title: Midazolam pharmacokinetics in morbidly obese patients following semi-simultaneous oral and intravenous administration: a comparison with healthy volunteers.
abstract: BACKGROUND
  While in vitro and animal studies have shown reduced cytochrome P450 (CYP) 3A activity due to obesity, clinical studies in (morbidly) obese patients are scarce. As CYP3A activity may influence both clearance and oral bioavailability in a distinct manner, in this study the pharmacokinetics of the CYP3A substrate midazolam were evaluated after semi-simultaneous oral and intravenous administration in morbidly obese patients, and compared with healthy volunteers.
  
  
  METHODS
  Twenty morbidly obese patients [mean body weight 144 kg (range 112-186 kg) and mean body mass index 47 kg/m(2) (range 40-68 kg/m(2))] participated in the study. All patients received a midazolam 7.5 mg oral and 5 mg intravenous dose (separated by 159 ± 67 min) and per patient 22 samples over 11 h were collected. Data from 12 healthy volunteers were available for a population pharmacokinetic analysis using NONMEM(®).
  
  
  RESULTS
  In the three-compartment model in which oral absorption was characterized by a transit absorption model, population mean clearance (relative standard error %) was similar [0.36 (4 %) L/min], while oral bioavailability was 60 % (13 %) in morbidly obese patients versus 28 % (7 %) in healthy volunteers (P < 0.001). Central and peripheral volumes of distribution increased substantially with body weight (both P < 0.001) and absorption rate (transit rate constant) was lower in morbidly obese patients [0.057 (5 %) vs. 0.130 (14 %) min(-1), P < 0.001].
  
  
  CONCLUSIONS
  In morbidly obese patients, systemic clearance of midazolam is unchanged, while oral bioavailability is increased. Given the large increase in volumes of distribution, dose adaptations for intravenous midazolam should be considered. Further research should elucidate the exact physiological changes at intestinal and hepatic level contributing to these findings.
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Margreke J E
authors.initials: MJ
authors.lastname: Brill
authors.forename: Anne
authors.initials: A
authors.lastname: van Rongen
authors.forename: Aletta P I
authors.initials: AP
authors.lastname: Houwink
authors.forename: Jacobus
authors.initials: J
authors.lastname: Burggraaf
authors.forename: Bert
authors.initials: B
authors.lastname: van Ramshorst
authors.forename: René J
authors.initials: RJ
authors.lastname: Wiezer
authors.forename: Eric P A
authors.initials: EP
authors.lastname: van Dongen
authors.forename: Catherijne A J
authors.initials: CA
authors.lastname: Knibbe
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D001682:Biological Availability; D016022:Case-Control Studies; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008874:Midazolam / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D008954:Models, Biological; D009767:Obesity, Morbid / Q000097:blood* / Q000378:metabolism; D011446:Prospective Studies; D013997:Time Factors; D055815:Young Adult
chemical_list: D006993:Hypnotics and Sedatives; D008874:Midazolam