WEBVTT 00:00:00.400 --> 00:00:04.370 Welcome to the Integrated Chemical Environment, also known as ICE. 00:00:04.440 --> 00:00:09.690 In this video, we will go over how to build a query in the ICE PBPK tool. 00:00:09.760 --> 00:00:12.770 This tool lets you build a physiologically based, 00:00:12.840 --> 00:00:18.610 pharmacokinetic or PBPK model to explore chemicals' ADME characteristics, 00:00:18.680 --> 00:00:23.160 how the chemical is absorbed, distributed, metabolized, and excreted 00:00:23.226 --> 00:00:25.410 in the body of a human or animal. 00:00:25.480 --> 00:00:30.290 To run the PBPK tool, you need to specify the chemicals to model. 00:00:30.360 --> 00:00:33.570 You must also select several input parameters. 00:00:33.640 --> 00:00:38.370 We'll first look at these parameters and then talk about how to specify chemicals. 00:00:38.440 --> 00:00:44.290 Default settings of the input parameters are provided and shown here. 00:00:44.360 --> 00:00:47.130 You must choose a species used for modeling. 00:00:47.200 --> 00:00:51.040 Currently, selections are limited to rat and human, with human 00:00:51.106 --> 00:00:53.370 as the default option. 00:00:53.440 --> 00:00:57.210 For certain ADME parameters, if rat values are not available, 00:00:57.280 --> 00:01:02.000 human values are substituted with proper allometric scaling. 00:01:02.600 --> 00:01:08.050 Next, you must choose the source of the ADME data used in PBPK modeling. 00:01:08.120 --> 00:01:10.290 There are three options here. 00:01:10.360 --> 00:01:14.920 The Default option uses experimentally measured values wherever they are 00:01:14.986 --> 00:01:19.050 available, and in silico predictions where they are not. 00:01:19.120 --> 00:01:24.690 The second option, Measured, uses only experimentally measured values. 00:01:24.760 --> 00:01:27.800 This may result in fewer predictions because chemicals lacking 00:01:27.866 --> 00:01:30.770 these data will not be modeled. 00:01:30.840 --> 00:01:36.170 Lastly, the In Silico option uses only in silico predictions. 00:01:36.240 --> 00:01:41.120 In silico predictions used for the Default and In Silico options are provided 00:01:41.186 --> 00:01:45.120 by models in OPERA: the OPEn (Quantitative) structure– 00:01:45.186 --> 00:01:49.160 activity/property Relationship App. 00:01:49.440 --> 00:01:55.450 The tool uses PBPK models from the open-source httk R package developed 00:01:55.520 --> 00:01:58.890 by the US Environmental Protection Agency. 00:01:58.960 --> 00:02:03.450 These models generate estimates of pharmacokinetic profiles. 00:02:03.520 --> 00:02:07.840 They also predict Cmax, the maximum concentration of the chemical 00:02:07.906 --> 00:02:10.210 in plasma and in each tissue compartment. 00:02:10.280 --> 00:02:15.690 Some PBPK models, (such as Solve_pbtk), also predict Css, 00:02:15.760 --> 00:02:20.880 the concentration of the chemical at steady-state in the compartment. 00:02:21.280 --> 00:02:25.080 The tool allows you to select one of three multi-compartment PBPK 00:02:25.146 --> 00:02:27.450 models for simulation. 00:02:27.520 --> 00:02:32.170 The Solve_pbtk model simulates chemical distribution following 00:02:32.240 --> 00:02:36.530 exposure via the intravenous injection or oral route. 00:02:36.600 --> 00:02:42.410 The Solve_fetal_pbtk model simulates maternal and fetal chemical distribution 00:02:42.480 --> 00:02:47.880 following exposure via the intravenous injection or oral route. 00:02:48.360 --> 00:02:53.080 The Solve_gas_pbtk model simulates chemical distribution following 00:02:53.146 --> 00:02:55.400 gas inhalation exposure. 00:02:56.440 --> 00:02:59.480 Depending on model type, you can parameterize each model 00:02:59.546 --> 00:03:05.840 for exposure route, exposure interval, exposure length, and simulation length. 00:03:06.480 --> 00:03:10.810 For this example, we will choose the Solve_pbtk model 00:03:10.880 --> 00:03:13.410 and the oral exposure route. 00:03:13.480 --> 00:03:18.250 We'll keep the default parameter parameters which are: human species, 00:03:18.320 --> 00:03:23.650 default ADME input option, body weight of 70 kilograms, 00:03:23.720 --> 00:03:27.410 exposure dose of 1 milligram per kilogram 00:03:27.480 --> 00:03:32.250 per dose, 24-hour exposure interval, 00:03:32.320 --> 00:03:38.560 simulation length of three days, and output unit of micromolar. 00:03:38.720 --> 00:03:44.200 Additional model information can be found in the downloadable user guide. 00:03:46.640 --> 00:03:50.970 The input field for chemicals is located below the modeling options. 00:03:51.040 --> 00:03:54.160 You can choose an ICE Chemical Quicklist by clicking on the 00:03:54.226 --> 00:03:56.320 "Select Chemicals" button. 00:03:56.600 --> 00:04:01.890 For this example, we will choose the "ER In Vivo Agonist" list. 00:04:01.960 --> 00:04:08.800 This list contains 43 chemicals that can be used to easily explore ICE tools. 00:04:12.560 --> 00:04:16.010 You can also paste in the list of chemical identifiers. 00:04:16.080 --> 00:04:19.530 You can use any combination of the following identifiers: 00:04:19.600 --> 00:04:27.010 Chemical names, CASRNs, DTXSIDs, SMILES, and InChIKeys. 00:04:27.080 --> 00:04:31.210 Examples of these identifiers are provided in the information box 00:04:31.280 --> 00:04:34.640 located in the Chemical Input field. 00:04:35.120 --> 00:04:39.370 The PBPK tool will return results for any chemicals that have 00:04:39.440 --> 00:04:41.890 parameters available in ICE. 00:04:41.960 --> 00:04:46.810 While in silico parameter predictions are available for over one million chemicals, 00:04:46.880 --> 00:04:52.014 we encourage users to limit input to 100 chemicals per query to improve 00:04:52.080 --> 00:04:53.690 performance and minimize wait times. 00:04:53.760 --> 00:05:00.040 When you have built your PBPK query, click on "Run" at the top of the page. 00:05:00.120 --> 00:05:05.490 Note that the simulation may take a few minutes depending on the model and inputs. 00:05:05.560 --> 00:05:11.520 See the results video for an overview of understanding and interpreting results. 00:05:22.560 --> 00:05:28.010 Thank you for watching our video on how to build a PBPK query in ICE. 00:05:28.080 --> 00:05:32.200 For more detailed information on the tool, go to "Help" and select "User Guides".