DallphinAtoM: Physiologically based pharmacokinetics software predicting human PK parameters based on physicochemical properties, in vitro and animal in vivo data. (April 2022)

• Record Type: Journal Article
• Authors: Choi, Suein; Han, Sungpil; Lee, So Jin; Lim, Byunghee; Bae, Soo Hyeon; Han, Seunghoon; Yim, Dong-Seok
• Is Part Of: Computer methods and programs in biomedicine. Volume 216(2022)
• Publication Date: 2022-04
• Subjects: Physiologically based pharmacokinetics (PBPK) -- Allometric scaling -- In vitro-in vivo extrapolation (IVIVE) -- Simulation -- Population pharmacokinetics; A amount of drug in the GI tract (e.g., mg, μmol) -- B/P Blood-to-plasma partition ratio -- Caco-2 human colorectal adenocarcinoma cell -- CP plasma concentration -- CL clearance -- CLh hepatic clearance -- CLint intrinsic clearance -- CYP cytochrome P450 -- Fa fraction absorbed (used as the extent of bioavailability for compartment models) -- Fa_PSA fraction absorbed calculated using PSA -- GI gastrointestinal -- HIM human intestine microsome -- HLM human liver microsome -- i.v. intravenous -- IVIVE In vitro to in vivo extrapolation -- ka first-order absorption rate constant from the GI tract to plasma or blood -- KBF kidney blood flow -- ke first-order elimination rate constant -- ki rate constants of intestinal transit -- Kpi tissue-to-blood partition coefficient -- logD log of the octanol to water distribution coefficient -- logP log of the octanol to water partition coefficient -- MPPGL microsomal protein (mg)/g liver -- PK pharmacokinetics -- PSA polar surface area -- Q inter-compartmental distribution term -- Qh hepatic blood flow -- RSF rat scaling factor -- SAHHEP the surface area of one million hepatocytes -- Vc volume of central compartment -- Vd volume of distribution -- Vp volume of peripheral compartment -- Vss volume of distribution at steady state; Medicine -- Computer programs -- Periodicals; Biology -- Computer programs -- Periodicals; Computers -- Periodicals; Medicine -- Periodicals; Médecine -- Logiciels -- Périodiques; Biologie -- Logiciels -- Périodiques; Biology -- Computer programs; Medicine -- Computer programs; Periodicals; Electronic journals; 610.28
• DOI: 10.1016/j.cmpb.2022.106662
• Languages: English
• ISSNs: 0169-2607

Abstract

Highlights: In silico experiments and simulations using physiologically based pharmacokinetic (PBPK) and allometric approaches have played an important role in pharmaceutical research and drug development. Commercial PBPK platforms or relevant services are costly and generally demand a large amount of input data, but their prediction methods or key references are not fully known to users. We developed DallphinAtoM, a user-friendly GUI tool predicting human PK through assessment of various references on PBPK and allometric methods. DallphinAtoM is a free, straightforward and transparent tool enabling fast and reliable human PK simulation. Abstract: Background and objectives: In silico experiments and simulations using physiologically based pharmacokinetic (PBPK) and allometric approaches have played an important role in pharmaceutical research and drug development. These methods integrate diverse data from preclinical and clinical development, and have been widely applied to in vitro - in vivo extrapolation (IVIVE) of absorption, distribution, metabolism, and excretion (ADME). Methods: To develop a user-friendly open tool predicting human PK, we assessed various references on PBPK and allometric methods published so far. They were integrated into a software system named "DallphinAtoM" (Drugs with ALLometry and PHysiology Inside-Animal to huMan), which has a user-friendly platform that can handle complex PBPK models and allometric models with a relatively small amount of essential information of the drug. The models of DallphinAtoM support the integration of data gained during the nonclinical development phase, enable translation from animal to human, and allow the prediction of concentration-time profiles with predicted PK parameters. Results: We presented two illustrative applications using DallphinAtoM: (1) human PK simulation of an orally administered drug using PBPK method; and (2) simulation of intravenous infusion following a two-compartment model using the allometric scaling method. Conclusions: We conclude that this is a straightforward and transparent tool allowing fast and reliable human PK simulation based on the latest knowledge on biochemical processes and physiology and provides valuable information for decision making during the early-phase drug development.