Cardiac Safety Assessment. In-Vitro/In-Vivo Extrapolation

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Marion McCoy
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1 Cardiac Safety Assessment In-Vitro/In-Vivo Extrapolation

Drugs removed from the market for arrhythmia risk Courtesy of Dr.

And Now For Something Completely Different

And Now For Something Completely Different Trimebutine

Physiology disruption can it be clinically significant? Bisacodyl During her hospitalization she had two episodes of torsades de pointes requiring cardiac defibrillation.

10 Physiology disruption can it be clinically significant? Bisacodyl During her hospitalization she had two episodes of torsades de pointes requiring cardiac defibrillation. [ ] she admitted her laxative abuse and surrendered her supply of Dulcolax tablets. Pantoprazol 53-year-old chronic alcoholic male patient, [ ] on a proton pump inhibitor for peptic ulcer prophylaxis, which resulted in resistant hypomagnesemia associated with a storm of life-threatening arrhythmias, namely Torsades de Pointes (TdP) Copyright 2014 Certara, L.P. All rights reserved. 10

11 TdP risk surrogates one drug really? IKr IC 50 = 5.95 µm INa IC 50 = 38 µm IKr IC 50 = 12.1 µm INa IC 50 = 8.5 µm Redfern system Category 5 (no TdP) Mirams system Category 5 (no TdP) pro-drug high extraction rate, low concentration Kramer system Category 0 (no TdP) CredibleMeds possible TdP risk Figure from Dimmit DC et al. CancChemPharm, 1999; 43: Copyright 2014 Certara, L.P. All rights reserved. 11

12 One drug really? Problem insight parent+metabolites PO IV single drug analysis might be misleading multiple drug analysis might be necessary metabolite(s) should be analyzed in parallel with the parent compound pharmacokinetics plays significant role Copyright 2014 Certara, L.P. All rights reserved. 12

14 TdP risk of the drug combinations Droperidol and ondansetron both found to prolong the QT interval Utilized in the treatment of postoperative nausea and vomiting May be used in combination The effects of droperidol and ondansetron in combination on QT interval duration unknown Copyright 2014 Certara, L.P. All rights reserved. 14

18 One drug really? Problem insight PD DDIs single drug analysis does not explain the clinical effect multiple drug analysis might be necessary perpetrator(s) should be analyzed in parallel with the parent compound pharmacokinetics not significant how does it transfer to TdP risk? Copyright 2014 Certara, L.P. All rights reserved. 18

21 TdP risk surrogates problems example Risperidone Classification Redfern class 5 (safe) Mirams class 5 (safe) Clinical cases 15 LQTc cases recently reviewed 6 out of 15 (+)TdP Kramer (+)TdP CredibleMeds possible TdP risk Rajabi et al. (2011) sudden cardiac death -> risk factors were female sex, cotrimoxazole, and risperidone Raviña et al. (2007) TdP -> risk factors were female sex, age, and risperidone Blaschke et al. (2007) TdP -> risk factors were female sex, age, bradycardia, and concomitant use of risperidone, citalopram, and co-trimoxazole Novalbos et al. (2010) QT prolongation -> CYP2D6 Genotype (metabolites role) Llerena et al. (2004) QT prolongation -> CYP2D6 Genotype (metabolites role) Copyright 2014 Certara, L.P. All rights reserved. Viewerg 2013 Psychopharmacology 228:

Sola dosis facit venenum was Paracelsus right?

23 Algorithms for the TdP risk prediction issues CHANNELS INHIBITION SOURCE and QUALITY of INPUT DATA RISK CLASSIFICATIONS PREDICTION ALGORITHMS and ENDPOINTS EXPOSURE (active concentration surrogates) ACTIVE METABOLITES and INTERACTING DRUGS DEMOGRAPHIC, (PATHO)PHYSIOLOGICAL and GENETIC VARIABILITY COMORBIDITY DRUGS TRIGGERED PHYSIOLOGY MODIFICATION DIETARY HABITS NON-ELECTROPHYSIOLOGICALLY TRIGGERED QT prol / TdP PRODRUGS Copyright 2014 Certara, L.P. All rights reserved. 23

24 Separating Systems & Drug Information IVIVE Systems Data Drugs Data Trial Design Age Weight Tissue Volumes Tissue Composition Cardiac Output Tissue Blood Flows Cardiac Myocytes Volume Electric capacitance Plasma ions MW LogP pka Protein binding BP ratio In vitro Metabolism Permeability, Transport Ionic currents inhibition Dose Route Frequency Co-administered drugs Populations studied Time of the day Mechanistic IVIVE PBPK/PBPD models Prediction of drug PK (PD) in population of interest Copyright 2014 Certara, L.P. All rights reserved. 24

variability (despite of what people say - TdP is NOT a yes/no event) Analyze the simulated

25 Simcyp/Certara proposition Cardiac Safety Simulator PURPOSE OF THE CSS Integrate available in vitro data Utilize the early clinical data if accessible Account for the inter-individual variability (despite of what people say - TdP is NOT a yes/no event) Analyze the simulated data Assess both QT and non-qt toxicities Copyright 2014 Certara, L.P. All rights reserved. 25

Multiple endpoints from one system Cardiac Safety Simulator exposure SIMCYP multiple drugs cell

ion currents (QSAR) in silico currents other in silico ion currents (QSAR) (QSAR) in silico

(measured) in vitro currents other in ion vitro (measured) currents (measured) in vitro

demography action potential (APD90) - AP prolongation - AP shape analysis - EADs pseudoecg

26 Multiple endpoints from one system Cardiac Safety Simulator exposure SIMCYP multiple drugs cell contractility - EM window herg in silico (QSAR) other ion currents other in ion other silico ion currents (QSAR) in silico currents other in silico ion currents (QSAR) (QSAR) in silico (QSAR) herg in vitro (measured) other ion currents other in ion other vitro ion currents (measured) in vitro currents other in ion vitro (measured) currents (measured) in vitro (measured) CONTRACTILITY MODEL HUMAN HEART LEFT VENTRICULAR CELL MODEL virtual population demography action potential (APD90) - AP prolongation - AP shape analysis - EADs pseudoecg (QTc) physiology genetics Copyright 2014 Certara, L.P. All rights reserved. - QT prolongation - iceb - J-T peak, T peak -T end 26

27 Simulation results Mean ΔQTc (SD) [ms] Risperidone observed predicted SOURCE and QUALITY of INPUT DATA RISK CLASSIFICATIONS PREDICTION ALGORITHMS and ENDPOINTS EXPOSURE (active concentration surrogates)! ACTIVE METABOLITES and INTERACTING DRUGS 5 0 RISPERIDONE DEMOGRAPHIC, (PATHO)PHYSIOLOGICAL and GENETIC VARIABILITY DRUGS TRIGGERED PHYSIOLOGY MODIFICATION Harrigan 2004 JClinPsychopharm 24:62 69 Glinka 2014 CompBiolMed 47:20 26 Copyright 2014 Certara, L.P. All rights reserved. 27

Simulation results Mean ΔQTc (95% CI) [ms] Risperidone plasma heart 5 2 EnhQSAR predicted IC50 [µm] IKr IKs INa ICaL risperidone_cid_5073 0.141 0.060 37.1 48.1 paliperdione_cid_115237 0.207 0.090 17.

28 Simulation results Mean ΔQTc (95% CI) [ms] Risperidone plasma heart 5 2 EnhQSAR predicted IC50 [µm] IKr IKs INa ICaL risperidone_cid_ paliperdione_cid_ ΔQTc obs ΔQTc pred SOURCE and QUALITY of INPUT DATA EXPOSURE (active concentration surrogate) ACTIVE METABOLITES GENETIC VARIABILITY 0 EM IM PM UM Copyright 2014 Certara, L.P. All rights reserved. Novalbos 2014 JClinPsychopharm 30:

Simulation results ACUTE INTOXICATION - IVIVE at the individual level - RESULTS Citalopram 36-yo woman after a suicidal attempt high dose of citalopram measured plasma concentration (~33 hour after

29 Simulation results ACUTE INTOXICATION - IVIVE at the individual level - RESULTS Citalopram 36-yo woman after a suicidal attempt high dose of citalopram measured plasma concentration (~33 hour after the last dose) - Citalopram 477 ng/ml (1.47 μm); therapeutic concentration: ng/ml ( μm) - Desmethylocitalopram ng/ml (0.4 μm); therapeutic concentration: ng/ml ( μm) hypokalemia 3.1 mmol/l; heart rate /minute Copyright 2014 Certara, L.P. All rights reserved. 29

30 Simulation results ACUTE INTOXICATION - IVIVE at the individual level - RESULTS Citalopram (+ desmethylcitalopram) CSS Ionic current Citalopram [IC 50 ]/n Reference and/or model input parameters Desmethylcitalopram [IC 50 ]/n Reference and/or model input parameters I Kr 3.97/0.75 [Witchel 2002] 1.59/1 QSAR predicted I Ca 65/1 [Witchel 2002] 2.93/1 QSAR predicted 1 K + - physiological (4.1 mm ±CV 10%) RR physiological (750 ms ±CV 5%) heart drugs concentration (Kp~1.2) 2 K + - disrupted (3.1 ±CV 10%) RR disrupted (500 ms ±CV 5%) heart drugs concentration (Kp~1.2) 5 Copyright 2014 Certara, L.P. All rights reserved. 30

31 Simulation results AP (ms) ACUTE INTOXICATION - IVIVE at the individual level - RESULTS Citalopram (+ desmethylcitalopram) OBS PRED_2 PRED_1 Mean-APD90 (ms) (4.3) 394 (6.5) Triangulation - 54 (5.3) 42 (4.2) CSS Mean-QTcB (ms) (22.3) 436 (19.0) Time (ms) Copyright 2014 Certara, L.P. All rights reserved. 31

33 Acknowledgements Simcyp Nikunjkumar Patel Amin Rostami-Hodjegan Jagiellonian University Medical College Barbara Wiśniowska Anna Glinka Kamil Fijorek Aleksander Mendyk Copyright 2014 Certara, L.P. All rights reserved. 33

34 Conclusions IVIVE in the TdP risk assessment area REMEDY not yet USEFUL TOOL yes, already is (borderline drugs) WHERE different scenarios testing POPULATION ANALYSIS important ENVIRONMENTAL PARAMETERS matters I HOPE YOU DON T AGREE AND WE CAN HAVE A NICE ARGUMENT Copyright 2014 Certara, L.P. All rights reserved. 34

35 THANK YOU

37 Simulation results ANTIARRHYTHMIC DRUG - IVIVE at the population level - RESULTS Flecainide 24 healthy individuals (12M + 12F) two formulations (IR-solid, CR-open) two doses (100 mg-circle, 200 mg-sqaure) two scenarios (single, multiple dose) Copyright 2014 Certara, L.P. All rights reserved. 37

38 PRED Simulation results PRED PRED PRED ANTIARRHYTHMIC DRUG - IVIVE at the population level - RESULTS Flecainide I kr 3.91 µm (HEK, 37 0 C); I Na 0.9 µm (HEK, 22 0 C) analysed endpoint - ΔQRS CSS o 100 IR 100 CR 200 IR 200 CR OBS OBS OBS OBS Copyright 2014 Certara, L.P. All rights reserved. 38

Benchmarking In Silico Models and Candidate Metrics for Assessing the Risk of Torsade de Pointes

Benchmarking In Silico Models and Candidate Metrics for Assessing the Risk of Torsade de Pointes Sara Dutta Division of Applied Regulatory Science/OCP/CDER CRSC/HESI/SPS/FDA Meeting December 11, 2014 Silver