Safety Pharmacology Society Webinar Series: Safety Pharmacology Endpoints: Integration into Toxicology Studies Integrating functional CNS observations into toxicology studies: the CONS! Will Redfern, PhD Safety Assessment UK Alderley Park Cheshire United Kingdom September 20, 2012 Reasons for attrition of candidate drugs Meanwhile, ADME failures have been reduced by a ‘frontloading’ approach Kola & Landis (2004) Nature Reviews: Drug Discovery 3: 711-715. Attrition due to inadequate safety – why? Shortcoming Impact Solution? 1. Lack of early ‘Doomed’ compounds enter in Improve frontloaded screening: in detection of safety vivo tox phase silico and in vitro signals 2. Lack of detection of ‘Doomed’ compounds enter Improve quality and increase safety hazards clinical development information content of safety preclinically pharmacology and toxicology studies 3. Lack of Defective risk assessment: Improve risk assessment and confidence/knowledge/ ‘Doomed’ compounds may be decision-making by better precision in preclinical- let through, anticipating a large understanding of the translation of clinical translation safety margin; ‘safe’ the preclinical signals to humans. compounds may be stopped, anticipating an inadequate safety margin. 3 Attrition due to inadequate safety – why? Shortcoming Impact Solution? 1. Lack of early ‘Doomed’ compounds enter in Improve frontloaded screening: in detection of safety vivo tox phase silico and in vitro signals 2. Lack of detection of ‘Doomed’ compounds enter Improve quality and increase safety hazards clinical development information content of safety preclinically pharmacology and toxicology studies 3. Lack of Defective risk assessment: Improve risk assessment and confidence/knowledge/ ‘Doomed’ compounds may be decision-making by better precision in preclinical- let through, anticipating a large understanding of the translation of clinical translation safety margin; ‘safe’ the preclinical signals to humans. compounds may be stopped, anticipating an inadequate safety margin. 4 Impact of adverse effects of drugs by organ function throughout the pharmaceutical life cycle Phase ‘Nonclinical’ Phase I Phase I-III Phase III/ Post- Post- Marketing Marketing Marketing Information: Causes of Serious ADRs Causes of ADRs on label Serious ADRs Withdrawal from attrition attrition sale Source: Car (2006) Sibille et al. Olson et al. BioPrint® (2006) Budnitz et al. Stevens & Baker (1998) (2000) (2006) (2008) Sample size: 88 CDs stopped 1,015 subjects 82 CDs stopped 1,138 drugs 21,298 patients 47 drugs Cardiovascular: 27% 9% 21% 36% 15% 45% Hepatotoxicity: 8% 7% 21% 13% 0% 32% Haematology/BM: 7% 2% 4% 16% 10% 9% NERVOUS SYSTEM: 14% 28% 21% 67% 39% 2% Immunotox; photosensitivity: 7% 16% 11% 25% 34% 2% Gastrointestinal: 3% 23% 5% 67% 14% 2% Reprotox: 13% 0% 1% 10% 0% 2% 2010 Update: Musculoskeletal: 4% 0% 1% 28% 3% 2% Respiratory: 2% 0% 0% 32% 8% 2% Renal: 2% 0% 9% 19% 2% 0% Genetic tox: 5% 0% No change in 10 years! 0% 0% 0%Increased contribution 0% from Nervous System Carcinogenicity: 3% 0% 0% 1% 0% AEs in 2010 0% Other: 0% 0% 4% 16% 2% 2% The various toxicity domains have been ranked first by contribution to products withdrawn from sale, then by attrition during clinical development. 0% 1-9% 10-19% >20% Adapted from Redfern WS et al. SOT 2010; 2011 Impact of functional adverse effects on the nervous system on drug development during 2010: Source: DIA Daily January to December 2010 Impact of functional adverse effects on the nervous system on drug development during 2010: Impact of QT/TdP issues on drug development during 2010 by comparison: Source: DIA Daily January to December 2010 Functional measurements in repeat-dose toxicity studies Scientific drivers Regulatory drivers Doing it in addition to Doing it instead of standalone safety standalone safety pharmacology studies pharmacology studies Rationale: Rationale: •To provide early warning flags well ahead To opt for the minimum regulatory requirement of the regulatory GLP SP core battery for FTIM: studies (by incorporating into early tox/MTD studies). ICHS6 (Biologics) •To assess whether findings in acute SP studies persist, intensify, or diminish after ICHS9 (Oncology Products) repeated dosing, and to demonstrate FDA Guidance on Exploratory IND recovery after cessation of dosing. Studies •To provide functional correlates of by incorporating SP core battery assessments histopathological findings in previous tox into the 1-month regulatory tox studies. studies. •To assess potential effects that may only I have reservations about this. This will be develop after prolonged exposure. what I’m focusing on today. I’m OK with this. Let’s have more of it! Starting point... • Clearly, adverse effects on the nervous system make a significant contribution to attrition of candidate drugs during clinical development. • Therefore, the last thing we should do is reduce the quality of the preclinical CNS safety pharmacology assessment. • So, do more ‘as well as’, and reduce the temptation to go for ‘instead of’*. *In other words, do include CNS safety pharmacology endpoints in repeat-dose toxicity studies as well as standalone single-dose safety pharmacology studies, rather than instead of. Why not replace standalone CNS safety pharmacology studies with assessments in repeat-dose toxicity studies – what’s the big deal? 1. The laboratory conditions in toxicology holding rooms/procedure rooms are not optimal for obtaining high quality behavioural data (due to noise; disturbance etc.). 2. The phenomenon of tolerance means that the responses measured on Day X may be diminished compared to Day 1 (ie, first administration). 3. By Day X, what you may be measuring is not the pharmacological response to the compound, but the effects of overt toxicity (inappetance; weight loss; general malaise). 4. Circumventing ‘2’ and ‘3’ above by doing the assessments on Day 1 of dosing causes logistical difficulties. Limitations of SP endpoints in tox studies • The primary aim of a repeat-dose toxicity study is to expose animals to different levels of a test compound over a prolonged period, and to assess a standard list of in-life parameters (incl. clinical chemistry; body weights, food & water consumption; routine clinical observations; ophthalmoscopy; ECG, etc.), toxicokinetics, and post-mortem histological changes. • Any additional functional measurements MUST NOT interfere with these aims or affect their outcome. • The study design and laboratory conditions may be sub-optimal for obtaining high-quality functional data. Differences in in-life environments (etc.) Safety pharmacology studies General toxicology studies Dosing staggered to accommodate functional Animals dosed all in one session (usually a.m.) measurements TK sample taken after key functional TK sampling takes priority measurements No necropsy to consider Scheduled to accommodate necropsy slots Studies powered to detect the functional effect Studies adequate to detect histopathological effects Behavioural studies usually require young rats Sexually mature animals used Usually restricted to male animals Equal numbers of both sexes used May require non-standard strains (e.g. Restricted to standard strains pigmented rats) Functional measurements may require pre- Rarely required training of animals Functional measurements require a quiet room Sometimes anything but! Equipment/software may not be fully GLP- GLP sacrosanct compliant Should be run by experienced safety Toxicology facilities may be geographically pharmacologists and technicians fully au fait remote from available safety pharmacology with safety pharmacology measurements and expertise, or such expertise may not be data interpretation available within the company. Example of a custom-designed, fit-for-purpose in vivo safety pharmacology suite CNS evaluations done here Features: •Testing labs located remote from corridor noise (e.g., trundling of cage racks; loud conversations). •Primary access to suite via single entry door, with warning to limit entry to essential visits and to minimise noise level. •Staff requiring access to the other animals on the study can do so without disturbing the safety pharmacology observations/measurements. •Entry to the testing labs restricted to staff involved in the observations/measurements. •Designed to accommodate bulky test equipment, ergonomically. •Lighting control with local (manual) override. Example of toxicology study holding rooms with ante room CNS evaluations done here Drawbacks (for CNS safety pharmacology observations/measurements): •Testing area adjacent to corridor noise (e.g., trundling of cage racks; loud conversations). •Access from corridor directly into testing area. •Staff requiring access to the other animals on the study disturb the safety pharmacology observations/measurements. •Entry to the testing area unrestricted. •Bulky test equipment may be difficult to accommodate ergonomically. •Automated lighting control with no manual override. Development of tolerance with repeat-dosing A DECREASE in response/clinical efficacy with repeat-dosing Drug Therapeutic Effects target Opiate analgesics Pain Rapid tolerance to most effects develops on repeat-dosing Baclofen Spasticity Tolerance develops to muscle relaxant effects due to down-regulation of GABA-B receptors Benzodiazepines Anxiety Tolerance develops to initial sedative effect L-DOPA; bromocriptine Parkinson’s Reduced efficacy SSRI’s Depression Reduced efficacy Haloperidol; Schizophrenia Reduced efficacy chlorpromazine Anticonvulsants Epilepsy Reduced efficacy ‘‘Some form of adaptive syndrome is the inevitable consequence of the reciprocal interaction between most or all classes of drugs and the organism’’. W Haefely (1986) Pupillary light reflex in a repeat-dose toxicology study in rats: tolerance developing to a mydriatic effect Drug X (slow) µmol/kg po (slow) (slow) (n = 6 each) (slow) (No further dosing at high dose level) Redfern WS et al. (2007) A simple method for estimating pupil diameter in conscious rats and dogs during repeat-dose toxicity studies. J Pharmacol Toxicol Methods 56: e50. Saliva production in a repeat-dose toxicology study in dogs: tolerance developing to a salivatory effect Salivation quantified by placing a pre-weighed gauze swab inside a jowl for 20 s; removed and re-weighed. First measurement was on Day 3 of study. (AZ in-house data) Example of tolerance, increased response, and no change in response in the same study with the same compound! Effects of once-daily dosing with baclofen (10 mg/kg po) in the Irwin test in rats (3M; 3F) Day 1 Day 2 Day 3 Effect Abnormal 6/6 3/6 2/6 Diminishing respiration Decreased 6/6 6/6 6/6 Stable activity Increased 0/6 0/6 3/6 Delayed onset scratching Conclusion: Change in magnitude of effect over repeated dosing is both pharmacology- and parameter-specific – and can’t be predicted in advance. AZ in-house data: courtesy of Lorna Ewart Logistics for rodent studies… If you choose to go down this route (replacing the standalone safety pharmacology study), it is preferable to conduct functional measurements on Day 1 of the repeat-dose toxicity studies for the reasons outlined earlier (ie, you may miss an acute response that diminishes with repeat- dosing). But Day 1 of a tox study is usually mayhem, with timed TK bleeds etc. So, you could do the measurements on Day 2 of the repeat-dose study. However, you won’t get through all the Irwin tests (multiple time points) and whole-body plethysmography (WBP) measurements (4 hours’ recordings) on the vehicle and 3 dose levels (Irwin: 24 rats; WBP: 32 rats) in one day! So you could do (say) the Irwin tests on Day 2 and the WBP measurements on Day 3. Even then, you still won’t complete either of these evaluations in a single day. So you may have to stagger the start of the rodent 1-month study, e.g.: MON TUE WED THU Day 1 Start cohort 1 Day 2 cohort 1: Irwin Day 3 cohort 1: WBP Day 4 cohort 1 Day 1 Start cohort 2 Day 2 cohort 2: Irwin Day 3 cohort 2: WBP And you’ll have to reduce the standard number of time points in the Irwin test. Do you have enough quiet space to run Irwin and WBP simultaneously, close to the tox holding room…? Conclusions • Replacement of the ‘standalone’ CNS safety pharmacology study with ‘CNS safety pharmacology assessments’ in a repeat-dose tox study represents a dumbing-down of the preclinical CNS risk assessment. • This would be like replacing the dog telemetry cardiovascular assessment with a ‘snapshot ECG’ in a tox study to assess QT risk. • You wouldn’t do that, would you...? Acknowledgements Colleagues at AstraZeneca Alderley Park: Sharon Storey; Helen Prior; Claire Grant; Louise Marks; Lorna Ewart; Kat Greenwood; Claire Barnard; Dave Simpson; Sally Robinson; Jean-Pierre Valentin.
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