Admetry® User Manual
Contents
1. Authentication Code E Copy Authentication Cade O4wSDFfstw3w3223490vmdlvy 3490tfw eDKkK3r fBasdtjdsfqqeb3sz 3tr S c dr g tbvdcvxcvbC Eef Obtain vau authorization code by enter your authentication code to web page https J nexteeainc com Pk ki PublicContentGuthornzesdmetry aspx Authorization Code ge Paste Authorization Code Activation Status Mot Activate dl Activate Admetry Cancel Admetry should now be activated If activation is not successful the CD key may already be registered Email Admetry nextcea com should you experience any problems during activation 14 User Manual Admetry Getting Started 36 Step 5 Obtaining the Authorization Code through Nextcea s website 1 duni About Nextcea Home Contact Us Biomarker Services DMPK ADME Products ADME Drug Induced Mew Drug Drug Drug Bioinformatics Synthetic PL Drug Efficacy Drug Safety Phasphalipidasis Indications Metabolite ID Interactions Admetry Biomarker 4 e Please enter your Authentication Code dd amp 84s42sp23 96 12 3 2301 pno57aqh48vhk1 vma c4nh amp 696 Tfam amp 5024s42sp23 57agh48vhk19204Biad SAMPLE Nextcea Website This is your Authorization Code roo ee SS Z mrr yrrrmeg Xrm 95ad amp 84sa1ab2sp23 12 3 2301 ncbno5795qh48vhk1 vma f Copy Authorization Code c4nh amp 6 7fam amp 50 4s42sp23 _577aqh48vnk179204Biadaa2457 A Aa a IF activation is successful Activa2. 1 2678 1 V 0 01111 1 5 1 2706 006 O12 018 0 24 0 3 1 S O Inhibitor Eadie Hofstee Mz 9 997 V S 2678 V 30 06 V S 2706 10 20 30 40 50 60 70 80 930 No Inhibitor S O Inhibitor 46 User Manual Admetry IC Determination 13 1 About IC Determination This function calculates of the effectiveness of a compound in inhibiting biological function It calculates the half maximal inhibitory concentration IC e e e e so from submitted substrate concentration information 1650 Select user input data format Substrate and Inhibitor Conc Paste Data Clear Data Measured Substrate Initial Substrate Inhibitor Conc S Conc Conc User Manual Admetry 47 IC Determination Sy cm 13 2 Using IC Determination Select either of P450 Inhibition or Substrate and Inhibitor Conc data input Manually enter or paste in data from Excel Click calculation button View results IC is calculated IC Select user input data format Se Of P450 Inhibition v TUT Ewe TT of P450 Inhibition 2 3 4 5 6 7 8 g 0001 0 001 O 01 4 1 10 100 Drug uM 10 E 2 o jJ uoniqijur OStd J0 95 48 User Manual Admetry Technical Support For questions or comments about Admetry Desktop please contact Nextcea Admetry nextcea com 9 800 225 1645 toll free o9 781 457 4010 Nextcea Inc 600 W Cummings Par
3. 005 mamy 0 004 0 003 0 002 0 001 lt gt Mo Inhibitor D Inhibitor Non Competitive or Competitive Inhibition Noncompetitive Inhibition Competitive Inhibition Non Competitive Competitive lt 6 Competitive inhibitor gm ae Competitie inhibitor CHO No inhibitor present OOO No inhibitor present 1 5 Noncompetitive inhibition Competitive inhibition DDI Non competitive Competitive User Manual Admetry 45 9 GIRD e Hanes Woolf and Eadie Hofstee equations eK _ V__ and K are calculated e Click Save to User Database to save e DDI Non competitive Competitive Back To Data Entry Study Title Compound Names NEXO001 Incubation Time 60 min Species Rat CYP P450 Enzymes 1A2 Nextcea Strain Type V max 9 997 ng ml 2678 ng ml min 0 1003 ng ml Michaelis Menten Henri v 22678 9 997 S 0 005 v 2706 s 30 06 o 0 004 0 003 0 002 o 0 001 D 8 o nud 0 10 20 30 40 50 60 70 80 90 S O Inhibitor o lo 200 E EE En EE EW EE BE Em Ez ME No Inhibitor Hanes Woolf S v 0 0003734 0 003733 e S V S 0 0003695 0 01114 Inhibitor Concentration No Inhibitor The results are graphed using Michaelis Menten Henri Lineweaver Burk Click Back to Data Entry to go back to background study design information Save To User Database 20 ng ml Lineweaver Burk 1 V 0 003733 1 S
4. across multiple species Drug Metabolite Allometry Scan Calculates the human equivalent dose from any animal model based ones surface area and body weight Human Equivalent DDI Non competitive Dose Competitive Quickly references FDA preferred and accepted substrates inhibitors and inducers of CYP450 isoforms with chemical structures provided Automatically identifies potential Phase and Phase II metabolites Additional software license is required Calculates drug drug competitive and non competitive interactions using 4 different models 6 User Manual Admetry Getting Started 36 2 1 Installing Admetry Installing Admetry is easy Admetry Setup Wizard will start automatically upon inserting CD It Setup Wizard does not start automatically e Insert Admetry CD e Open My Computer e Double click Admetry Setup icon My Computer File Edit view Favorites Tools Help Back a yo Search TEBI Folders Fa ie Folder Syne Address rg My Computer System Tasks E Local Disk C 28 Nextcea Inc E View sustem information i Add ar remove programs BR Change a setting Other Places a My Network Places My Documents 53 Shared Documents G Control Panel User Manual Admetry 7 Getting Started gem e Click Next i Admetry Welcome to the Admetry Setup Wizard The installer wall quide wou through the steps required to install Admet on you
5. be installed onto one computer per license Email Admetry nextcea com should you experience any problems during activation 12 User Manual Admetry Getting Started 36 2 5 Web Activation for computers with limited internet access Web activation is intended for computers with internet activation problems due to firewall limited internet access or no internet access Note This method requires a flash drive to transfer small files Type or Paste in the CD Key found in the Admetry activation email from Nextcea An authentication code will be generated in the text box Click Copy Authentication Code to copy the code to your clipboard 3 Paste the authentication code into Notepad and save the file on a flash drive 4 On a computer with internet access log onto P Copy and paste the authentication code into the textbox labeled Please enter your authentication code Click Submit Copy the Authorization Code from the textbox below and paste it back into Notepad and save it on the flash drive Return the flash drive to the original computer with Admetry installed and paste the Authorization Code into the Authorization Code textbox 7 Click Activiate Admetry User Manual Admetry 13 Getting Started CY icon Fleasgesater valid CD key and click Verity button to create authentication code B5BQWE3 QDNTS GFPAA B8BSE 21GFV SAMPLE CD KEY Direct Activation Web Activation
6. zero Q Instead Admetry excludes data points with BLQ concentrations in all PK TK parameter calculations When inputting bio analytical data for single oral dose the first data point should be time 0 concentration 0 3 8 Enter bio analytical data Bio analytical data may be entered for single or multiple patients animals Enter data for multiple animals sequentially As an example enter all concentration time data for patient one followed by all concentration time data for animals two and three Concentration entries of matching time points are averaged prior to PK TK analysis e Enter bio analytical data manually or with the Paste Bio analytical Data function 20 User Manual Admetry Pharmacokinetic and Toxicokinetic Analysis How to input bio analytical data from Excel C D 1 Single Administration of One Dose Level 2 3 IV 4 Dose 1 mg kg 5 6 Time hr Conc ng mL T e Copy data from Excel spreadsheet e In Admetry window click Faste Bioanalytical Data le ar All Paste Bioanalytical Data 01 sd Paste Bioanalytical Data x L select your paste data format first then click OK to process pasted e Identify the columns and click OK 2 c2 columna 00 0 cms ly 48445 n Note As a default Column 1 is set to n UT H u n as Time and Column 2 is set to Conc 1240 0 104n8 0 8052 0 v S User Manu
7. 5 Mini Pig 0 446 o 015 o 89 User Manual Admetry 31 In Vitro to In Vivo Drug Metabolism Prediction Toe 8 1 About In Vitro to In Vivo Drug Metabolism Prediction This tool is used to predict in vivo clearance values for a species based on well stirred and parallel tube models 32 In User Manual Admetry Vitro to In Vivo Drug Metabolism Prediction 2 Using In Vitro to In Vivo Drug Metabolism Prediction Specify the species from the Species dropdown menu Enter in vitro half life t min and incubation volume mL hy Input the Animal Body Weight manually by selecting standard body weight or specified body weight and enter the weight manually Specify f unbound fraction in blood Enter the amount mg of microsomes S9 or number of hepatic cells used Click Calculate to predict in vivo clearance values In Vitro to In vivo Drug Metabolism Prediction Species In Vitro T h Incubation Volume PY mL Body Weight 002 kg f unbound fraction in blood Of Microsome Po mg Q S9 mg Hepatocyte Cells million s CL In vitro intrinsic clearance fs mL min ku Well stirred model In vivo hepatic clearance CL mL min kg Parallel tube model In vivo hepatic clearance CL mL min kg User Manual Admetry 33 Metabolite ID Q Da 9 1 About Metabolite ID Metabolite ID is used to quickly generate all possible met
8. C JY aces Admetry User Manual Pharmacokinetic and Drug Metabolism Data Analysis for Everyone Nextcea Inc e 600 W Cummings Park Suite 6375 Woburn MA 01801 tel 800 225 1645 Admetry nextcea com www nextcea com 2 User Manual Admetry Forward Admetry User Manual Registered amp 2010 by Nextcea Inc All Rights Reserved Worldwide User Manual Admetry 3 Table of Contents CY cen Table of Contents 3 About Admetry 5 Getting Started 6 2 1 Installing Admetry 6 2 2 Select Installation Folder 8 2 3 Completing Installation 9 2 4 Direct Activation for computers with internet connection 10 2 5 Web Activation for computers without internet connection 12 Pharmacokinetic and Toxicokinetic Analysis 15 3 1 About PK TK Analysis 15 3 2 Enter dosing regimen 16 3 3 Enter route of administration and dosing level 17 3 4 Calculate steady state optional 17 3 5 Protein binding optional 18 3 6 Bioavailability optional 18 3 7 Bio analytical data requirements 19 3 8 Enter bio analytical data 19 3 9 Submit analysis 21 3 10 Editing data after viewing results 21 3 11 PK TK Parameter Tables and Graphics 21 3 12 Single dose results 22 3 13 Multiple Repeat dose results 23 3 14 Determining Bioavailability 24 Clinical Pharmacological Database 25 4 1 About Clinical Pharmacological Database 25 4 2 Using Clinical Pharmacological Database 26 Human Equivalent Dose Calculation 27 5 1 Abo
9. DE PK TK Allometric Visualizer 88 4 mL hour m C Dose 9 69e 3 ng mL mg kg The calculated PK values from all different 2 91e4 ng mL mag m animal species are allometrically converted to human PK values and then compared against 500 marketed drugs in the human clinical PK database PK TK Allometric Visualizer This visualizer uses allometric calculations to predict PK TK parameters from human models then plot them on a logarithmic scale along with 500 marketed drugs Clearance mL min kg Drug Names Half Lifethr Cetrorelix 5 574 Liothyronine Sodium Cytomel 6 376 Pimecralimus Cream Elidel 5 589 65440 Human 0 00001401 0 0001348 Half Life hr 0 001297 User Manual Admetry 23 Pharmacokinetic and Toxicokinetic Analysis Se Volume of Distribution amp Clearance Meter Displays 3 levels low medium high of each species Volume of distribution meter is determined by intracellular extracellular fluid total body fluid in individual animal species Clearance meter is determined by the total blood flow of liver and kidneys in individual animal species Volume of Distribution Clearance Hepatic Renal Low lt 30 total body fluid Low 3055 total blood flow Medium gt 30 and lt 70 of total body fluid Medium gt 30 and 7075 of total blood flow High gt 70 of total body fluid High gt 70 of total blood flow Volume of distribution Clearance An animal icon
10. Pepaglinide Rosiglitazone isemfibrazil Trimethoprim Rifampin User Manual Admetry 39 Drug Metabolite Scan pim 11 1 About Drug Metabolite Scan oti tt DESEE KA HH AT i gd F L UOL kj GE EES ME IRA EEL RA HE ME WE RE Drug Metabolite Scan is a utility to help automate the drug metabolite identification process Note Additional software license is required A converted wiff file from Analyst QSTAR LC MS MS to a specify data format is required to use this function 40 User Manual Admetry DDI Non competitive Competitive 12 1 About DDI Non competitive Competitive Non Competitive Competitive Drug Drug Interaction calculates drug drug interactions using Michaelis Menten Henri Lineweaver Burk Hanes Woolf and Eadie Hofstee models User Manual Admetry 41 DDI Non competitive Competitive C JY acea 12 2 Using DDI Non competitive Competitive Enter background study design information e Study Title e Compound Name e Species e Strain CYP450 Enzymes Incubation Time and Inhibitor Concentration DDI Non competitive Competitive Study Title fs Compound Drug candidate Names fs Incubation Time NENNEN E Inhibitor Concentration o Species Strain Type CYP P450 Enzymes Substrate Conc oduct Con Product Conc With Inhibitor 42 User Manual Admetry DDI Non competitive Competitive e Copy drug drug i
11. R 2005 28 User Manual Admetry Human Equivalent Dose Calculation 5 2 Using Human Equivalent Dose Calculation e Specify the species from the Species dropdown menu Input the Animal Body Weight manually by selecting Standard body weight or Specified body weight and enter the weight manually Enter the Animal Dose Level in mg kg Select Adult or Child and specify the Human Body Weight Click to project human equivalent dose levels Human Equivalent Dose Calculation Admetry calculates animal doses to human equivalent doses HED based on body surface area The HED calculations are based on recommendations by the Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers FDA CDER 2005 Species Animal Body Weight Standard body weight Animal Dose Level NEN mg kg Human Body Weight Standard body weight Human Equivalent Dose Level fo mg kg mg m User Manual Admetry 29 Symbol Definitions 6 1 About Symbol Definitions Common pharmacokinetic and toxicokinetic symbols are explained Symbol Definition AUC AUC AUMC _ t AUMC J m 5s awg M max m ss max 55 mir CL CL Area under the plasma rug concentration time curve from time 0 to time t Area under the plasma rug concentration time curve from time 0 to time infinity Total ar
12. abolites to identify when looking for Phase and Phase Il metabolites 34 User Manual Admetry MATIGI 9 2 Using Metabolite ID Enter the Exact Mass of the parent compound structure of the drug candidate if possible Click to generate a list of possible metabolite ion values Select either positive or negative ionization method M H or M H Check any number of Phase and or Phase Il metabolisms based on the Note Scroll over the metabolite ion values to see the corresponding metabolic reactions Metabolite ID Exact Mass Ionization Method M H Calculate Drug Metabolism Calculated Metabolite Results Phase I Metabolites mE Twa hree E One Two TeS P Three v Hydrogenation Readion ficcutinns Combined Combined Hydroxylation Oxidation Epoxidation Aromatic amp i NO Reactions Reactions Aliphatic T Ta S Coidalion 451 9866 379 9654 J 409 976 411 9917 P Oxidation S replacement 481 9972 430 9866 454 0023 425 9709 v Hydrolysis Ester O2C O CH3 gt OH r Hydrolysis Ester O C O CH2 CH3 gt O C OH 526 0235 528 0392 467 9815 425 9709 Hydrolysis Amide Q C NH CH3 gt OH 540 0027 555 9976 467 9815 469 9972 v Hydrolysis Amide O2C NH CH2 CH3 gt NH2 LAM Oa 0 QCC MOTA 9 ADGA md ABM OTD User Manual Admetry 35 Druc Int
13. al Admetry 21 Pharmacokinetic and Toxicokinetic Analysis Toe 3 9 Submit analysis e Click to perform PK TK analysis e View results To reset ALL data input click 3 10 Editing data after viewing results e Click Back To Data Entry in the PK TK Analyzer results page to return to data entry e Click Save To User Database and enter in a brief description of the results e Click Export To Excel to save data in Microsoft Excel format Significant Digit Back To Data Entry Save To User Database Export To Excel 3 11 PK TK Parameter Tables and Graphics PK TK parameters are viewed in downloadable tables and graphics Users can select the number of significant digits to report 22 User Manual Admetry Pharmacokinetic and Toxicokinetic Analysis 9 3 12 Single dose results PK TK Parameters IV Dose Parameters Drug concentration vs time graph ice li evel 5 00 mg kg en Iv Concentration VS Time Protein Binding 0 00 5 06e 4 ng mL oe Po n max 4 84e 4 ng mL m 1000 EEN 0 0170 hour et o t Terminal Phase 6 54 hour o CE i i100 t Distributiorn Phase 0 273 hour z Taaa AUC g t 1 67e 5 hour ng mL n E AUC 1 70e4 5 hour ng mL AUMC g t 9 272 5 hour hour ng mL BN ll BERD D DA U EN AUMC 1 052 6 hour hour ng mL i 20 20 40 So MRT 6 21 hour Time hour V 278 mL kg 835 mL m Ves 183 mL kg 549 mL m CL 29 5 mL hour kg a E
14. date to check for any critical updates to the MET Framework Cancel 10 User Manual Admetry eT file Started OY Activating Admetry v When Admetry first opens after installation you will be prompted to activate the software You can activate Admetry via Direct Activation or Web Activation After purchasing an Admetry license Nextcea will email you an activation CD key 2 4 Direct Activation for computers with internet connection Nextcea Admetry Please enter valid CD key and click Verify button to create authentication code CD Key SQWE3 QDNTS GFPA4 896SE 21GFV SAMPLE CD KEY Direct Activation Web Activation e Type in CD Key obtained from Nextcea to activate Admetry In order to activate your application directly you need to have internet connection and be able to access https nextceainc com If this computer can not connect to internet use eb Activation to generate Authentication code and obtain Authoirzation code from Nextcea Inc web site using other computer and enter it to activate Activation Status Not Activated e Click Verify Cancel Please allow a few minutes to connect to Nextcea s server for activation User Manual Admetry 11 Getting Started a e f activation is successful Activation Status will read Activated e f activation is not successful the CD key may already be registered Please note that each CD key is only allowed to
15. ea under the first moment time curve from time 0 to time t Total area under the first moment time curve from time 0 to time infinity Initial plasma concentration Average drug concentration in plasma at steady state Highest drug concentration observed in plasma following administration of IV or oral dose Maximum drug concentration in plasma at steadv state E min F D e vy 1 e F D V 1 e Minimum drug concentration in plasma at steady state C 55 min Total systemic clearance of drug from plasma Total systemic clearance of drug from plasma at steady state CL Dose AUC 30 User Manual Admetry 7 1 About Allomelry Allometry is used to predict PK parameters across different species 7 2 Using Allometry e Specily the species from the Species dropdown menu e Enter any 2 of either half life clearance or volume of distribution e Click Calculate to generate PK parameters for all other animal species Enter any two of t 2r CL and V CH 5o MEN Vol odent Species Primates ouse 0 053 0 000 0 000 Rabbit 0 187 0 002 0 043 ey 0 216 0 003 0 069 Hamster 0 078 0 000 0 002 Dog 0 303 0 006 0 2314 Marmoset 0 118 0 000 0 009 Rat 0 093 0 000 0 004 d 0 368 0 010 0 411 0 138 0 001 0 015 0 113 0 000 0 008 o 123 0 000 0 0 10 0 319 0 007 0 254 Human Child 0 868 0 010 0 411 Adult 0 500 0 020 1 15
16. elect dose by weight or surface area PharmacoKinetic And ToxicoKinetic Analysis Tutarial PK TK Data Study Pratocal Title Species Unspecified lw Strain Tvpe HA v Body Weight m Dose By Weight ko A Gender Combined Gender EL Single ar Multiple Administration single administration of one dose level lw User Manual Admetry 17 Pharmacokinetic and Toxicokinetic Analysis Sem 3 3 Enter route of administration and dosing level e Select IV and or Extravascular Dose checkbox for route of administration e Specily the dose level Select checkbox for route of administration Select checkbox for route of administration IW Dose _ Extravascular Dose Oral Tropical Inhalation MPercutanenus Rectal Transdermal and Subcutaneous Option One Option One Calculate steady state after repeat dose F Calculate steady state after repeat dose Dose Interval Minute Dose Interval Minute Dose Time J Minute Dose Time OU Minute Option Two Option Twoj Bioavailability 1 Protein Binding r l Ni Protein Binding Si Dose kg Dose mg v kg 3 4 Calculate steady state optional e Select checkbox for steady state calculation after repeat dose e Enter dose interval and time Option One Calculate steady state after repeat dose Dose Interval Dose Time 18 User Manual Admetry Pharmacokinetic and Toxicokinetic Analysis 9 6 3 5 Protein binding optional Inputting
17. eractions Tr 10 1 About Drug Drug Interactions Drug drug interaction is a quick reference for in vitro and in vivo drug drug interaction study designs 36 User Manual Admetry Drug Drug Interactions 10 2 Using Drug Drug Interactions DDI Table e Shows FDA preferred substrates inhibitors and inducers of the major CYP450 isoforms e Scroll over any compound to see the metabolic reaction chemical structure formula and exact mass Drug Drug Interaction DDI Table In Vivo Table Drug Drug Interaction In Vitro Table Inhibitor Inducer 1a2 Phenacetin Furatylline Omeprazole 746 Coumarin Tranylcypromine Dexamethasone 3A4 5 Midazolam Testoerone ketoconazole Rifampin 2B Bupropion Ticlopidine Phenobarbital 2C8 Amaodiaquine Quercetin Rifampin 2600 Tolbutamide Sulfaphenazoale Rifampin 2018 S mephenytoin Omeprazole Rifampin 2D6 Destramethorphan Ouinidine Dexamethasone 2E1 Chlorzoxazone Diethyldithiacarbamate Isoniazid User Manual Admetry 37 Drug Drug Interactions CY n In Vitro Table Table e Shows FDA preferred and accepted substrates inhibitors and inducers of the major CYP450 isoforms for in vitro studies Note Based on Guidance to the Industry documents using the preferred list of substrates inhibitors and inducers is strongly encouraged however the FDA will accept data generated using co
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19. mpounds in the accepted list e Scroll over any compound to see the metabolic reaction chemical structure formula and exact mass Drug Drug Interaction TIBET Vitro Table JUROR e In Vitro Table QE Substrate Inhibitor rm rm Acceptec IM zz Liv 7 ethoxyresorutin 0 18 O deet ration 0 21 Preferred Preferred Ki uM Accepted Theaphvlline M Phenacetin O demethylation deethylatian a aphthoflavone Caffeine 3 N demethylation Chemical Formula C 4IT W Exact Mass 241 A7 Nicotine C oxidatian 38 User Manual Admetry Drug Drug Interactions In Vivo Table Table e Shows FDA preferred and accepted substrates inhibitors and inducers of the major CYP450 isoforms for in vivo studies Note Based on Guidance to the Industry documents using the preferred list of substrates inhibitors and inducers is strongly encouraged however the FDA will accept data generated using compounds in the accepted list e Scroll over any compound to see metabolism reaction chemical structure formula and exact mass Drug Drug Interaction DDI Table In Vitro Table 4 In Vivo Table In Vivo Table CYP Inhibitor Substrate z m Inducer Strong Moderate Weak Acyclovir Famotidine Ciprofloxacin Theophylline i Mesiletine A Fluvoxamine Norfloxacin Caffeine 1 4 0 5 Verapamil Propatenone Cimetidine amp 8 3 zileuton 2 2C8
20. nteraction data from Excel V Velocity umol min 2 S uM No inhibition Inhibition 10 Inhibitor Conc 2mM 2000 uM 17 In Excel 13 e In Admetry click Paste Data DDI Non competitive Competitive Study Title Compound Drug Candidate Names Incubation Time Inhibiter Concentration Species CYP P450 Enzymes Clear Data Paste Data Substrate Conc Prod Product Conc With Inhibitor DDI Non competitive Competitive User Manual Admetry 43 9 GIRD Note Make sure data is copied from columns in the following order from left to right Substrate concentration Velocity without inhibition Velocity with inhibition e Click OK Paste User Data Hd tn c tn in e Click Calculate to calculate to graph results Cancel OK DDI Non competitive Competitive Compound Drug Candidate Names Inhibitor Concentration Species Strain Type CYP P450 Enzymes 1 2 3 4 5 6 Substrate Conc Product Conc Product Conc Without Inhibitor With Inhibitor Loo dH j 44 User Manual Admetry DDI Non competitive Competitive e Select either Non Competitive or Competitive inhibition based on the resulting graph Note Non Competitive Inhibition graphs intersect on the Y axis 1 V Competitive Inhibitions graphs intersect on the X axis 1 S 0 008 O 007466e 0 0007468 0 022214 0 0007390 0 008 0 007 0 006 0
21. protein binding data from dialysis studies is strongly recommended to accurately determine in vivo and in vitro PK parameters If protein binding data is not included Admetry defaults protein binding as 0 When preparing samples for PK analysis the drug extraction procedure artificially dissociates the drug from plasma serum proteins ie protein binding 0 by organic solvents acetonitrile methanol Option Two e Specify protein binding Protein Binding 3 6 Bioavailability optional Inputting bioavailability data is also strongly recommended to accurately determine in vivo and in vitro PK parameters If bioavailability data is not included Admetry detaults bioavailability as 100 e Specify bioavailability if known oral administration only e Determine bioavailability by following the steps in Section 3 14 User Manual Admetry 19 Pharmacokinetic and Toxicokinetic Analysis Toe 3 7 Bio analytical data requirements The bio analytical data requirements for single repeat and multiple repeat dose analysis are listed below e Single administration of one dose level Time Concentration e Single dose with one different levels Dose Level Time Concentration e Multiple Repeat dose with different dose levels Dose Level Schedule Time Concentration Admetry recognizes the term BLQ as a concentration below the limit of quantitation It does not convert BLQ concentration entries to
22. r computer WARNING This computer program is protected by copyright law and international treaties Unauthorized duplication or distribution of this program or any portion of iE may result In severe civil ar criminal penalties and will be prosecuted to the maximum extent possible under the law Cancel 8 User Manual Admetry Getting Started 36 2 2 Select Installation Folder e Specily the directory where Admetry will be installed e Choose Everyone or Just me installation options depending on who will be using Admetry e Click Next ix Admetry Select Installation Folder The installer wall install amp dmetry to the following folder To install in this Folder click Next To mstall ta a different folder enter it below ar click Browse Browse lnstall Admet for yourself or Far anyone who uses this computer Everone Just me Cancel User Manual Admetry 9 Getting Started CY dn 2 3 Completing Installation e Admetry will install please be patient as it normally takes a few minutes Note Microsoft NET Framework version 3 5 is required If you do not have Microsoft NET Framework 3 5 Admetry will install it to your computer automatically e Click Close to complete the installation ie Admetry Installation Complete Admetry has been successtully installed Click Close ta exit Please use Windows Up
23. tion Status will read Activated If activation is not successful the CD key may already be registered Email AdmetryGnextcea com should you experience any problems during this step User Manual Admetry 15 Pharmacokinetic and Toxicokinetic Analysis S 3 1 About PK TK Analysis PK TK Analysis includes modules for single repeat and multiple dose analysis and calculations are based on non compartmental models Intravenous IV or extra vascular ie oral subcutaneous topical inhalation rectal or percutaneous dose analysis are available Concentration time data can be entered manually or imported from Excel using the data paste function The results are presented graphically and in list form 16 User Manual Admetry Pharmacokinetic and Toxicokinetic Analysis 9 3 2 Enter dosing regimen e Enter Study Protocol Title optional e Select animal species and gender optional Note If animal species is not selected the resulting PK parameters will be displayed in per kg units If animal species is selected the resulting PK parameters will include per m in addition to per kg Units without species selected Units with species selected 52 8 mL kg W 52 8 mL kg Vae 36 6 mL kg 158 mL m CL 5 91 mL hour kg Yaj 366 mL kg 110 mL m CL 5 81 mL hour kg 17 7 mL hour m 1 e Select standard body weight or enter a specitied body weight optional e Select single repeat or multiple dose regimen e S
24. tribution mL min kg Benzocaine 21 2 1 04 1 75 Cefotaxime Claforan 7 5 1 2 1 2 Cimetidine Tagamet 8 3 1 2 Cromolyn Opticrom 15 6 1 8 1 3 Didanosine Videx 16 1 4 26 User Manual Admetry Clinical Pharmacological Database 4 2 Using Clinical Pharmacological Database Input a range of search values for either Half Life Volume of Distribution and or Clearance Type in drug name optional Click Search Scroll over compounds to view the PK parameters and drug information Clinical Pharmacology Database Half Life hr 0 5 Search Volume Distribution L kg Half Life hr E Or search by Cocaine 0 8 Flumazenil 17 1 0 9 Glycd yrrolate Robinul 30 1 4 0 5 Hydralazine 56 Penicillamine Cuprimine 9 3 Flumazenil Bioavailability oral 20 Clearance mL min kg i Volume Distribution L kg 1 Half Life hr 0 9 Therapeutic Class Sedative effects of benzodiazepines Chemical Formula C45H 4FN 0 Molecular Weight 303 2884 en n F NU User Manual Admetry 27 Human Equivalent Dose Calculation 7 dila 5 1 About Human Equivalent Dose Calculation This tool converts animal doses to human equivalent doses HED based on body surface area The HED calculations are based on recommendations by the Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers FDA CDE
25. ut Human Equivalent Dose Calculation 27 5 2 Using HED Calculation 28 Symbol Definitions 29 6 1 About Symbol Definitions 29 4 User Manual Admetry Table of Contents Allometry 30 7 1 About Allometry 30 7 2 Using Allometry 30 In Vitro to In Vivo Drug Metabolism Prediction 31 8 1 About In Vitro to In Vivo Drug Metabolism Prediction 31 8 2 Using Allometry In Vitro to In Vivo Drug Metabolism Prediction 32 Metabolite ID 33 9 1 About Metabolite ID 33 9 2 Using Metabolite ID 34 Drug Drug Interactions 35 10 1 About Drug Drug Interactions 35 10 2 Using Drug Drug Interactions 36 Drug Metabolite Scan 39 11 1 About Drug Metabolite Scan 39 DDI Non competitive Competitive 40 12 1 About DDI Non competitive Competitive 40 12 2 Using DDI Non competitive Competitive 41 IC Determination 46 13 1 About IC Determination 4 13 2 Using IC Determination 47 Technical Support 48 dmetry is a user friendly software for pharmacokinetic toxicokinetic and User Manual Admetry 5 drug metabolism data analysis Itis ideal for those who are new to pharmacokinetics and drug metabolism but also DMPK experts who prefer to perform PK calculations and drug metabolism analysis in an intuitive interface Calculates standard PK parameters C AUC half life and compares user drug candidate against 500 marketed drugs in humans Drug Drug Interaction Projects and compares half life clearance or volume of distribution values
26. will be displayed when an animal species is selected during data entry IV Cmax Chart IV AUC 0 t Chart Baz H ri ja kan foo AUC O0 t hr ng mL 24 User Manual Admetry Pharmacokinetic and Toxicokinetic Analysis 9 3 14 Determining Bioavailability Select checkboxes for both IV and extravascular routes of administration ie oral topical subcutaneous etc Enter IV and extravascular routes dose levels and bio analytical data into Admetry Click calculate button Bioavailability is reported in the PK TK parameters table Pharmacokinetic ToxicoKinetic Parameters IV Dose Parameters Oral Dose Parameters Parameter Name Unit Dose Level 1 00 mg kg Protein Binding 0 0096 Co 0 00 ng mL Lo 4 84e 4 ng mL max 0 0170 hour User Manual Admetry 25 Clinical Pharmacological Database T 4 1 AboutClinical Pharmacological Database The clinical pharmacological database contains 500 marketed drug compounds in humans Users can instantly find valuable human PK parameters based on a variety of search options By pointing to a drug the structure chemical formula therapeutic class human PK ie bioavailability clearance will be displayed Clinical Pharmacology Database Half Life hr E sea Clearance miming DH n Or search by Drug Name Volume Clearance Dis
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