Anil R Maharaj1, Huali Wu1, Kanecia O Zimmerman1,2, Julie Autmizguine3, Rohit Kalra4, Amira Al-Uzri5, Catherine M T Sherwin6,7, Stuart L Goldstein8, Kevin Watt1,2, Jinson Erinjeri9, Elizabeth H Payne9, Michael Cohen-Wolkowiez1,2, Christoph P Hornik1,2. 1. Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA. 2. Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA. 3. Department of Pediatrics, CHU Sainte-Justine, Montreal, Canada. 4. Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA. 5. Oregon Health and Science University, Portland, OR, USA. 6. Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, UT, USA. 7. Department of Pediatrics, Wright State University, Boonshoft School of Medicine, Dayton Children's Hospital, Dayton, OH, USA. 8. Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA. 9. The Emmes Company, LLC, Rockville, MD, USA.
Abstract
AIMS: The aim of this study was to evaluate the population pharmacokinetics (PopPK) of olanzapine in children and devise a model-informed paediatric dosing scheme. METHODS: The PopPK of olanzapine was characterized using opportunistically collected plasma samples from children receiving olanzapine per standard of care for any indication. A nonlinear mixed effect modelling approach was employed for model development using the software NONMEM (v7.4). Simulations from the developed PopPK model were used to devise a paediatric dosing scheme that targeted comparable plasma exposures to adolescents and adults. RESULTS: Forty-five participants contributed 83 plasma samples towards the analysis. The median (range) postnatal age and body weight of participants were 3.8 years (0.2-19.2) and 14.1 kg (4.2-111.7), respectively. The analysis was restricted to pharmacokinetic (PK) samples collected following enteral administration (oral and feeding tube). A one-compartment model with linear elimination provided an appropriate fit to the data. The final model included the covariates body weight and postmenstrual age (PMA) on apparent olanzapine clearance (CL/F). Typical CL/F and apparent volume of distribution (scaled to 70 kg) were 16.8 L/h (21% RSE) and 663 L (13% RSE), respectively. Developed dosing schemes used weight-normalized doses for children ≤6 months postnatal age or <15 kg and fixed doses for children ≥15 kg. CONCLUSION: We developed a paediatric PopPK model for enterally-administered olanzapine. To our knowledge, this analysis is the first study to characterize the PK of olanzapine in participants ranging from infants to adolescents. Body weight and PMA were identified as influential covariates for characterizing developmental changes in olanzapine apparent clearance.
AIMS: The aim of this study was to evaluate the population pharmacokinetics (PopPK) of olanzapine in children and devise a model-informed paediatric dosing scheme. METHODS: The PopPK of olanzapine was characterized using opportunistically collected plasma samples from children receiving olanzapine per standard of care for any indication. A nonlinear mixed effect modelling approach was employed for model development using the software NONMEM (v7.4). Simulations from the developed PopPK model were used to devise a paediatric dosing scheme that targeted comparable plasma exposures to adolescents and adults. RESULTS: Forty-five participants contributed 83 plasma samples towards the analysis. The median (range) postnatal age and body weight of participants were 3.8 years (0.2-19.2) and 14.1 kg (4.2-111.7), respectively. The analysis was restricted to pharmacokinetic (PK) samples collected following enteral administration (oral and feeding tube). A one-compartment model with linear elimination provided an appropriate fit to the data. The final model included the covariates body weight and postmenstrual age (PMA) on apparent olanzapine clearance (CL/F). Typical CL/F and apparent volume of distribution (scaled to 70 kg) were 16.8 L/h (21% RSE) and 663 L (13% RSE), respectively. Developed dosing schemes used weight-normalized doses for children ≤6 months postnatal age or <15 kg and fixed doses for children ≥15 kg. CONCLUSION: We developed a paediatric PopPK model for enterally-administered olanzapine. To our knowledge, this analysis is the first study to characterize the PK of olanzapine in participants ranging from infants to adolescents. Body weight and PMA were identified as influential covariates for characterizing developmental changes in olanzapine apparent clearance.
Authors: Ron J Keizer; Michel van Benten; Jos H Beijnen; Jan H M Schellens; Alwin D R Huitema Journal: Comput Methods Programs Biomed Date: 2010-06-02 Impact factor: 5.428
Authors: Matthew M Laughon; Daniel K Benjamin; Edmund V Capparelli; Gregory L Kearns; Katherine Berezny; Ian M Paul; Kelly Wade; Jeff Barrett; Phillip Brian Smith; Michael Cohen-Wolkowiez Journal: Expert Rev Clin Pharmacol Date: 2011-09 Impact factor: 5.045
Authors: Leslie Citrome; Virginia L Stauffer; Lei Chen; Bruce J Kinon; Darcie L Kurtz; Jennie G Jacobson; Richard F Bergstrom Journal: J Clin Psychopharmacol Date: 2009-06 Impact factor: 3.153