Anne van Rongen1,2, Janelle D Vaughns3,4, Ganesh S Moorthy5, Jeffrey S Barrett5, Catherijne A J Knibbe1,2, Johannes N van den Anker4,6,7. 1. Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, the Netherlands. 2. Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands. 3. Division of Anesthesiology and Pain Medicine, Children's National Medical Center, Washington DC, USA. 4. Division of Clinical Pharmacology, Children's National Medical Center, Washington DC, USA. 5. Laboratory for Applied PK/PD, Children's Hospital of Philidelphia, Philidelphia, USA. 6. Department of Paediatric Pharmacology, University Children's Hospital, Basel, Switzerland. 7. Intensive Care and Department of Pediatric Surgery, Erasmus MC Sophia Children's Hospital, Rotterdam, the Netherlands.
Abstract
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 (WTexcess ) instead of body weight related to growth (WTfor 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.
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 obesepatients 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 (WTexcess ) instead of body weight related to growth (WTfor 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.
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