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NONCLINICAL SAFETY STUDIESFOR DRUGS

Pharmacology

Pharmacodynamics (Pharmacology)

Mechanism(s) of actionof drug

Pharmacokinetics

Movementof drug

Pharmacology

Primary Pharmacodynamics

Mode of action related to the proposed therapeutic indication

Secondary Pharmacodynamics

Actions other than those related to the proposed therapeutic indication

Safety Pharmacology

Effect of drug on specific physiological systems

Pharmacodynamic Drug Interactions

Primary Pharmacodynamics

in vitroand in vivodata

Rational drug design and biotechnologicals:

E.g., for MAb: special attention to antigen specificity, immunogenicity, tissue cross-reactivity
screen, anti-product antibodies, etc.

assays for pharmacodynamic monitoring (surrogate marker)

Safety Pharmacology (Effect of drug on specific physiological systems)



Core test battery

CNS (motor activity, behavioral changes, coordination, reflex, body temperature, etc.,)

Cardiovascular (blood pressure, heart rate, ECG, etc.,)

Respiratory System (respiratory rate and depth etc.,)

Follow up and supplemental studies (CNS, cardiovascular, respiratory, renal/urinary, autonomic
nervous system, GI)
Safety Pharmacology (Effect of drug on specific physiological systems)

Pharmacokinetics

Blood levels of parent drug and key metabolites -Tmax,Cmax, AUC, t1/2

ADME

absorption –into blood, i.v. and intended route

distribution -plasma protein binding, volume of distribution ([body organs] vs. [blood])

metabolism –pathway and activity of metabolites

excretion –clearance

Pharmacokinetics

Biotechnologicals:

metabolism (catabolism) of biologicals often difficult to characterize and study

degradation similar to endogenous protein

when to stop examining breakdown products (catabolites not functionally active)

Toxicology

Single Dose Toxicity

Repeat Dose

Genotoxicity

Carcinogenicity

Reproductive Toxicity

Other Studies

Acute Toxicity Testing



To assess and evaluate the toxic characteristics and to try to predict health hazards to humans
likely to arise from short term exposure (poisoning)

Mortality, clinical signs, and onset, duration and reversibility of toxicity

Lethal dose or maximum tolerated dose data

2 mammals; clinical route and intravenous

Appropriate dose for multiple-dose studies

Repeated Dose Toxicity



To determine harmful effects produced by a drug when administered repeatedly

Toxicologic profile (target organs); margin of safety (NOAELs); reversibility; species/sex
differences

Duration dependent on intended clinical use, trial duration

Rodent, nonrodent species

Toxicokinetics
Repeated Dose Toxicology

Biotechnologicals:

GLP-quality data not always obtainable

conventional approaches may not be appropriate and duration of treatment may be limited
(potential immunogenicity, neutralizing antibodies)

use relevant species/animal models of disease (e.g., homologous protein in a rodent model)

Genotoxicity

To determine the potential to induce DNA/chromosome defects (somatic cell) or heritable
defects (germ cell)

Prior to 1996, not an FDA requirement

Standard Test Battery

In vitromutagenicity (Ames Assay)

In vitro clastogenicity in mammalian cells

In vivoclastogenicity

Genotoxicity

Biotechnologicals:

standard battery may not be appropriate (not designed to deal with proteins/peptides)

process contaminants (may need testing)

Carcinogenicity

To determine carcinogenic potential

Typically required for “chronic use” (greater than 6 months) and “Intermittent use” where total
cumulative lifetime exposure > 3 months

Use intended clinical route or (more than 1), route providing greatest systemic exposure

Begin studies after evidence of efficacy, typically provide at registration

Carcinogenicity Assessment Committee (CAC)



Primary consulting body on issues

Tertiary review of carcinogenicity studies

Request review 60 days in advance

Carcinogenicity
Biotechnologicals:

standard rodent bioassay usually inappropriate (lack of biological activity, immunogenicity
issues)

may require other approaches

e.g., in vitro(cell culture) indices such as cell proliferation (mitogenicity)

must use scientifically-based approach if rodent assay considered necessary

Reproductive Toxicity

In US, perform early to include women early in trials

Reproductive Toxicity
Need for these, or extent of evaluation, depends on product, indication, population, disease
severity, availability of animal model, pharmacodynamicactivity of product

Biotechnologicals:

May require alternative approaches and/or special studies

rodent often inappropriate

primate studies may be necessary

Regulations versusguidance -sufficient pharmacology and toxicology data to obtain permission


for clinical trials or registration for use in humans

Factors to Consider
1.Type of product –reviewing division, new active substance (NAS), chemistry and
manufacturing
2.Indication –benefit/risk
3.
Clinical treatment regimen –dose, route of administration, frequency, duration
4.Strategy to meet drug development milestones

EXAMPLES OF NONCLINICAL REQUIREMENTS FOR REGISTRATION


(NCE, oral, chronic)
Acute toxicity
single doseRatOral (gavage)
single doseDogOral (gavage)
Repeated Dose Toxicity
7-dayRatOral (gavage)
7-dayDogOral (gavage)
2-weekRatOral (gavage)
2-weekDogOral (gavage)
2-weekMouseOral (diet)
4-weekRatOral (gavage)
4-weekDogOral (gavage)
13-weekRatOral (gavage)
13-weekDogOral (capsule)
13-weekMouseOral (diet)
Chronic Toxicity
6-monthRatOral (gavage)
9-MonthDogOral (capsule)
Carcinogenicity
104-weekRatOral (gavage)
104-weekMouseOral (diet)

Genotoxicity
BacterialS. typhimuriumTA98,TA100,TA1535,TA1537,
E. coliWP2 uvrA(in vitro)
Chrom AbsChinese hamster ovary cells(in vitro)
MicronucleusRat (oral gavage)
Reproductive Toxicology/Teratology
Fertility(ICH A-B)RatOral (gavage)
Teratology (range finding)RatOral (gavage)
Teratology(ICH C-D)RatOral (gavage)
Teratology (range finding)RabbitOral (gavage)
Teratology(ICH C-D)RabbitOral (gavage)
Perinatal (ICH C-F)RatOral (gavage)

Special Studies/Safety Pharmacology


CNSRat and mouseOral (gavage)
CV/hemodynamicsDogIV and oral
Renal SystemRatOral (gavage)
Digestive systemMouseOral (gavage)
AntigenicityGuinea pigIV
Dermal sensitizationGuinea pigTopical
Dermal irritationRabbitTopical
Eye irritationRabbitOcular

Other Toxicity Studies



Antigenicity

Immunotoxicity

Mechanistic studies

Dependence

Metabolites

Impurities