WEBVTT 1 00:00:00.680 --> 00:00:04.770 Welcome to the Integrated Chemical Environment, also known as ICE. 2 00:00:04.800 --> 00:00:10.460 In this video, we will go over how to build a query in the ICE PBPK tool. 3 00:00:10.490 --> 00:00:13.060 This tool lets you build a physiologically 4 00:00:13.090 --> 00:00:17.580 based pharmacokinetic or PBPK model to explore a chemical's 5 00:00:17.600 --> 00:00:23.220 ADME characteristics: how the chemical is absorbed, distributed, metabolized, 6 00:00:23.240 --> 00:00:27.580 and excreted in the body of a human or animal. 7 00:00:27.600 --> 00:00:31.360 To run the PBPK tool, you need to specify the chemicals 8 00:00:31.390 --> 00:00:35.740 to model. You must also select a number of input parameters. 9 00:00:35.770 --> 00:00:41.980 We'll first look at these parameters and then talk about how to specify chemicals. 10 00:00:42.010 --> 00:00:47.060 Default settings of the input parameters are provided and are shown here. 11 00:00:47.090 --> 00:00:50.100 You must choose a species used for modeling. 12 00:00:50.130 --> 00:00:52.340 Currently, selections are limited to rat 13 00:00:52.370 --> 00:00:57.740 and human, with human as the default option. For certain PK parameters, 14 00:00:57.770 --> 00:00:59.900 if rat values are not available, 15 00:00:59.930 --> 00:01:05.290 human values are substituted with proper allometric scaling. 16 00:01:05.320 --> 00:01:10.050 Next, we'll select the source of the ADME data used in PK modeling. 17 00:01:10.080 --> 00:01:12.520 Specifically, these are the hepatocyte 18 00:01:12.550 --> 00:01:17.020 intrinsic clearance rate and the fraction of chemical unbound in plasma. 19 00:01:17.050 --> 00:01:19.020 We have three options here. 20 00:01:19.050 --> 00:01:23.180 The default option uses experimentally measured values whenever they are 21 00:01:23.210 --> 00:01:26.900 available, and in silico predictions where they are not. 22 00:01:26.930 --> 00:01:32.100 The second option, Measured, uses only experimentally measured values. 23 00:01:32.130 --> 00:01:34.140 This may result in fewer predictions 24 00:01:34.170 --> 00:01:38.180 because chemicals lacking these data will not be modeled. 25 00:01:38.210 --> 00:01:42.780 Lastly, the In Silico option uses only in silico predictions. 26 00:01:42.810 --> 00:01:45.210 In silico predictions used for the Default 27 00:01:45.240 --> 00:01:48.700 and In Silico options are provided by models in OPERA: 28 00:01:48.730 --> 00:01:53.210 the OPEn (Quantitative) structure- activity/property Relationship App. 29 00:01:53.240 --> 00:01:59.570 The tool uses open-source PBPK models from the httk R package developed by the U.S. 30 00:01:59.600 --> 00:02:02.260 Environmental Protection Agency. 31 00:02:02.290 --> 00:02:06.490 These models generate estimates of pharmacokinetic profiles. 32 00:02:06.520 --> 00:02:11.540 They also predict two parameters for plasma and each tissue compartment: 33 00:02:11.570 --> 00:02:15.890 Cmax, the maximum concentration of the chemical in the compartment, 34 00:02:15.920 --> 00:02:22.100 and Css, the concentration of the chemical in the compartment at steady state. 35 00:02:22.130 --> 00:02:24.980 The tool allows you to select one of two 36 00:02:25.010 --> 00:02:28.780 multi-compartment PBPK models for simulation. 37 00:02:28.810 --> 00:02:34.580 The Solve_pbtk model simulates the injection and oral gavage exposure 38 00:02:34.610 --> 00:02:42.480 routes, and the Solve_gas_pbtk model simulates the inhalation exposure route. 39 00:02:43.280 --> 00:02:46.540 Depending on model type, you can parameterize each model 40 00:02:46.570 --> 00:02:53.300 for exposure route, exposure interval, exposure length, and simulation length. 41 00:02:53.330 --> 00:03:00.540 For this example, we will choose to solve_pbtk model and the oral exposure route. 42 00:03:00.570 --> 00:03:05.700 And keep the default parameters which are human species, 43 00:03:05.730 --> 00:03:14.540 Default ADME input option, Exposure dose at 1 mg/kg/dose, 44 00:03:14.570 --> 00:03:21.380 Output unit of micromolar, 2 hour exposure interval, 45 00:03:21.410 --> 00:03:28.980 a 24 hour exposure interval, and a simulation length of 3 days. 46 00:03:29.010 --> 00:03:35.200 Additional model information can be found in the downloadable user guide. 47 00:03:35.440 --> 00:03:40.460 The input field for chemicals is located below the modeling options. 48 00:03:40.490 --> 00:03:43.100 You can choose an ICE chemical Quick List 49 00:03:43.130 --> 00:03:46.460 by clicking on the "Select Chemicals" button. 50 00:03:46.490 --> 00:03:53.180 For this example, we will choose the ER In Vitro Agonist Chemical Quick List. 51 00:03:53.210 --> 00:03:58.460 You can also enter Chemical Identifiers in User Chemical Identifier box. 52 00:03:58.490 --> 00:04:03.780 You can do this by typing in one or more individual chemical identifiers. 53 00:04:03.810 --> 00:04:14.660 For this example, we can type in "50-28-2", the CASRN for the chemical estradiol. 54 00:04:14.690 --> 00:04:18.340 You can also paste in a list of chemical identifiers. 55 00:04:18.360 --> 00:04:20.140 You can use any combination 56 00:04:20.160 --> 00:04:28.260 of the following identifiers: CASRNs, DTXSIDs, SMILES, and InChiKeys. 57 00:04:28.280 --> 00:04:30.740 Examples of these identifiers are provided 58 00:04:30.770 --> 00:04:35.700 in the information box located in the Chemical Input field. 59 00:04:35.720 --> 00:04:39.000 The PBPK tool will return results for any 60 00:04:39.000 --> 00:04:41.340 chemicals that have needed parameters available 61 00:04:41.360 --> 00:04:42.660 in ICE. 62 00:04:42.690 --> 00:04:47.980 While in silico parameter predictions are available for over 800,000 chemicals, 63 00:04:48.010 --> 00:04:50.780 we encourage users to limit input to 100 64 00:04:50.800 --> 00:04:55.720 chemicals per query to improve performance and minimize wait times. 65 00:04:56.360 --> 00:05:01.700 When you have built your PBPK query, click on "Run" at the top of the page. 66 00:05:01.720 --> 00:05:06.900 Note that the simulation may take a few minutes, depending on model and inputs. 67 00:05:06.920 --> 00:05:12.840 See the results video for an overview of understanding and interpreting results. 68 00:05:13.040 --> 00:05:18.140 Thank you for watching our video on how to build a PBPK query in ICE. 69 00:05:18.160 --> 00:05:22.680 For more detailed information on the tool, go to "Help" and select "User Guides."