric patients (black open dots) versus body weight (kg). Parameter values found for healthy volunteers studies from the literature were added for comparison (grey dots) (,–40).