PMID- 30097906 OWN - NLM STAT- MEDLINE DCOM- 20181105 LR - 20240502 IS - 1179-2019 (Electronic) IS - 1174-5878 (Print) IS - 1174-5878 (Linking) VI - 20 IP - 5 DP - 2018 Oct TI - A Population-Based Pharmacokinetic Model Approach to Pantoprazole Dosing for Obese Children and Adolescents. PG - 483-495 LID - 10.1007/s40272-018-0305-1 [doi] AB - BACKGROUND AND AIMS: Pharmacokinetic data for proton pump inhibitors (PPIs), acid-suppression drugs commonly prescribed to children, are lacking for obese children who are at greatest risk for acid-related disease. In a recent multi-center investigation, we demonstrated decreased, total body weight adjusted, apparent clearance (CL/F) of the PPI pantoprazole for obese children compared with their non-obese peers. Subsequently, we developed a population-based pharmacokinetic (PopPK) model to characterize pantoprazole disposition and evaluated appropriate pantoprazole dosing strategies for obese pediatric patients, using simulation. METHODS: Pharmacokinetic data from the only prospective study of PPIs in obese children (aged 6-17 years; n = 40) included 273 pantoprazole and 256 pantoprazole-sulfone plasma concentrations, after single oral-dose administration, and were used for pantoprazole model development and covariate analysis (NONMEM((R))). Model evaluation was performed via bootstrapping and predictive checks, and the final model was applied to simulate systemic pantoprazole exposures for common dosing scenarios. RESULTS: A two-compartment PopPK model, which included CYP2C19 genotype and total body weight, provided the best fit. Resultant, typical, weight-normalized pantoprazole parameter estimates were different than previously reported for children or adults, with significantly reduced pantoprazole CL/F for obese children. Of the dosing scenarios evaluated, the weight-tiered approach, approved by the US Food and Drug Administration, achieved pantoprazole exposures [area under the curve (AUC(0-infinity))] within ranges previously reported as therapeutic, without over- or under-prediction for obese children. CONCLUSIONS: Our data argue against empiric dose escalation of PPIs for obese children and support current FDA-approved pediatric weight-tiered dosing for pantoprazole; however, 3- to 5-fold inter-individual variability in pantoprazole AUC(0-infinity) remained using this dosing approach. FAU - Shakhnovich, Valentina AU - Shakhnovich V AD - The Children's Mercy Hospital, Kansas City, MO, USA. vshakhnovich@cmh.edu. AD - University of Missouri-Kansas City School of Medicine, Kansas City, USA. vshakhnovich@cmh.edu. FAU - Brian Smith, P AU - Brian Smith P AD - Duke Clinical Research Institute, Durham, NC, USA. FAU - Guptill, Jeffrey T AU - Guptill JT AD - Duke Clinical Research Institute, Durham, NC, USA. FAU - James, Laura P AU - James LP AD - Arkansas Children's Hospital, Little Rock, AR, USA. FAU - Collier, David N AU - Collier DN AD - East Carolina University, Greenville, NC, USA. FAU - Wu, Huali AU - Wu H AD - Duke Clinical Research Institute, Durham, NC, USA. FAU - Livingston, Chad E AU - Livingston CE AD - Duke Clinical Research Institute, Durham, NC, USA. FAU - Zhao, Jian AU - Zhao J AD - The Emmes Corporation, Rockville, MD, USA. FAU - Kearns, Gregory L AU - Kearns GL AD - Arkansas Children's Hospital, Little Rock, AR, USA. FAU - Cohen-Wolkowiez, Michael AU - Cohen-Wolkowiez M AD - Duke Clinical Research Institute, Durham, NC, USA. CN - Best Pharmaceuticals for Children Act-Pediatric Trials Network LA - eng GR - T32 HD069038/HD/NICHD NIH HHS/United States GR - HHSN275201000003C/HD/NICHD NIH HHS/United States GR - HHSN275201000003I/HD/NICHD NIH HHS/United States GR - L40 TR000598/TR/NCATS NIH HHS/United States GR - HHSN272201500006C/AI/NIAID NIH HHS/United States GR - R01 HD076676/HD/NICHD NIH HHS/United States GR - HHSN272201300017C/AI/NIAID NIH HHS/United States GR - HHSN272201300017I/AI/NIAID NIH HHS/United States PT - Journal Article PL - Switzerland TA - Paediatr Drugs JT - Paediatric drugs JID - 100883685 RN - 0 (2-Pyridinylmethylsulfinylbenzimidazoles) RN - 0 (Proton Pump Inhibitors) RN - D8TST4O562 (Pantoprazole) SB - IM MH - 2-Pyridinylmethylsulfinylbenzimidazoles/administration & dosage/*pharmacokinetics MH - Administration, Oral MH - Adolescent MH - Area Under Curve MH - Body Weight MH - Child MH - Female MH - Humans MH - Male MH - Metabolic Clearance Rate MH - *Models, Biological MH - Obesity/*complications MH - Pantoprazole MH - Prospective Studies MH - Proton Pump Inhibitors/administration & dosage/*pharmacokinetics PMC - PMC6178956 MID - NIHMS1503443 FIR - Benjamin, Daniel K IR - Benjamin DK FIR - Berezny, Katherine Y IR - Berezny KY FIR - Cohen-Wolkowiez, Michael IR - Cohen-Wolkowiez M FIR - Smith, Brian IR - Smith B FIR - Kearns, Gregory L IR - Kearns GL FIR - Laughon, Matthew M IR - Laughon MM FIR - Paul, Ian M IR - Paul IM FIR - Smith, Michael J IR - Smith MJ FIR - van den Anker, John IR - van den Anker J FIR - Wade, Kelly IR - Wade K FIR - Siegel, David IR - Siegel D FIR - Taylor-Zapata, Perdita IR - Taylor-Zapata P FIR - Zajicek, Anne IR - Zajicek A FIR - Ren, Zhaoxia IR - Ren Z FIR - Tsilou, Ekaterini IR - Tsilou E FIR - Pagan, Alice IR - Pagan A FIR - Anand, Ravinder IR - Anand R FIR - Clemons, Traci IR - Clemons T FIR - Simone, Gina IR - Simone G FIR - James, Laura P IR - James LP FIR - Howard, Lee IR - Howard L FIR - Shakhnovich, Valentina IR - Shakhnovich V FIR - Weigel, Jaylene IR - Weigel J FIR - Collier, David N IR - Collier DN FIR - Darden-Saad, Nancy IR - Darden-Saad N EDAT- 2018/08/12 06:00 MHDA- 2018/11/06 06:00 PMCR- 2019/10/01 CRDT- 2018/08/12 06:00 PHST- 2018/08/12 06:00 [pubmed] PHST- 2018/11/06 06:00 [medline] PHST- 2018/08/12 06:00 [entrez] PHST- 2019/10/01 00:00 [pmc-release] AID - 10.1007/s40272-018-0305-1 [pii] AID - 10.1007/s40272-018-0305-1 [doi] PST - ppublish SO - Paediatr Drugs. 2018 Oct;20(5):483-495. doi: 10.1007/s40272-018-0305-1.