Extrapolation for a pharmacokinetic model for acetaminophen from adults to neonates: A Latin Hypercube Sampling analysis |
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| Affiliation: | 1. Auckland Bioengineering Institute, The University of Auckland, Auckland, 1010, New Zealand;2. Chongqing Institute for Food and Drug Control, Chongqing City, China;1. Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, 565-0871, Japan;2. Laboratory of Biochemistry and Molecular Biology, School of Pharmaceutical Sciences, Osaka University, Osaka, 565-0871, Japan;3. Laboratory of Hepatocyte Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, 567-0085, Japan;4. PRESTO, Japan Science and Technology Agency, Saitama, 332-0012, Japan;5. Global Center for Medical Engineering and Informatics, Osaka University, Osaka, 565-0871, Japan;6. Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka, 565-0871, Japan;1. Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd, Kainan, Japan;2. Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima-city, Japan;3. Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Japan;1. Division of Pharmacology, Department of Biomedical Sciences, Nihon University School of Medicine, Japan;2. Division of Research Planning and Development, Medical Research Support Center, Nihon University School of Medicine, Japan;3. Division of Companion Diagnostics, Department of Pathology of Microbiology, Nihon University School of Medicine, Japan;4. Division of Genomic Epidemiology and Clinical Trials, Clinical Trials Research Center, Nihon University School of Medicine, Japan;1. Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Japan;2. Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan;3. Department of Obstetrics, Hokkaido University Hospital, Sapporo, Japan;1. Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai, 980-8578, Japan;2. Food Safety Commission, Cabinet Office, Government of Japan, Akasaka Park Bldg. 22F 5-2-20 Akasaka, Minato-ku, Tokyo, 107-6122, Japan;3. Division of Risk Assessment, National Institute of Health Sciences, Tonomachi 3-25-26, Kawasaki-ku, Kanagawa, 210-9501, Japan;4. Essential Medicines and Health Products, Access to Medicines, Vaccines and Pharmaceuticals, World Health Organization, Avenue Appia 20, 1211, Geneva 27, Switzerland;5. Regulatory Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1, Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan |
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| Abstract: | Physiological and drug-specific parameters need to be adjusted when extrapolating a pharmacokinetic (PK) model from adults to neonates, so as to reproduce the time profiles of the studied drug(s) consistent with clinical, in vivo data or in vitro cell line measurements. In this paper we present a parameter analysis method, i.e. the Latin Hypercube Sampling (LHS) method for an acetaminophen (APAP) PK model. The original model consists of two compartments (the blood and the urine) with Michaelis-Menten kinetic parameters determined for APAP and its metabolites. The physiological parameters are scaled through allometric laws from adults to neonates, and APAP-specific parameters are adjusted for enzymatic maturational changes. The LHS method is used to statistically investigate the interplay between these parameters. The results for the extrapolated APAP model are consistent with published APAP PK data in neonates. We found the sulphation clearance parameter played a crucial role in the neonatal PK model, but its influence was weakened if the volume of distribution parameters were included. We suggest that this kind of in silico experiment could be valuable as the first step in PK model extrapolation between different ages. |
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| Keywords: | Acetaminophen Neonates Extrapolation Pharmacokinetic modelling Metabolism |
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