Toxicology for Industrial and Regulatory Scientists Safety Pharmacology for Human Pharmaceuticals Russell Bialecki, Ph.D. AstraZeneca Pharmaceuticals Waltham, MA April 27, 2015
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Toxicology for Industrial and Regulatory Scientists
Safety Pharmacology for Human Pharmaceuticals
Russell Bialecki, Ph.D. AstraZeneca Pharmaceuticals
Waltham, MA
April 27, 2015
Historical Perspective
“The adverse drug reactions which the standard toxicological test procedures do notstandard toxicological test procedures do not aspire to recognize include most of the functional side-effects.
Clinical experience indicates, however, that functional side-effects are much more frequent than the toxic reactions due tofrequent than the toxic reactions due to morphological and biochemical lesions…”
Gerhard Zbinden, 1979
2
Main reasons for compound attrition duringnon-clinical & clinical developmentnon clinical & clinical development
• ABPI review of reasons for attrition (FGLPD to
ORGAN No. %
Cardiovascular 64 28for attrition (FGLPD to phase III) was carried out by Safety Biomarker Working Group
Liver 42 19Musculoskeletal 15
• In total 225 drugs were analysed
Immune system 13Kidney 12 5CNS 10 5
• The summary does not classify the therapeutic area solely the organ
CNS 10 5Testes 10Gastro-intestinal 8 4
area, solely the organ where the pathology of the adverse drug reaction is expressed
Eye 7 3Genetic toxicology 7
pReproductive toxicity
7
3
Causes of AEs/ attrition
Phase Nonclinical Phase I Phase 1-III Phase III/ Marketing
Marketing Marketing
Information Causes of attrition Serious ADRs Causes of attrition
ADRs on label Serious ADRs Withdrawal from sale
Source Car (2006) Sibille et al. (1998) Olson et al. (2000)
BioPtint® (2006) Budnitz et al. (2006) Stevens & Baker (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%
Nervous system 14% 28% 21% 65% 39% 2%
Respiratory 2% 0% 0% 32% 8% 2%
Gastrointestinal 3% 23% 5% 67% 14% 2%
Renal 2% 0% 9% 19% 2% 0%
Hepatotoxicity 8% 7% 21% 13% 0% 32%Hepatotoxicity 8% 7% 21% 13% 0% 32%
Reprotox 13% 0% 1% 11% 0% 2%
Genetic tox 5% 0% 0% 0% 0% 0%
Carcinogenicity 3% 0% 0% 0% 0% 0%
Haematology/BM 7% 2% 4% 16% 10% 9%
Musculoskeletal 4% 0% 1% ? 3% 2%Immunotox;
photosensitivity7% 16% 11% 5%(+) 34% 2%
Other 0% 0% 4% ? 2% 2%
1-10% 10-20% >20%0%Redfern, et al, 2010
4
AgendaIntroduction (5 minutes)Background: (10 minutes)Background: (10 minutes)Safety pharmacology evaluation: (ICH S7A and S7B; 60 minutes)
The core battery (CV, CNS, and Respiratory)Study design Follow-up studiesSupplemental studiesCombination studiesThe QT issueSpecial situations (novel excipients human-specific metabolites)Special situations (novel excipients, human-specific metabolites)Special considerations including biopharmaceuticalsStrategic considerationsE l li i l i lExploratory clinical trials
Interpretation of safety pharmacology studies5
Lecture Goals & MetricsParticipants should be able to:• Explain why safety pharmacology evaluation is performed and
h t SP i i t d d t id th t i i dditi dwhat SP is intended to provide that is in addition and complementary to general toxicology evaluations
• Identify the human populations that current SP evaluations are t lik l t t tmost likely to protect
• Identify the ICH guidance that impact the conduct of SP studies for particular human pharmaceuticals and situations
• Identify the SP Core Battery organ systems and the types of models most often used
• Discuss the most important components of safety pharmacology study designs
• Discuss the critical elements of analysis, interpretation, and risk assessment derived from of safety data
• Discuss differences in SP evaluations for small and large molecules
6
Origins of Safety PharmacologyGeneral Pharmacology Studies
• The US, Europe and Japan considered general pharmacology t di t b i t t t f d f t tstudies to be an important component of drug safety assessment,
and accepted the data for assessment of marketing applications• The Japanese Ministry of Health and Welfare (MHW) issued the
Guideline for General Pharmacology’ in 1991Guideline for General Pharmacology in 1991A seminal paper published in 1994 delineated general
pharmacology studies into 2 categories;• Pharmacological profiling studies (e g secondary pharmacology)• Pharmacological profiling studies (e.g. secondary pharmacology)• Safety profiling studies (e.g. safety pharmacology)
The authors posited that while pharmacological profiling was limited only by imagination (and budget), safety profiling could logically be confined to y g ( g ), y p g g ythose organs where acute deficits in function could constitute a clinical emergency. The authors identified the priority for clinicians to know in advance of any potential threat to a critical organ system, and any rescue or antidotes identified.
Kinter, L.B., Gossett, K.A., and Kerns, W.D. Status of safety pharmacology in the pharmaceutical industry - 1993. Drug Dev. Res. 32:208-216, 1994.
7
Guidance on Safety PharmacologyGu da ce o Sa ety a aco ogy
ICH M3(R2): Nonclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals, 1997Section 4.1: ‘The aim of the safety pharmacology studies should be to reveal any functional effects on the major physiological systems (e.g.,
di l i t l d t l t ) ’cardiovascular, respiratory, renal and central nervous system).’
ICH M3(M): Nonclinical Safety Studies for Conduct of HumanICH M3(M): Nonclinical Safety Studies for Conduct of Human Clinical Trials for Pharmaceuticals , 2000Section 2: ‘Safety pharmacology includes the assessment of effects on vital functions such as cardiovascular central nervous andon vital functions, such as cardiovascular, central nervous, and respiratory systems and these should be evaluated prior to human exposure. These evaluations may be conducted as additions to toxicology studies or as separate studies.’
8
Guidance on Safety PharmacologyGu da ce o Sa ety a aco ogy
ICH S7A: Safety Pharmacology Studies for Human Pharmaceuticals, 2000Section 2.3.2: ‘In conducting in vivo studies on vital functions, it is preferable to use unanesthetized animals. Data from unrestrained animals that may be chronically instrumented for telemetry … are preferable to data from restrained or unconditioned animals.’
ICH S7B Th N li i l E l ti f th P t ti l f D l dICH S7B: The Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT prolongation) by Human Pharmaceuticals, 2005Section 2 3 2: ‘An in vivo QT assay measures indices of ventricularSection 2.3.2: An in vivo QT assay measures indices of ventricular repolarization such as QT interval. This assay can be defined to meet the objective of both ICH S7A and S7B. This will reduce the use of animals and other resources.’
9
Guidance on Safety PharmacologyGu da ce o Sa ety a aco ogy
ICH M3(R2): Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorizations for Pharmaceuticals, June, 2009Section 2: Safety pharmacology and pharmacodynamic (PD) studies are defined in ICH S7A.
The core battery of safety pharmacology studies includes assessment of effects on cardiovascular central nervous and respiratory systemsof effects on cardiovascular, central nervous, and respiratory systems, and should generally be conducted before human exposure, in accordance with ICH S7A and S7B.
Primary PD studies (in vivo & in vitro) are intended to investigate the mode of action and/or effects of a substance in relation to its desired therapeutic target… These studies can contribute to dose selection for both nonclinical and clinical studiesboth nonclinical and clinical studies.
10
General Concepts3 categories of pharmacology studies (Section 1.5):
• 1o and 2o pharmacodynamic (PD) studies • Safety pharmacology studiesy p gy
Vital organ systems, most important to assess, are those whose functions are acutely critical for life• Safety Pharmacology Core Battery: Cardiovascular, respiratory,
and central nervous systems … should be studied (Section 2.7)• Other organ systems (e.g., renal, GI) whose functions can be
transiently disrupted without causing irreversible harm are of lesstransiently disrupted without causing irreversible harm are of less immediate investigative concern and studied for cause (Section 2.2)
fIn conducting in vivo studies, it is preferable to use unanesthetized animals. • Data from unrestrained animals that may be chronically
instr mented for telemetr or other s itable instr mentation orinstrumented for telemetry, or other suitable instrumentation… or animals conditioned to the laboratory environment are preferable to data from restrained or unconditioned animals. (Section 2.3.2) 11
Study ObjectivesStudy Object es
1. Identify undesirable PD properties …that may have relevance to human safety
2. Evaluate adverse PD and/or patho-physiological effects p p y g…observed in toxicology and/or clinical studies
3 Investigate the mechanism of the adverse PD effects observed3. Investigate the mechanism of the adverse PD effects observed and/or suspected
The investigational plan to meet these objectives should be clearlyThe investigational plan to meet these objectives should be clearly identified and delineated.
12
Test Systems(Section 2 3)(Section 2.3)
Selection of relevant animal models or other test systems so that scientifically valid information can be derived.y
In vivo, ex-vivo, and in vitro preparations can be used and include:• Isolated organs and tissues• Isolated organs and tissues• Cell cultures• Cell fragments• Subcellular organelles• Subcellular organelles• Receptors• Ion channels• Transporters• Transporters• Enzymes• Etc.
13
Test SystemsTest Article
14
Test Systems
Test Article
Bioassay
Hypothesis-based
15
Test SystemsHypothesis testing
• Directed at a prospectively identified molecular target (or targets) or pathways
• Anticipated pharmacologic, pharmacokinetic, pharmacodynamic, and/or molecular responses (specific experimental endpoints)P ibilit t iti t l t• Possibility to use positive control agents
• Reductionist : Applicable only to previously identified mechanisms• Applications in mechanism of action, Proof of Principle, etc.
ED ID th h ld i• ED50, ID50, threshold response, maximum response• Ion channels (e.g., hERG), Follow-up and Supplemental studies• Cross-species translation via mechanism and pathway analyses
S f i b d i l ffi i / ll• Safety margins based upon test article affinity/potency, as well as exposure multiples
16
Test SystemsBioassay testing:
• Characterization of test article responses• No specific prospective experimental hypothesis p p p p yp• No anticipated responses (routine experimental endpoints; Clin
Obs, Clin Path, etc.)• Integrative: Responses are a summation of individual
actions/effects• Positive control agents less informative• Applications in screening: therapeutic identification, hazard
id ifi iidentification• MTD/MFD, LOEL/LOAEL, NOEL/NOAEL, LD50
• SP Core Battery studies (except hERG)• Cross-species translation is qualitative
• Most sensitive species• Severity, monitorability, and reversibility of effect• Suitable biomarkers available?• Suitable biomarkers available?• Safety margins based upon human equivalent dose (HED) conversion,
and exposure margins17
Critical Determinants• Genetics
• Expression of critical genes (specific mechanisms of action)G ti t bilit ti ( t f ti d ift)• Genetic stability over time (e.g., management of genetic drift)
• Environmental factors• Diet (food and water)
• Contaminants• Nutrient sources (animal- vs. vegetable-sourced proteins, fats)
E i t l diti (li hti t t h idit )• Environmental conditions (lighting, temperature, humidity)• Animal welfare parameters (caging, socialization, enrichment, etc.)
H f t• Human factors• Training/experience with specific in-life procedures• Test article/control group cross-contamination
18
Hypothesis-basedModel selection
• Mechanism-driven (access, sensitivity, pathway linkages, etc.)Study designStudy design
• Test article and controls (vehicle, sham, etc.)• Positive and negative controls
Group size (by prospective statistical power analysis)• Group size (by prospective statistical power analysis)• Surgical interventions (e.g., catheters, telemetry)• Randomized vs. blocked study designs
T t ti l• Test article exposure Dose selection
• Establish dose-responseRoute and duration of administrationProspective in-life procedures and endpoints
• Instrumentation for endpoint detectionAnimal welfare considerations (3Rs)
19
BioassayModel selection
• ‘Fit for purpose’ (often driven by regulatory guidance)p p ( y g y g )Study design
• Test article & control groups• Group size (often driven by regulatory guidance/expectation)Group size (often driven by regulatory guidance/expectation)• Age/weight ranges, sex (by regulatory guidance/expectation)• Satellite groups (TK, telemetry, etc.)
Dose selectionDose selection• Maximum tolerated exposure vs. exposure multiples• NOEL/NOAEL (for calculation of first dose in humans)
Route and duration of administration (by regulatory guidance)Route and duration of administration (by regulatory guidance)Proscriptive in-life procedures and endpointsAnimal welfare considerations (3Rs)
20
Experimental Design(Section 2 3 3)(Section 2.3.3)
• Sample size and use of controls• Group sizes sufficient to allow meaningful scientific interpretation ofGroup sizes sufficient to allow meaningful scientific interpretation of
the data• adequate to demonstrate or rule out the presence of a biologically
significant effect
• Route of administration• Intended clinical route • Exposure to parent and major metabolites should be similar to or
greater than that achieved in humans when such information is available
21
Experimental Design(Sections 2 4 2 5)(Sections 2.4, 2.5)
Dose levels or concentrations of test substance• Dose- or concentration-response relationships of the adverse effectDose or concentration response relationships of the adverse effect• Time course (onset, duration) of the adverse effect, when feasible• Doses/exposures should include and exceed the primary PD or
therapeutic rangep g• High dose/exposure should be one that produces moderate
adverse effects in the present study or others of similar route and duration, or is limited by physio-chemical properties
• Testing of a single group at the limiting dose may be sufficient in the absence of adverse effects.
S f t h l t di ll i l dSafety pharmacology studies are generally single dose administration.
22
Experimental Design(Section 2 6)(Section 2.6)
Metabolites, Isomers, and Finished Products• Parent compounds and major metabolites that achieve/anticipateParent compounds and major metabolites that achieve/anticipate
significant human exposure should be evaluated.• Disproportionate or unique human metabolites
• Testing of individual isomers should be considered with the product contains an isomeric mixture
• Testing of finished product formulations should only be conducted for formulations with substantially altered PK or PD of the active substance in comparison to formulations previously tested.
23
Core Battery(Section 2 7)(Section 2.7)
Central Nervous System• Endpoints include motor activity, behavioral changes, coordination,
sensory/motor reflex responses body temperaturesensory/motor reflex responses, body temperature• Suggested systems: Functional observation battery (FOB), modified
Irwin’s Screen
Cardiovascular System• Endpoints include blood pressure, heart rate, ECG• Suggested systems: In vivo and ex vivo/in vitro evaluations, including gg y g
repolarization and conductance abnormalities
Respiratory System E d i t i l d i t t tid l l d h l bi O• Endpoints include respiratory rate, tidal volume and hemoglobin O2saturation
• Suggested systems: Appropriate methodologies (plethysmography) • N B : Clinical observations of animals are generally not adequate to assess• N.B.: Clinical observations of animals are generally not adequate to assess
respiratory function
24
Core Battery: Central Nervous System Function
HOME CAGE OBSERVATIONS
Study Sequence - Modified Irwin’s Screen
HOME CAGE OBSERVATIONSPosture and unusual behaviors (possible convulsion; shivering; vocalisation; stimulation; stereotypy) [~1-2 min]
OPEN FIELD ACTIVITYSpontaneous motor activity; supported rears; unsupported rears; gait abnormalities; stereotypicSpontaneous motor activity; supported rears; unsupported rears; gait abnormalities; stereotypic behaviour; irritability; body tone; salivation; lacrimation; piloerection; catalepsy; micturition; defecation [~5 min]
AUTONOMIC ACTIVITY ASSESSMENT (SENSORIMOTOR REFLEX)
Touch response (passivity); startle response; righting reflex; palpebral reflex; tail pinch; thermal p (p y); p ; g g ; p p ; p ;nociception; grasping reflex; ataxia; rectal temperature; pupil response [~10 min]
25
Modified Irwin’s Screen Parameters
AUTONOMIC NEUROMUSCULAR
tsalivationlacrimationpiloerectionexcessive urination
posturegaitbody tonegrasping reflext / l idiarrhoea/loose faeces
rectal temperaturetremor/convulsionsshivering
SENSORIMOTOR BEHAVIOURALSENSORIMOTOR
grasping reflexpupil responsetouch response
BEHAVIOURAL
stimulationvocalisationirritability
palpebral reflextail pinch responsestartle reflex (air puff)righting reflex
stereotypyunusual behavioursupported rearsunsupported rears
Also: mortality at 24 hr26
Core Battery: Cardiovascular Function• Assess appropriately:
– blood pressuresystolic diastolic meansystolic, diastolic, mean
– heart rate– Lead II ECG
•Usually from freely moving conscious telemetered dogs or monkeys•Usually from freely moving, conscious telemetered dogs or monkeys• Anesthetized study if toxicity or lack of exposure prevent above
•Measurement of QT interval used to comply with ICH S7B
• Consider also:– in vivo, in vitro and/or ex vivo evaluations, including methods for
repolarization and conductance abnormalities
27
Core Battery: Respiratory Function • Freely moving, conscious rats
– Clinical observations of animals generally not sufficient• Measurement of ventilatory parameters using indirect or direct• Measurement of ventilatory parameters using indirect or direct
methods– Respiratory rate– Tidal volume– Minute volume– Resistance and/or compliance (direct method only)– Resistance and/or compliance (direct method only)
• Typically performed using whole body plethysmography • Multidose dose study with parameters being monitored for several
hours– Dose should reach 100 times predicted therapeutic plasma
concentration (if possible)( p )
28
Rodent Whole Body Plethysmograph
29
Follow-up Studies(Section 2 8 1)(Section 2.8.1)
Central Nervous System• Behavioral pharmacology learning and memory ligand-specificBehavioral pharmacology, learning and memory, ligand specific
binding, neurochemistry, visual and auditory, and/or electrophysiological examinations, etc.
Cardiovascular System• Cardiac output, ventricular conductivity, vascular resistance, effects
on endogenous and exogenous substances on cardiovascular responses, etc.
Respiratory System • Airway resistance, lung compliance, pulmonary hemodynamics,
blood gases, blood pH, etc.
30
Supplemental Studies(Section 2 8 2)(Section 2.8.2)
Renal/Urinary System• Urine volume, specific gravity, osmolality, pH, fluid/electrolyte balance,
t i t l d bl d h i t ( ti i lproteins, cytology, and blood chemistry (e.g., creatinine, urea, plasma proteins)
Autonomic Nervous System• Receptor binding, functional responses to agonists and antagonists in
vivo and in vitro, direct stimulation of autonomic nerves and measurement of cardiovascular responses, baroreflex testing, heart rate variabilityy
Gastrointestinal System• Gastric secretion, gastrointestinal injury potential, bile secretion, transit
time in vivo ileal contraction in vitro gastric pH and emptying intestinaltime in vivo, ileal contraction in vitro, gastric pH and emptying, intestinal pooling
Other Organ Systems (only when there is reason for concern)• e.g., Abuse/dependency potential
31
Combination studies
• Integrative pharmacology approaches determine the inter-relationships of drug-determine the inter relationships of drugmediated effects on different organs• e.g., combination of CV telemetry and
respiratory plethysmography (shown)• Allows for:
• Time-dependent effects• Insight into possible mechanismg p• 3R’s benefits• Cost and resource benefits
• Other examples:Other examples:• FOB/Irwin’s with tox studies• FOB/Irwin’s with EEG• CV EEG and renal with blood samplingCV, EEG and renal with blood sampling
32
Automated Blood Sampling + Telemetry (ABST)
BASi ABS System DSI Radio Telemetry
Litwin, et al. BioMedical Engineering OnLine 2011, 10:5 doi:10.1186/1475-925X-10-533
ABST Parameters Measured Simultaneously• Cardiovascular
• Heart Rate• Mean Arterial BP
Systolic BP• Systolic BP• Diastolic BP• Pulse pressure
• CNSCNS• Electroencephalogram (EEG) with spectra• Behaviors (limited)• Activity counts
• Body temp• Renal
• Urinary electrolytesBi k f i j• Biomarker of injury
• Glomerular filtration rate and renal plasma flow• Plasma exposures (DBS or microsamples)
Bl d tit t• Blood constituents
34
Case study #1: Combination parameters with toxicokineticsparameters with toxicokinetics
550
600176
interictal activity
spike & wavecontinuous seizure
400
450
500
550
MABPHR[AZDXXXX]
76
101
126
151
n
mm
Hg o
200
250
300
350
303540455051
bea
ts/m
in
or [CM
PD X (
0
50
100
150
051015202530 M
)]
-60 0 60 120
150 mg/kg po50 mg/kg po
150 165 180 195 210 225 240Time post 1st oral dose (minutes)
Spectral analysisSpectral analysis
35
Case Example #2:Value of Longitudinal ObservationValue of Longitudinal Observation
Methods:8 conscious Han Wistar rats ( 300 gm) were pre implanted with• 8 conscious Han Wistar rats (~300 gm) were pre-implanted with radiotelemetry transmitters and externalized cannula.
• After 1-day acclimation and baseline recording in ABST, rats were treated with a single dose of Cisplatin (15 mg/kg i p ) and the sametreated with a single dose of Cisplatin (15 mg/kg, i.p.) and the same parameters recorded for 3 days.
• Parameters included:Bl d l (PK t t d li )• Blood samples (PK; automated sampling)
• Cortical electroencephalography (EEG)• Blood pressures (systolic, diastolic, mean) and heart rate (HR)
B d t t• Body temperature• Renal hemodynamics (GFR and RPF) and excretory functions• Biomarkers of drug-induced kidney injury (DIKI)• Histopathology
36
Case Example #2 (cont.):Value of Longitudinal Observation g
Results:Results:• Pharmacokinetics (PK):
Tmax
(hr)
t1/2(hr)
Cmax
(µg/mL)
AUC(µg*h/mL)
0.25 33.7 10.1 66.6
37
Case Example #2 (cont.):Value of Longitudinal Observation g
• Pharmacodynamics (PD):Compared with control, Cisplatin significantly (*p<0.05; t-test)Compared with control, Cisplatin significantly ( p 0.05; t test) decreased HR, Temp, GFR, RPF, and elevated DIKI biomarkers which correlated with histopathological renal tubular injury on day 3.
PD parameters Day 1 Day 2 Day 3PD parameters Day 1 Day 2 Day 3 CV (% change over control)MAP 1% –2% 4%HR –9% –28% –30%*EEG Frequency Band (δ, θ, α, β and γ)
spectral analysis none none none Body Temp –2% –6% –8%*
RenalGFR (mL/min) –28% –62%* –73%*ERPF (mL/min) 9% –8% –24%*DIKI biomarkers (fold increase over control)
α‐GST 4* 40* 222*GSTYb1 3* 24* 24*clusterin 2 8* 16*albumin 2* 171* 57*
Osteopontin 1 2 4*
38
Case Example #2 (cont.):Value of Longitudinal ObservationValue of Longitudinal Observation
• Renal histopathology:Acute renal tubular necrosis were observed on day 3 after a singleAcute renal tubular necrosis were observed on day 3 after a single administration of Cisplatin in rats.
Histopathology of rat renal cortex on study day 3. (A) saline control; normal. (B) Cisplatin (15 mg/kg, i.p.) induces necrosis of tubular epithelium (black arrows) and
i i l l i l dil ti ( t i k ) H&E 200Xminimal luminal dilation (asterisks). H&E, 200X
39
Relation to Clinical Development(Section 2 10)(Section 2.10)
Prior to First Administration to Humans (FTIH)• Core battery studiesCore battery studies• Any follow-up or supplemental studies identified, based upon
cause for concern• Supports IND pp
Studies During Clinical Development• SP studies to clarify observed or suspected adverse effects inSP studies to clarify observed or suspected adverse effects in
animals or humans during clinical development• e.g., abuse potential studies in animals for CNS active compounds
Studies Before Approval• Follow-up and supplemental studies listed in Section 2.8, unless
not warranted, in which case this should be justified., j
40
Applicability of GLP(Section 2 11)(Section 2.11)
Core Battery Studies• Ordinarily conducted in compliance with GLP
Follow-up and Supplemental Studies• Conducted in compliance with GLP, to the greatest extent feasible
Primary and Secondary Pharmacology Studies• GLP compliance not required unless the data is used as a pivotal
contribution to the safety evaluation for potential adverse effects in y phumans, in which case GLP compliance is expected
When SP studies or portions of studies are not conducted in compliance ith GLPcompliance with GLP:• Study reconstruction should be ensured through adequate
documentation of study conduct and archiving of data• Non compliance with GLP should be justified and potential impact• Non-compliance with GLP should be justified, and potential impact
on evaluation of SP endpoints explained
41
SP Studies May Not Be Necessary(Section 2 9)(Section 2.9)
In cases of:Locall applied agents (dermal or occ lar) here the• Locally applied agents (dermal or occular) where the pharmacology is well characterized and systemic exposure or distribution to other organs is demonstrated to be low
• Cytotoxic agents for treatment of end-stage cancer; however, for agents with novel mechanisms of action SP studies may be of valuevalue
• Biotechnology-derived products
• New formulations having similar PK and PD properties
42
ICH S7B: ‘The QT issue’• Consequences for drug prolonging QT Interval
– Withdrawn from market– Prenylaminey– Terodiline– Astemizole– Grepafloxacin– Terfenadine
Cisapride– Cisapride– Droperidol– Sertindole
– Prescribing restrictions– Pimozide– Thioridazine– Halofantrine
– Approval delayedApproval delayed– Ziprasidone
– Labelling implications– Far too many examples!…incl. Zomig, Nolvadex, Seroquel
43
ICH S7B: Objectives(Sections 1 1 2 1)(Sections 1.1, 2.1)
Describes a non-clinical testing strategy for assessing the potential of a test substance to delay ventricular repolarizationof a test substance to delay ventricular repolarization
• Non-clinical assays• Identify the potential of a test substance and its metabolites to• Identify the potential of a test substance and its metabolites to
delay ventricular repolarization
• Integrated risk assessment• Integrated risk assessment• Relate the extent of delayed ventricular repolarization to
concentrations of test substance and its metabolites
44
What does the QT interval represent?
• Biological background– The electrocardiogram (ECG) reflects the activity of every cardiac cell
when recorded at the body surfacewhen recorded at the body surface
R VRR VV
Q
P
S
T~1 mV
Q
P
S
T
Q
P
S
T~1 mV
S
d l i ti f t i l ll
SS
d l i ti f t i l ll
depolarisation of ventricular cells
depolarisation of atrial cells
depolarisation of ventricular cells
depolarisation of atrial cells
repolarisation of ventricular cellsrepolarisation of ventricular cells
4545
• Biological backgroundImportance of the hERG-encoded channelBiological background– QT interval is a measure of overall ventricular cell action potential duration– K+ ion efflux is critical for repolarisation of the cardiac action potential– The K+ current known as Ikr (hERG) plays a key role– An intense burst of hERG channel activity carrying IKr ensures rapid repolarisationAn intense burst of hERG channel activity carrying IKr ensures rapid repolarisation
P
R
T~1 mV
V
Q S
Ventricular repolarisationVentricular depolarisation
+30 mVVoltmeter
myocyte
Voltmeter
myocyte
Current meterCurrent meterCurrent meter
-90 mVy yy y
K+
hERG-expressing cell line
K+K+K+K+
hERG-expressing cell line pA 46
• Biological backgroundQT and Torsades de Pointes
Biological background– Selective block of hERG-encoded channel
– Increases action potential duration and QT interval– This can lead to a fatal cardiac arrhythmia – Torsades de Pointes– Delayed repolarization leading to early after depolarisations (EADs) is aDelayed repolarization leading to early after depolarisations (EADs) is a
key initiating event
hERG blocker
EADs
Torsadesde Pointes
4747
Background biology• Cardiac action potential is generated by current flow through
several ion channel types
• The channel carrying IKr current (hERG-encoded channel) is central to the QT issue
• However, action potential prolongation may result from several ff ( f fpharmacological effects (e.g. block of IKs or IKr, enhancement of
INa or ICa)48
48
Biological backgroundhERG is pharmacologically promiscuous
• Biological background– Aromatic side chains line the channel – favors binding of lipophilic bases– Other channels have aliphatic side chains
Channel S6 Domain Sequence
Kv1.1 AGVLTIALPVPVIVAGVLTIALPVPVIV
Kv1.5 AGVLTIALPVPVIV
Kv2.1 AGVLVIALPVPVII
Kv3.1 AGVLTIAMPVPVIV
Kv4.1 SGVLTIALPVPVIV
Kv4 3 SGVLTIALPVPVIVKv4.3 SGVLTIALPVPVIV
KCNQ1 FAISFFALPAGILG
hERG IGSLMYASIFGNVS
- Probable greater cavity volume in the closed state contributesto pharmacological promiscuity 49 49
QT Prolongation/Arrhythmia ADRs
Drugs
IK
Concomitant Risk Factors
IKr
APD QT TdP+ + +
Other Ion
Channels
APD QT TdP
Channels
TdPDeath
Other Factors50
ICH S7B: hERG and QT Studies• “In vitro IKr assay” data generated using automated patch clamp
electrophysiology (e.g., IonWorks planer patch clamp technology) or GLP-complaint conventional patch clamp electrophysiology• Test to complete inhibition or limit of solubility• Consider other cardiac relevant ion channelsConsider other cardiac relevant ion channels
• “In vivo QT assay” data come from QT interval measurements for ICH S7A CV study• Lead II ECG in conscious telemetered dog or monkey
51
Testing StrategyNon-clinical Testing Strategy
Ch i l/
Non-clinical Testing Strategy
Ch i l/In Vitro IKrAssay
In Vivo QT Assay
Chemical/Pharmacological
Class
In Vitro IKrAssay
In Vivo QT Assay
Chemical/Pharmacological
Class
Integrated RiskFollow-upRelevant Non-
clinical and ClinicalIntegrated RiskFollow-upRelevant Non-
clinical and ClinicalIntegrated Risk Assessment
Follow up Studies
clinical and Clinical Information
Integrated Risk Assessment
Follow up Studies
clinical and Clinical Information
Evidence of RiskEvidence of Risk
52
Integrated Risk Assessment Effect of M123456 in QT-related assays
120 40hERG Margins from
80
100
ERG 25
30
35
APD
90
Predicted free CmaxDog telemetryPurkinje fibre (0.33 Hz)Purkinje Fibre (1 Hz)
gpredicted free Cmax in man at efficacious
40
60
% in
hibi
tion
hE
10
15
20
hang
e Q
TcV/
A dose to:• hERG IC50
• 10% increase APD
20
40%
0
5
10
% c
• 10% increase QTcV
00.001 0.01 0.1 1 10 100 1000
[M123456] (M)
-5
53
New Approaches…
Nature vol. 3 DOI:10.1038/srep02100, July 2013 54
New Initiatives…
• Comprehensive In Vitro Proarrhythmia Assay (CIPA)
• Objective: “…to facilitate the adoption of a new paradigm for assessment of clinical potential of TdP that is not measured exclusivelyassessment of clinical potential of TdP that is not measured exclusively by potency of hERG block and not at all by QT prolongation”
• The new model to consist of mechanistically based in vitro assays coupled to in silico reconstructions of cellular cardiac electrophysiologic p p y gactivity
• Verification of predicted and observed responses in human-derived cardiac myocytes
• Once operational, CIPA will require modification or replacement of ICH S7A/B guidelines and elimination of E14 guidelines
• Although progress can be made in the short term under the existing• Although progress can be made in the short term under the existing regulatory construct
55
Evolution of methodologies to detect QT risk preclinically
56
Relation to Clinical Development(Section 2 4)(Section 2.4)
First Administration to Humans (FTIH)• Nonclinical studies assessing risk of delayed ventricularNonclinical studies assessing risk of delayed ventricular
repolarization and QT interval prolongation
During Clinical Developmentg p• Nonclinical results, as part of an integrated risk assessment, can
support the planning and interpretation of subsequent clinical studies (e.g., Clinical Robust QT Prolongation Study; ICH E14)
57
Applicability of GLP(Section 1 4)(Section 1.4)
In vitro IKr and in vivo QT assays (described in sections 2.3.1 and 2.3.2), when performed for regulatory submission:2.3.2), when performed for regulatory submission:• Conducted in compliance with GLP
Follow-up studies (section 2.3.5)Follow up studies (section 2.3.5)• Conducted in compliance with GLP, to the greatest extent feasible
When SP studies or portions of studies are not conducted inWhen SP studies or portions of studies are not conducted in compliance with GLP:• Study reconstruction should be ensured through adequate
documentation of study conduct and archiving of datadocumentation of study conduct and archiving of data• Non-compliance with GLP should be justified, and potential impact
on evaluation of SP endpoints explained
58
Special ConsiderationsNovel excipients (FDA Guidance)
• http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079250.pdf
Disproportionate or unique human metabolites (FDA MIST guidance)• http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulat
oryInformation/Guidances/ucm079266.pdfBiopharmaceuticals
• http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129171.pdf
Exploratory clinical trials (FDA Guidance on Exploratory INDs)• http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulat
oryInformation/Guidances/UCM078933.pdfJuvenile animals
• http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079247.pdf
59
Biopharmaceuticals
Highly-specific receptor targeting (e.g humanized mAbs)• Often sufficient (e g feasible) to evaluate SP endpoints as part ofOften sufficient (e.g. feasible) to evaluate SP endpoints as part of
toxicology and/or PD studies• Non-rodent species only (usually a non-human primate)• Limited to cardiovascular and respiratory endpoints
Novel therapeutic classes and/or products that do not achieve highly specific targeting – a more extensive SP evaluation h ld b id dshould be considered.
Surrogate moleculesPreclinical species homolog of a h man specific biopharmace tical• Preclinical species homolog of a human-specific biopharmaceutical
Transgenic approaches• Knock out and knock in models• Knock-out and knock-in models • Surrogate constructs
60
Exploratory CTA Requirements(ICH M3(R2) 2009)
eCTA Preclinical Species
High Dose Selection
GeneTox & Safety Pharm
Clinical Start Dose
Clinical Stop Dose
Micro-Dose 1
SD rodent*, w/ extended observations
~10 mg/kg (1000x, mg/kg or mg/m2)
Not Applicable (but include any SAR w/CTA)
100 g 100 g
Micro- 7-day rodent ~10 mg/kg Not Applicable 100 g x5 100 g x5Micro-Dose 2
7 day rodent 10 mg/kg (1000x, mg/kg or mg/m2)
Not Applicable (but include any SAR w/CTA)
100 g x5 100 g x5
Single-D
Pharm model,SD d t* &
MTD, MFD, or limit dose
Ames assay;SP b tt
1/50th NOAEL (mg/m2 basis)
½ NOAEL (mg/m2 basis)Dose SD rodent* &
nonrodent*or limit dose (1g/kg)
SP core battery (mg/m basis) (mg/m basis)
Repeat-Dose 1
Pharm model,14-day rodent &
10x (anticipated h
Ames, clastogen assays
1/50th NOAEL (mg/m2 basis) or 1/50th AUC t
1/10th, ½, or AUC at
(14 days)y
nonrodent human exposure) SP core battery 1/50th AUC at
NOAELNOAEL
Repeat-Dose 2
Pharm model,14-day rodent &
MTD, MFD, or limit dose (1 /k )
Ames, clastogen assays
1/50th NOAEL (mg/m2 basis)
½, or AUC at NOAEL
(14 days) confirmatory nonrodent
(1 g/kg) SP core battery
ICH M3(R2), June 200961
Exploratory Clinical TrialsTactical Application
• Candidate Drug (CD or later)
Strategic Application
• Lead compounds• Candidate Drug (CD, or later) • De-risk a compound or compound
selection• GMP chemistry
p• De-risk basic biology (e.g., therapy
target)• Pre-GMP chemistryGMP chemistry
• Investigational drug is possible launch candidate
• Clinical endpoints:
• Investigational drug (probably) not a launch candidate
• Clinical endpointsp• PK, ADME• PD• Efficacy biomarker
• Proof of Principle (PD, biomarker)• Select chemistry platform (PK,
ADME)
• Select Phase I CD• Confirm back-up CD
62
Integration of SP Endpoints in Traditional Toxicology StudiesTraditional Toxicology Studies
Integration of SP endpoints in general toxicity (GT) studies can reduce the total number of individual studies and total numbers of animals used, and aid in integrative interpretations.• SP modules (or satellite groups) in GT studies
• CNS (FOB, modified Irwin screen)• Respiratory (plesythmography)• Cardiovascular
• ECG and heart rate• Blood pressure (?)Blood pressure (?)
• Toxicokinetics
Technical considerations:• SP requirements must not confound interpretation of GT endpoints,SP requirements must not confound interpretation of GT endpoints,
and visa versa:• Introduction of pathological artifacts (e.g., surgery for telemetry implants)• Introduction of stress artifacts (e.g., extra handling, novel environments)• MTD (GT) vs. MTD (SP)• NOEL vs. low multiple therapeutic exposure
63
SP Data Integration & Risk Assessment
Chemical /Pharmacological Classes
Core BatteryAssays
Follow-up Assays
S l t l A
Pharmacological Classes Assays Assays
Follow-up studies
Supplemental Assays
General pIf necessaryIntegrated risk assessmentGeneral
Tox Studies
Signal of Risk
None Weak Strong64
Safety Margin ConsiderationsO
NSE
RES
PO 50% Standard approach compare IC50 values
IC l bR IC20 values may be more appropriate but not always accurate
log(EXPOSURE)
65
Transition to Human TrialsFor small molecules
• NOAEL dose in most sensitive species/modelp• Calculate human equivalent dose using body surface area scaling
(HED)• Start does is 1/50th HED (for human volunteers)
Alternatively, for some new drugs (e.g., some biopharmaceuticals) the minimum active biological effect level (MABEL) in preclinical g ( ) pspecies may be more appropriate than the NOAEL for estimating a safe first human dose.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm078932.pdf
66
Acknowledgements• Lew Kinter, Ph.D.• Tim Hammond Ph D• Tim Hammond, Ph.D.• Jean-Pierre Valentin, Ph.D.• Silvana Lindgren, Ph.D.
67
Advice in Searching for Risk
(from G Zbinden)(from G. Zbinden)1. Do not do something just because you can.2. Do not do something just because it has always been done.3 Do not do something just because others do it3. Do not do something just because others do it.4. Do not do something because (you believe) it is expected.5. Do not do something the results of which cannot be interpreted.
Do something because there is a reasonable expectation it will provide knowledge necessary for an accurate decision.
Robert Hamlin. A Search to Predict Potential for Drug-Induced Cardiovascular Toxicity, Toxicologic Pathology. 34 (1): 75-80, 2006.
68
Selected Reading1. Kinter, L.B., Gossett, K.A., and Kerns, W.D. Status of safety pharmacology in the pharmaceutical industry -
1993. Drug Dev. Res. 32:208-216, 1994.2. Sullivan, A.T. and L.B. Kinter. Status of safety pharmacology in the pharmaceutical industry - 1995. Drug
Dev. Res. 35:166-172, 1995.3 Kinter L B and L W Dixon Safety pharmacology program for pharmaceuticals Drug Dev Res 35:1793. Kinter, L.B. and L.W. Dixon. Safety pharmacology program for pharmaceuticals. Drug Dev. Res. 35:179-
182, 1995.4. Kinter, L.B. General pharmacology/safety pharmacology: customers, biologics, and GLPs. Drug Dev. Res.
35:142-144, 1995.5. Kinter, L.B. Cardiovascular telemetry and laboratory animal welfare: new reduction and refinement
lt ti M h D t S i I tl St P l MO 1996alternatives. Monograph. Data Sciences Intl., St. Paul, MO, 1996.6. Kramer, K., Kinter, L.B., Brockway, B.P., Voss, H-P., Remie, R., and van Zutphen, B.L.M. The use of radio-
telemetry in small animals: recent advances. Contemporary Topics in Laboratory Animal Science 40:6-18, 2001.
7. Kinter, L.B. and Valentin, J-P. Safety Pharmacology and Risk Assessment. Fund. Clin. Pharmacol. 16:175-182 2002182, 2002.
8. Kramer, K., and Kinter, L.B. Evaluation and application of radiotelemetry in small laboratory animals. Physiol. Genomics 13:197-205, 2003.
9. Kinter, L.B., Siegl, P.K.S., and Bass, A.S. New Preclinical Guidelines on Drugs Effects on Ventricular Repolarization: Safety Pharmacology Comes of Age! J. Pharmacol Toxicol. Methods 49(3): 153-158, 2004.
10.Bass, AS, Vargas, HM, and Kinter, LB. Introduction to nonclinical safety pharmacology and the Safety Pharmacology Society. J. Pharmacol. Toxicol. Methods 49(3): 141-144, 2004.
11. Bass, AS, Kinter, LB, and Williams, P. Origins, practices and future of safety pharmacology. J. Pharmacol. Toxicol. Methods 49(3): 145-151, 2004.
12.Murphy, D.J. Safety Pharmacology of the Respiratory System; Techniques and Study Design. Drug Dev. Res. 32: 237-246, 1994
69
Selected Reading (cont.)13. Kinter, L.B., Murphy, D.J., Mann, W.A., Leonard, T.B., and Morgan, D.G. Major Organ Systems Toxicology:
an integrative approach to pharmacodynamic safety assessment studies in animals. In: Comprehensive Toxicology Eds I.G. Sipes, C.A. McQueen, and A.J. Gandolfi, Vol. 2 Toxicological Testing and Evaluation, Ed by P.D. Williams and G.H. Hottendorf, Elsevier Science, New York, pp. 155-168, 1997.
14 Kinter L B and Johnson D K Remote monitoring of experimental endpoints in animals using radiotelemetry14. Kinter, L.B., and Johnson, D.K. Remote monitoring of experimental endpoints in animals using radiotelemetry and bioimpedance technologies. In: Proc. Intl. Conference on Humane Endpoints in Animal Experiments for Biomedical Research. Edited by C.F.M. Hendriksen and D.B. Morton, The Royal Society of Medicine Press Ltd., London, pp. 58-65, 1999.
15. Kinter, L.B., Safety Pharmacology of the Renal and Gastro-Intestinal Systems. In: Safety Pharmacology - A Practical Guide Eds P Williams and A S Bass TherImmune Corporation Gaithersburgh MD 2003 pp 67-Practical Guide. Eds. P. Williams and A.S. Bass. TherImmune Corporation, Gaithersburgh, MD, 2003, pp 67-98.
16. Kinter, L.B., and Johnson, D.K. Safety Pharmacology of the Cardiovascular System. In: Safety Pharmacology - A Practical Guide. Eds. P. Williams and A.S. Bass. TherImmune Corporation, Gaithersburgh, MD, 2003, pp 99-116.
17 Hart S E and Kinter L B Assessing Renal Effects Of Toxicants In Vivo In Renal Toxicology Eds L Lash17.Hart, S.E., and Kinter L.B. Assessing Renal Effects Of Toxicants In Vivo. In Renal Toxicology , Eds., L. Lash and J. Tarloff. Target Organ Toxicology Series, CRC Press, Boca Raton, FL 2005, pp. 81-148.
18. Anon, Guidance for Industry: S7A Safety Pharmacology Studies for Human Pharmaceuticals, U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER), 2001.
19 Anon Guidance for Industry: S7A Safety Pharmacology Studies for Human Pharmaceuticals U S19. Anon, Guidance for Industry: S7A Safety Pharmacology Studies for Human Pharmaceuticals, U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER), 2001.
20. Anon, The Non-Clinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT interval Prolongation) by Human Pharmaceuticals S7B, U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation andDrug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER), 2005a.
70
Selected Reading (cont.)21. Anon, Guidance for Industry: S7A Safety Pharmacology Studies for Human Pharmaceuticals, U.S. Department of Health
and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER), 2001.
22. Anon, Guidance for Industry: S7A Safety Pharmacology Studies for Human Pharmaceuticals, U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for g g ( )Biologics Evaluation and Research (CBER), 2001.
23. Anon, The Non-Clinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT interval Prolongation) by Human Pharmaceuticals S7B, U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER), 2005a.
24. Anon, E14: The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic , g y yDrugs, U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER), 2005b.
25. Anon, Guidance for Industry, Investigators, and Reviewers: Exploratory IND Studies, Center for Drug Evaluation and Research, Food and Drug Administration. Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER), 2006.
26. Claude & Claude. 2004. Safety pharmacology: an essential interface of pharmacology and toxicology in the non-clinical assessment of new pharmaceuticals. Toxicological Letters. 151:1 25-28.
27. Lindgren, et al. 2008. Benchmarking Safety Pharmacology regulatory packages and best practice. Journal of Pharmacological and Toxicological Methods. 58:2 p 99-109
28. Pugsley, et al. 2008. Methods in safety pharmacology in focus. Journal of Pharmacological and Toxicological Methods. 8 ugs ey, e a 008 e ods sa e y p a aco ogy ocus Jou a o a aco og ca a d o co og ca e ods58:2 p 69-71.
29. Pugsley, Authier, & Curtis. 2008. Principles of Safety Pharmacology. British Journal of Pharmacology. 154:7 p1382-1399.
30. Redfern, W. S, et al. 2003. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug developmentand torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development Cardiovascular Research: 58 (1),32–45.
31. Valentin & Hammond. 2008. Safety and secondary pharmacology: successes, threats, challenges, and opportunities. Journal of Pharmacological and Toxicological Methods. 58:2 77-87.
71
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