A. van Rongen (1), J.D. Vaughns (2), G. Moorthy (3), J.S. Barrett (3), S.N. de Wildt (4), C.A.J. Knibbe (1,5), J.N. van den Anker (2,4)
(1) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands; (2) Children’s National Medical Center, Washington DC, USA; (3) Children’s Hospital of Philadelphia, Philadelphia, USA; (4) Intensive Care, Erasmus MC Sophia Children’s Hospital, Rotterdam, The Netherlands; (5) Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands.
Objectives: Midazolam is a commonly used CYP3A4 metabolized benzodiazepine for preoperative sedation in pediatric anesthesia. Although there are numerous studies investigating the pharmacokinetic (PK) properties of midazolam in children with normal weight, no data are available in overweight and obese children. The aim of this study is to determine the pharmacokinetics of midazolam in obese, overweight and non-obese adolescents.
Methods: In a prospective study, nineteen overweight (BMI percentile between 85th and 94th) and obese (BMI percentile > 95th) patients with a mean body weight of 102.7 kg (62 – 149.8 kg), mean BMI of 36.1 kg/m2 (24.8 – 55 kg/m2) and a mean age of 15.9 years (range 12.5 – 18.9) and 1 non-obese patient (63 kg, BMI 21.2 kg/m2, 15.2 years) received 2 or 3 mg intravenous midazolam as pre-operative sedative drug. Blood samples were drawn at 0 (pre-dose), (5), 15 and 30 minutes and 1, 2, 4, 6 and (8) hours post dose. Midazolam and its metabolites were determined using HPLC-tandem MS. In addition, data were available of 5 non-obese patients with a mean body weight of 48.0 kg (range 36.4-60.1 kg), mean BMI of 18.7 kg/m2 (range 14.3 – 22 kg/m2) and mean age of 14.9 years (range 12.1-16.2 years) [1]. Population PK and covariate modelling was performed using NONMEM 7.2.
Results: A two compartment pharmacokinetic model best described the data for midazolam in obese, overweight and non-obese adolescents. The covariate analyses identified total body weight as covariate for clearance, central- and peripheral volume of distribution with population values of CL (L/min) = 0.599+0.00839*(WT-88.6), Vcentral (L) = 30.5*(WT/88.6)2.02 and Vperipheral (L) = 89.3*(WT/88.6)2.48, respectively. Based on the individual patients in the study, this yielded individual values for clearance between 0.15 and 1.06 L/min, central volume of distribution between 5.1 and 88.1 L and peripheral volume of distribution between 7.6 and 297.2 L.
Conclusions: In this study, an important influence of total body weight was found on clearance, central- and peripheral volume of distribution in obese, overweight and non-obese adolescents. Further analysis on the basis of a model which distinguishes between bodyweight related to growth and bodyweight related to obesity [2] is needed to further explore the impact of different degrees of obesity in adolescents.
References:
[1] de Wildt SN, Riva L, van den Anker JN, Murray DJ. Does age alter the pharmacokinetics of midazolam and 1-OH midazolam in paediatric patients? Clin Pharmacol Ther 2000 Mar; 67:104
[2] Bartelink IH, van Kesteren C, Boelens JJ, Egberts TC, Bierings MB, et al. 2012. Predictive performance of a busulfan pharmacokinetic model in children and young adults. Ther Drug Monit 34: 574-83
Reference: PAGE 23 (2014) Abstr 3211 [www.page-meeting.org/?abstract=3211]
Poster: Drug/Disease modeling - Paediatrics