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Population pharmacokinetics of midazolam and its metabolites in overweight and obese adolescents
Author(s) -
Rongen Anne,
Vaughns Janelle D.,
Moorthy Ganesh S.,
Barrett Jeffrey S.,
Knibbe Catherijne A. J.,
Anker Johannes N.
Publication year - 2015
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12693
Subject(s) - overweight , nonmem , medicine , midazolam , volume of distribution , pharmacokinetics , percentile , obesity , population , body mass index , anesthesia , statistics , mathematics , environmental health , sedation
Aim In view of the increasing prevalence of obesity in adolescents, the aim of this study was to determine the pharmacokinetics of the CYP3A substrate midazolam and its metabolites in overweight and obese adolescents. Methods Overweight (BMI for age ≥ 85 th percentile) and obese (BMI for age ≥ 95 th percentile) adolescents undergoing surgery received 2 or 3 mg intravenous midazolam as a sedative drug pre‐operatively. Blood samples were collected until 6 or 8 h post‐dose. Population pharmacokinetic modelling and systematic covariate analysis were performed using nonmem 7.2. Results Nineteen overweight and obese patients with a mean body weight of 102.7 kg (62–149.8 kg), a mean BMI of 36.1 kg m −2 (24.8–55 kg m −2 ), and a mean age of 15.9 years (range 12.5–18.9 years) were included. In the model for midazolam and metabolites, total body weight was not of influence on clearance (0.66 l min −1 (RSE 8.3%)), while peripheral volume of distribution of midazolam (154 l (11.2%)), increased substantially with total body weight ( P < 0.001). The increase in peripheral volume could be explained by excess body weight (WT excess ) instead of body weight related to growth (WT for age and length ). Conclusions The pharmacokinetics of midazolam and its metabolites in overweight and obese adolescents show a marked increase in peripheral volume of distribution and a lack of influence on clearance. The findings may imply a need for a higher initial infusion rate upon initiation of a continuous infusion in obese adolescents.