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Extrapolation of Animal Data to Man

Extrapolation of Animal Data to Man. September 19 th 2012 Professor Andrew Hughes MRCP, PhD, FFPM VP Early Phase Cancer Clinical Development, AstraZeneca Chair of Translational Medicine, University of Manchester AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield. SK10 4TG

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Extrapolation of Animal Data to Man

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  1. Extrapolation of Animal Data to Man September 19th 2012 Professor Andrew Hughes MRCP, PhD, FFPM VP Early Phase Cancer Clinical Development, AstraZeneca Chair of Translational Medicine, University of Manchester AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield. SK10 4TG Tel: 01625 512092 Fax: 01625 585626 e-mail: andrew.hughes@astrazeneca.com ILSI HT Project Aug 99

  2. Overview • Previous attempts to extrapolate • The ILSI project • Practical tips for punters • Your turn to play Safety Physician Key learning points: 1. Historically how has extrapolation of animal data to man been addressed 2. Inherent problems in answering this question 3. How is this question currently being addressed ILSI HT Project Aug 99

  3. Previous attempts to extrapolate ILSI HT Project Aug 99

  4. Previous General Retrospective Surveys I 6 compounds - retrospective intra- company review • Rats not that predictive • Dogs predict much better • “Typical rat & dog tox package” - • 70% concordance • Litchfield 1962 ILSI HT Project Aug 99

  5. Previous General Retrospective Surveys II 24 compounds - retrospective inter- company review For drugs terminated from development • 33% Concordance rate • Lumley 1990 ILSI HT Project Aug 99

  6. Previous General Retrospective Surveys III 139 drugs - retrospective literature review For drugs approved in Japan (1987-1991) • 57% concordance rate Best for - cardiovascular Worst for - cutaneous - hypersensitivity • Hepatobiliary toxicity poorly predicted • General pharmacology experiments very useful JPMA 1994 ILSI HT Project Aug 99

  7. Previous General Retrospective Surveys IV • Retrospective literature review for drugs withdrawn from market • 16% Concordance rate – 24 drugs (Heywood, 1990) • 5% Concordance rate – 114 drugs (Spriet-Pourra, 1994) ILSI HT Project Aug 99

  8. Cautionary notes • Its never going to be 100% concordance A. Other target toxicities preclude toxic doses B. Different species C. Different experimental methodology • Accurate estimation is impossible! ILSI HT Project Aug 99

  9. B. Species Pharmacokinetic Differences A - similar (NB not bioavailability) D - similar (protein binding can be different) M - different and unpredictable eg: • Rat - no gall bladder but enterohepatic circulation greater than other species • Cat - cant glucuronate • Dog - cant acetylate • Amphetamine: Rabbit deaminates; Man & monkey parahydroxylate E - different but predictable: (clearance = organ blood flow x extraction) (different) (similar) NB. Plasma concentrations are more important than dose to compare between species eg. to achieve a pharmacologically active (anti inflammatory) plasma level of 100-150 ug/ml phenylbutazone need only 5mg/kg in man but 300mg/kg in rabbit ILSI HT Project Aug 99

  10. C. Differences in experimental methodology Animals Man Subjects Number Large groups Individuals Age Young adult All ages State of health Healthy Usually sick Genetic background Homogenous Heterogenous Doses Magnitude Therapeutic to toxic Therapeutic Schedule Usually once daily Therapeutic optimum Circumstances Housing Uniform, optimal Variable Nutrition Uniform, optimal Variable Concomitant therapy Never Frequent Diagnostic procedures Verbal contact None Intensive Physical exam Limited Extensive Clinical lab Limited, standardized Individualised Timing Predetermined Individualised Autopsy Always Exceptional Histopathology Extensive Exceptional ILSI HT Project Aug 99

  11. Accurate estimation is impossible!: Sensitivity and specificity ILSI HT Project Aug 99

  12. The ILSI project International Life Sciences Institute ILSI HT Project Aug 99

  13. ILSI project: 1997 Objectives • How good are the animal surrogates for predicting the toxicity of drugs in humans ? • How could preclinical tests conducted today be improved ? • What toxicological information is important to discovery and development of pharmaceuticals in order to address safety in clinical trials ? ILSI HT Project Aug 99

  14. ILSI: Approach to data collection: • Collect the clinical data (select for Human toxicities and not other reasons for termination) • Collate the HT data (Phase I, II, III when first observed, • therapeutic class, COSTART organ system, etc.) • Seek non-clinical correlates from: • - toxicology/safety pharmacology studies • - identify corresponding organ system changes from • animal studies ILSI HT Project Aug 99

  15. ILSI: Definition of “Human Toxicity” • Adverse Event leading to project termination • Toxicity restricting - dose range, - patient population • Toxicity which results in drug level monitoring and individual patient adjustment • Idiosyncratic ILSI HT Project Aug 99

  16. ILSI Project: Data review • 221 Examples of Human Toxicity from 150 compounds from 12 pharmas. Abbot Novartis Pfizer Bayer Boehringer Ingelheim Pharmacia & Upjohn Eli Lilley Rhone-Poulenc Rorer Janssen Sanofi Zeneca Monsanto/Searle • International Workshop April 99 • Publication in peer-reviewed journal ILSI HT Project Aug 99

  17. Problem 1: ILSI Dataset is Selective for +ve HTs only ILSI HT Project Aug 99

  18. Aesthenia Confusion Amnesia Dizziness Nausea Headache Excitation Dyskinesia Problem 2: COSTART can blur predictivity: eg neurology ILSI HT Project Aug 99

  19. Neurology - 22% Anti-infectives - 17% Oncology - 11% Anti-inflammatory & analgesics - 10% Cardiovascular - 8% Respiratory - 8% Metabolic - 8% Gastrointestinal - 6% Anti-viral (incl HIV) - 5% Impotence - 2% Hematology - 1% Immunology - 1% Renal - 1% Problem 3: Database reflects what has been... ILSI HT Project Aug 99

  20. 10 questions* Who wants to be a millionaire**? *This is only a bit of fun to maintain interest levels during the next section of heavy data **London weighted mean annual salary for a toxicologist ILSI HT Project Aug 99

  21. Preclinical Species in which Human Toxicity predicted ( n = 214 ) Total 71%+ve Positive non rodents only were dog ( 49 ) ,primate (7) or both (1). Rodents only were rat (10), mouse (3), guinea pig (3) and rabbit (2). ILSI HT Project Aug 99

  22. Animal Concordance (%) by HT Categories ILSI HT Project Aug 99

  23. Animal Concordance (%) by Therapeutic Class

  24. Phase of Clinical Trial ( n=221 ) • 61% HTs in Phase I • 39% terminated. • 30% pharmacological • 29% HTs in Phase II • 43% terminated. • 38% pharmacological • 10% HTs in Phase III • 10% terminated. • 24% pharmacological ILSI HT Project Aug 99

  25. Therapeutic Class vs HT Onset in Phase I (%) ILSI HT Project Aug 99

  26. Pharmacological Basis for HTs by COSTART categories (%) ILSI HT Project Aug 99

  27. HT Categories for Anti-cancer Drugs n =25 n.b. high hematologic side-effects. ILSI HT Project Aug 99

  28. HT Categories for Anti-infectives Drugs n = 38 n.b. high GI effects ILSI HT Project Aug 99

  29. HT Categories for Cardiovascular Drugs n =18 n.b. High CV side-effects ILSI HT Project Aug 99

  30. HT Categories for Neurologic Drugs n =48 n.b. high neurologic, cardiovascular and gastrointestinal effects ILSI HT Project Aug 99

  31. Reasons for 29% being non-predictive?? • Toxicity studies too short? • Didn’t go to high enough doses? • Metabolic difference between species? • Human toxicity not assessable in animals? e.g. visual disturbance ILSI HT Project Aug 99

  32. Achievement of Limiting Toxicity where HT not Predicted 91% 90% N/C = HTs where no animal prediction where data available. ILSI HT Project Aug 99

  33. Correlation of Metabolism where HT not Predicted ( data for 29/63 cases) 86% • 89% (111/125) animal • human metabolite • correlates overall • ( incl. predictive cases ). Metabolism profile not broken down by animal species ILSI HT Project Aug 99

  34. Reasons for 29% being non-predictive?? • Toxicity studies too short? No evidence • Didn’t go to high enough doses? No evidence • Metabolic difference between species? No evidence • Human toxicity not assessable in animals? e.g. visual disturbance ILSI HT Project Aug 99

  35. Conclusions from ILSI Human Toxicity Project Data • 71% ( 151/214) human toxicities associated with toxicity in animals • 63% in non-rodents • 36% in rodent plus non-rodent combinations • 43% in rodents • 29% of human toxicities not predicted for by animals ( 8 HTs insufficient animal data). • Two species best predictor; for single species non-rodent better than rodent. ILSI HT Project Aug 99

  36. Practical tips for Punters ILSI HT Project Aug 99

  37. Administer to man? • Reversible • Monitorable • Treatable • Non-serious • Predictable No Yes Irreversible Unmonitorable Untreatable Clinically Serious Unpredictable ILSI HT Project Aug 99

  38. Your turn to play safety physician • Would you administer this drug to man? • If so, which population? ILSI HT Project Aug 99

  39. Arteritis • In Dog only • No evidence of reversibility • First observed at Cmax of 20ug/ml AUC of 8ug.hr/ml. Worse with higher concentrations • In vitro IC50 is 2ug/ml • No consequence ILSI HT Project Aug 99

  40. Seminiferous Tubule Atrophy • In Rat only • Considered pharmacologically related • Reversible • Occurs first at Cmax of 2ug/ml and AUC of 1.3 ug.h/ml. Worse with higher concentrations • In vitro IC50 is 2ug/ml ILSI HT Project Aug 99

  41. Reduction in red cell count • Observed in both rat and dog • Reversible • NEDL of most sensitive species is Cmax of 50ng/ml and AUC of 25ng.h/ml. Worse at higher concentrations with maximum reduction observed as 50% • In vivo active at 20ng/ml • Considered pharmacologically related ILSI HT Project Aug 99

  42. The last word…. “The more we know about the similarities of structure and if function of higher organisms at the molecular level, the more we are convinced that mechanisms of chemical toxicity are, to a large extent, identical in animals and man” Professor Zbinden

  43. Publications • Olson et al (2000) Concordance of the Toxicology of Pharmaceuticals in Humans and in Animals. Regulatory Toxicology & Pharmacology 32 (1) 56-67 • Heywood R. (1990) Clinical Toxicity - could it have been predicted? Post-marketing experience. In Animal Toxicity studies: their relevance for man. Eds: Lumley CE & Walker SW. Pubs: Quay Publishing, Lancaster, UK • Igarashi T, Nakane S, Kitagawa T (1995) Predictivity of clinical adverse reactions of drugs by general pharmacology studies. J. Toxicol Sci, 20, 77-92. • Litchfield JT. (1962) Evaluation of the safety of new drugs by means of tests in animals. Clin Pharmacol. Ther. 3, 665-672. • Lumley CE & Walker. (1990) CMT workshop: Animal Toxicity Studies; their relevance for man. Quay publishing, Lancaster, UK. • Spiret-Pourra C, Auriche M. SCRIP reports, New York, PJB, 1994 ILSI HT Project Aug 99

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