Pharmaceutical Toxicology: Assessment of Safety, Efficacy and Toxicity of New Substances

Discovery

Researchers identify a biological target and design or screen molecules that might act on it.

Preclinical

The candidate is tested in the lab and in animals for toxicity PK/PD and ADME studies show how the drug moves through the body and what it does, and the best “lead compound” is selected

Phase 0

A small, preliminary trial and very low doses are given to confirm the drug behaves in humans as predicted

Phase 1A

First-in-human safety testing, usually in healthy volunteers

Phase 1B

Safety testing with multiple ascending doses (MAD) over time, and checks the effect of food on how the drug is absorbed

Phase 2A

Phase where researchers find the right dose and keep evaluating safety

Phase 2B

Assessing drug efficacy ( will the drug work in this certain dose)

Phase 3

Large trials where they confirm efficacy, monitor side effects, and compare the drug with existing treatments.

Phase 4

After the drug is on the market, post-market surveillance tracks long-term safety, rare side effect

(NOAEL/ NOEL) No-Observed-Adverse-Effect Level/No-Observed-Effect Level

highest dose at which there is no observed toxic effect

(LOAEL) Lowest-Observed-Adverse-Effect

lowest dose at which there is an observed toxic effect

LD₅₀

• Dose expected to kill 50% of animals tested

• No longer recommended due to ethical concerns

• Only approved by regulatory agencies when justified by scientific necessity

(NTEL) No Toxic Effect Level

• The largest dose in the most sensitive species that produced no observed toxic effect

• used to determine the starting dose used in the first human trials

Parameters in Animal studies

LD₅₀

Parameters in human testing

• TD₅₀ ( Toxic Dose 50)

• ED₅₀ ( Effective Dose 50)

Dose Estimates of Toxic Effects

Quantitative metric derived from dose-response relationships that measure the amount of a substance required to produce a specific adverse or lethal outcome

Up-and-Down-method

Animals are dosed sequentially, not in large groups, so far fewer animals are needed.

OECD 402

Acute Dermal Toxicity

OECD 403

Acute Inhalation Toxicity

OECD 407

28-Day Repeated-Dose Oral Toxicity in Rodents

OECD 408

90-Day Sub-Chronic Oral Toxicity in Rodents

OECD 414

Prenatal Developmental Toxicity

OECD 421 / 422

Reproduction/Developmental Toxicity Screening Tests

OECD 420

Fixed Dose Procedure

OECD 423

Acute Toxic Class Method

OECD 425

Up-and-Down Procedure

OECD 451

Carcinogenicity Studies

OECD 452

Chronic Toxicity Studies

OECD 453

(Combined Chronic Toxicity/Carcinogenicity Studies)

Single Ascending Dose (SAD)

• Small groups of healthy participants receive a single dose

• First group gets a very low dose. If safe, the next group receives a higher dose.

• To establish initial safety, tolerability, and basic single-dose pharmacokinetics

Multiple Ascending Dose (MAD)

• Participants receive repeated doses of the drug over a period of time

• Participants receive escalating multiple-dose levels to monitor cumulative effects

• To see if the drug builds up in the body over time, evaluate long-term tolerability, and determine when a "steady state"

Safe Baseline

Based on the NTEL and NOAEL from the most sensitive animal

Human Equivalent Dose

Animal value is converted into equivalent dose based on body surface area scaling

The Safety Factor

Once human dose is established divide it by the standard safety factor ( usually at least 10-folds) to select an incredibly conservative, safe starting dose for Phase I Clinical Trials.

The efficacy Threshold

The minimum dose required to achieve the desired healing effect (ED₅₀)

The Toxicity Threshold

The dose where toxicity begins (LOAEL)

successful pharmaceutical candidate

 wide gap between its effective dose and its LOAEL.