Validation of the GastroPlus TM Software Tool and Applications

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1 Validation of the GastroPlus TM Software Tool and Applications Fagen Zhang and Leah Luna The Dow Chemical Company FZ/MB

2 Acknowledgements Michael Bartels Barun Bhhatarai (Novartis) Tyler Auernhammer Shubhra Chaudhuri (Charles River) Dan Wilson Scott Arnold Amy Beasley Bryce Landenberger Neha Sunger (West Chester Univ.) Jon Hotchkiss Amy Clark Tim Erskine Sean Gehen Reza Rasoulpour Sue Marty Pamela Spencer Simulations Plus, Inc.

3 Outline Introduction Validation Methods Validation Results Applications Conclusions

4 Introduction Major Systemic Toxicity Endpoints Sensitization (allergy) Repeat dose toxicity Toxicokinetics Carcinogenicity Reproductive toxicity Major five areas of systemic toxicity testing Need for faster, cheaper, more predictive, and animal-free methods

5 Product Development Timeline Toxicokinetics in Product Development Process Discovery Pre- Development Development Post Registration Re- Registration Toxicokinetic activities In silico Toxicokinetic modeling ADME study (OECD 417) Probe AME in vivo study (4 species) In vivo Toxicokinetics Endpoint In vitro Comparative metabolism study (EU) Preliminary PBPK model (interspecies) High-end PBPK models (interspecies & multiple routes) In silico High throughput PBPK models (IVIVE)

6 In Silico Predictive Toxicokinetics The Dow Toxicokinetics group conducts in silico Pharmacokinetic/Metabolism (ADME) assessments for a variety of product stewardship and regulatory needs De novo prediction of absorption (oral, inhalation, dermal) Systemic exposures (blood levels) Tissue distribution (bioaccumulation) Primary tools are: ACD/Percepta (ACD/Labs) (Human Oral only) Finite dose dermal penetration calculator (US CDC) Dermwin (US EPA EpiSuite) (Human dermal only) GastroPlus Software Suite (Simulations Plus)

7 HTS Toxicokinetic Model Requirements Modeling software criteria: Support for multiple exposure routes and regimens Oral, Inhalation, Dermal (critical for relevant Risk Assessments) Acute, steady-state Incorporates critical QSARs for: Absorption rates and amounts Metabolic clearance Plasma protein binding Tissue distribution Based on Compartmental PK or PBPK designs Provides model predictions of parent compound and metabolite(s) Supports various species and lifestages Minimal to no coding required Best option for regulatory buy-in Batch modeling feature Selected: GastroPlus from Simulations Plus

8 Outline Introduction Validation Methods Validation Results Applications Conclusions

9 Evaluation Methods The accuracy of key physical-chemical properties of a variety of chemical classes used within GastroPlus for prediction of pharmacokinetics was evaluated against experimental data -pka, LogP, Henry s Law Constant (HLC) -GastroPlus predictions compared to other well-validated QSAR tools- Pipeline Pilot, EPA EpiSuite The accuracy of toxicokinetic parameters predictions from GastroPlus was evaluated for a variety of chemical classes with measured data from the oral, dermal and inhalation routes of exposure, either in animal species or human volunteers The correlation of predicted toxicokinetic values vs. literature data from oral, inhalation or dermal exposures was then determined: -Fraction absorbed (Fa%), Cmax, and AUC Applications of GastroPlus for toxicology study design and high-throughput Exposure Assessments

10 Outline Introduction Validation Methods Validation Results Applications Conclusions

11 E x p e r i m e n t a l p K a E x p e r i m e n t a l p K a PhysChem Evaluation Results Experimental vs. Predicted pka Values A D M E T - p K a P P - p K a R 2 = R 2 = P r e d i c t e d p K a P r e d i c t e d p K a from ADMET Predictor model of GastroPlus (ADMET) or Pipeline Pilot (PP) The predicted pka values from ADMET correlated well with the literature data and were better than those predicted by PP.

12 E x p e r i m e n t a l L o g P E x p e r i m e n t a l L o g P PhysChem Evaluation Results Experimental vs. Predicted LogP Values A D M E T - L o g P E p i S u i t e - L o g P 6 R 2 = R 2 = P r e d i c t e d L o g P P r e d i c t e d L o g P from ADMET Predictor model of GastroPlus (ADMET) or US EPA EpiSuite The predicted LogP values from ADMET correlated well with the literature data and were comparable to those predicted by EpiSuite.

13 E x p e r im e n ta l lo g H L C (a tm -m 3 /m o le ) PhysChem Evaluation Results Experimental vs. Predicted HLC Values via ADMET 0 R 2 = P re d ic te d lo g H L C (a tm -m 3 /m o le ) The predicted values correlated well with the literature data.

acceptable: - 67% of predicted Clint values within 10x of

14 Major PK Parameter Evaluation Results 26% Metabolic clearance and Fup predictions by GastroPlus are quite acceptable: - 67% of predicted Clint values within 10x of empirical data - 87% of predicted Fup values within 30% of empirical data

15 E x p e r im e n ta l C m a x ( g /m L ) E x p e rim e n ta l A U C ( g -h r /m L ) Oral Exposures Pharmacokinetic Data Evaluation C m a x A U C R 2 = R 2 = P a r e n t C o m p o u n d T o ta l R a d io a c tiv ity P r e d ic te d C m a x ( g /m L ) P r e d ic te d A U C ( g -h r /m L ) The predicted pharmacokinetic values from GastroPlus correlated well with the literature data Cmax: 69% within 3-fold, and 88% within 10-fold of experimental data AUC: 54% within 3-fold, and 85% within 10-fold of experimental data

16 E x p e r im e n ta l C m a x ( g /m L ) P r e d ic te d A U C ( g -h r /m L ) Inhalation Exposures Pharmacokinetic Data Predictions C m a x A U C R 2 = R 2 = P r e d ic te d C m a x ( g /m L ) E x p e rim e n ta l A U C ( g -h r /m L ) Cmax: 50% within 3-fold, and 63% within 10-fold of experimental data AUC: 50% within 3-fold, and 63% within 10-fold of experimental data - generally over-predicted (conservative)

17 E x p e r i m e n t a l C m a x ( g / m L ) Dermal Exposures Pharmacokinetic Data Predictions C m a x R 2 = P a r e n t C o m p o u n d T o t a l R a d i o a c t i v i t y P r e d i c t e d C m a x ( g / m L )

obtained with SimCYP and overall conservative vs.

18 Accuracy of Steady-State Systemic Exposure Evaluation Steady state blood level predictions from GastroPlus consistent with those obtained with SimCYP and overall conservative vs. Reference data Predicted Css values generally improve with inclusion of measured Clint and Fup

19 Outline Introduction Validation Methods Validation Results Applications Conclusions

20 Applications of GastroPlus TM Toxicology Study Design Dose level selection for animal toxicity studies based on IVIVE (In Vitro-In Vivo Extrapolation) comparison to in vitro endpoints Inhalation study waiver Dose route selection for chronic toxicity study Exposure Assessment HEAT (High-Throughput Exposure Assessment Tool)

21 Applications of GastroPlus TM Dose level selection for animal toxicity studies based on IVIVE comparison to in vitro endpoints In vitro mouse hepatocyte dose (µm) for Compound A Mouse Dose (mg/kg/day Compound A) Predicted Cmax (µm) 4 Days 7 Days 14 Days The predicted in vivo dose levels (3, 10, and 30 mg/kg/day) that reach the corresponding in vitro concentrations.

22 Applications of GastroPlus TM Inhalation study (90-Day inhalation) waiver for Compound B Predicted Plasma concentration at dose level of 979 mg/kg The predicted plasma concentration that reaches the steady state after one week exposure and the bioaccumulation factor is around 1.

23 Applications of GastroPlus TM Inhalation study (90-Day inhalation) waiver for Compound B Predicted Compartment Absorption The total absorption for compound B by the inhalation route is predicted high (73%) - however, fraction absorbed through the pulmonary tissue is predicted low (0.1%) - These data support the rationale for waiving the inhalation study

24 Applications of GastroPlus Justification for the selection of administration route for 2-year rat chronic study of Compound C (Total mixture containing four similar components) Name C max in blood (µg/ml) C max in reproductive tissues (µg/ml) AUC0-t in blood (µg-h/ml) Component a Day dietary exposure Component b Component c Component d Total mixture Day inhalation exposure Component a Component b Component c Component d Total mixture MKD = 300 mg /kg

25 C o n c e n tr a tio n ( g /m L ) C o n c e n tr a tio n ( g /m L ) Applications of GastroPlus Justification for the selection of administration route for 2-year chronic study of compound C D ie ta r y E x p o s u r e In h a la tio n E x p o s u r e T im e (h o u r s ) T o ta l m ix tu re C o m p o n e n t a C o m p o n e n t b C o m p o n e n t c C o m p o n e n t d T im e (h o u rs ) T o ta l m ix tu re C o m p o n e n t a C o m p o n e n t b C o m p o n e n t c C o m p o n e n t d The predicted total steady Cmax from dietary was much higher than that from inhalation.

26 Applications in HEAT Methods for High Throughput Exposure assessment Tool (HEAT) Determine external exposures for Dow products - Using formulation data and validated Occupational or Consumer exposure models Pre-define predictions of blood levels across a range of external exposures ( mg/kg) - Oral, Inhalation and Dermal routes - Select most conservative formulation types (highest C max values) and exposure conditions for each route

27 B io a c c u m u la tio n F a c to r P la s m a C m a x (µ g /m L ) Applications in HEAT Trends in Systemic Exposure Predictions with GastroPlus L o g P D o s e (m g /k g ) Bioaccumulation after 28 days oral exposure Saturation of oral absorption

28 % F a Applications in HEAT Trends in Systemic Exposure Predictions T o ta l a n d P u lm o n a r y F r a c tio n A b s o r b e d a s a F u n c tio n o f L o g P P re d ic te d T o ta l % F a S o lu tio n P re d ic te d T o ta l % F a P o w d e r P re d ic te d P u lm o n a ry % F a S o lu tio n P re d ic te d P u lm o n a ry % F a P o w d e r L o g P Trends towards lower uptake of inhaled chemicals through pulmonary tissue - trend enhanced for solid formulations vs. solutions

29 P la s m a C o n c e n t r a t io n s ( u g /m L ) Applications in HEAT Selection of Optimal Exposure time for de novo Inhalation modeling E th y le n e G ly c o l C m a x v s. E x p o s u r e T im e E x p o s u r e T im e (1 m g /k g /h r in h a le d ) (h )

30 Outline Introduction Validation Methods Validation Results Applications Conclusions

31 Conclusions The prediction for Physico-chemistry properties was assessed and the experimental data correlated well with the predicted data GastroPlus TM was assessed for systemic exposure prediction via oral, dermal and inhalation routes Based on the validation results, GastroPlus TM is deemed acceptable for IVIVE evaluation by the oral, inhalation, and dermal routes. GastroPlus TM should be used for high throughput toxicokinetic predictions GastroPlus will allow for optimum implementation of animal alternatives in novel high throughput safety assessment programs (Tox21)

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