Physiologically-Based Pharmacokinetic Predictions of Lorazepam Paediatric Clearance
AbstractDrug clearance is an important pharmacokinetic parameter as it describes the rate of elimination of a drug from the body. The aim of this project was to develop a physiologically-based pharmacokinetic model, with the simulation program Simcyp, to predict the total plasma clearance for lorazepam for the entire paediatric age-range. The mean prediction error for observations in literature were 30% or below for all ages. This model can be used to assess the current dosing recommendations in children of all ages.
Chung, J.-Y. et al. Pharmacokinetic and pharmacodynamic interaction of lorazepam and valproic acid in relation to UGT2B7 genetic polymorphism in healthy subjects. Clinical Phamacology & Therapeutics, 83, 595–600 (2008).
Allegaert, K. et al. Neonatal clinical pharmacology. Paediatrics Anaesthesia, 24, 30–38 (2014).
Chao, P. et al. Use of intrinsic clearance for prediction of human hepatic clearance. Expert Opinion on Drug Metabolism & Toxicology, 6, 189–198 (2010).
Bavdekar, S.B. Pediatric clinical trials. Perspectives in Clinical Research, 4, 89–99 (2013).
Maharaj, A.R., et al. A workflow example of PBPK modeling to support pediatric research and development: case study with lorazepam. AAPS Journal, 15, 455–64 (2013).
Krekels, E.H.J. Size does matter Drug glucuronidation in children. PhD Thesis, Leiden University, Netherlands (2012).
Alkharfy, K.M. et al. High-performance liquid chromatographic assay for acetaminophen glucuronide in human liver microsomes. Journal of Chromatography B, 753, 303–308 (2001).
Wells, P.G. et al. Glucuronidation and the UDP-glucuronosyl transferases in health and disease. Drug Metabolism & Disposition, 32, 281–290 (2004).
Greenblatt, D.J. et al. Analysis of lorazepam and its glucuronide metabolite by electron-capture gas-liquid chromatography. Journal of Chromatography B, 146, 311–320 (1978).
Chung, J.Y. et al. Effect of the UGT2B15 genotype on the pharmacokinetics, pharmacodynamics, and drug interactions of intravenous lorazepam in healthy volunteers. Clinical Pharmacology & Therapeutics, 77, 486–494 (2005).
Court, M. H. et al. Stereoselective conjugation of oxazepam by human UDP-glucuronosyl-transferases (UGTs):S-oxazepam is glucuro-nidated by UGT2B15, while R-oxazepam is glucuronidated by UGT2B7 and UGT1A9, Drug Metabolism & Disposition, 30, 1257–1265 (2002).
Edginton, A.N. et al. A mechanistic approach for the scaling of clearance in children. Clinical Pharmacokinetcs, 45, 683–704 (2006).
Chamberlain, J.M. et al. The pharmacokinetics of intravenous lorazepam in pediatric patients with and without status epilepticus. Journal of Pediatrics, 29, 997–1003 (2012).
Wermeling, D.P. et al. Bioavailability and pharmacokinetics of lorazepam after intranasal, intravenous, and intramuscular administration. Journal of Clinical Pharmacology, 41, 1225–1231 (2001).
Greenblatt, D.J. et al. Pharmacokinetics and bioavailability of intravenous, intramuscular, and oral lorazepam in humans. Journal of Pharmaceutical Sciences, 68, 57–63 (1979).
Crom, W.R. et al. Age-related differences in hepatic drug clearance in children: studies with lorazepam and antipyrine. Clinical Pharmacology & Therapeutics, 50, 132–140 (1991).
McDermott, C.A. et al. Clinical and laboratory observations Pharmacokinetics of Iorazepam in critically ill neonates with seizures. Journal of Pediatrics, 120, 479–483 (1992).
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