E8: Phase I (Most typical kind of study: Human Pharmacology)

Question 1

Phase I

Pharmacology

Objective of Study:

Answer 1

• Assess tolerance
• Define/describe PK1and PD2
• Explore drug metabolism and drug interactions
• Estimate activity

Question 2

Phase I

Pharmacology

Study Examples:

Answer 2

• Dose-tolerance studies
• Single and multiple dose PK and/or PD studies
• Drug interaction studies

Question 3

3.1.3.1 Phase I (Most typical kind of study: Human Pharmacology)

Answer 3

Phase I starts with the initial administration of an investigational new drug into
humans.

Although human pharmacology studies are typically identified with Phase I, they may also be indicated at other points in the development sequence. Studies in this phase of development usually have non-therapeutic objectives and may be conducted in healthy volunteer subjects or certain types of patients, e.g. patients with mild hypertension. Drugs with significant potential toxicity, e.g. cytotoxic drugs, are usually studied in patients. Studies in this phase can be open, baseline controlled or may use randomisation and blinding, to improve the validity of observations.

Question 4

3.1.3.1 Phase I (Most typical kind of study: Human Pharmacology)

a. Estimation of Initial Safety and Tolerability

Answer 4

The initial and subsequent administration of an investigational new drug into
humans is usually intended to determine the tolerability of the dose range expected to
be needed for later clinical studies and to determine the nature of adverse reactions
that can be expected. These studies typically include both single and multiple dose
administration.

Question 5

3.1.3.1 Phase I (Most typical kind of study: Human Pharmacology)

b. Pharmacokinetics

Answer 5

Characterisation of a drug’s absorption, distribution, metabolism, and excretion continues throughout the development plan. Their preliminary characterisation is an important goal of Phase I. Pharmacokinetics may be assessed via separate studies or as a part of efficacy, safety and tolerance studies. Pharmacokinetic studies are particularly important to assess the clearance of the drug and to anticipate possible accumulation of parent drug or metabolites and potential drug-drug interactions. Some pharmacokinetic studies are commonly conducted in later phases to answer more specialised questions. For many orally administered drugs, especially modified release products, the study of food effects on bioavailability is important. Obtaining pharmacokinetic information in sub-populations such as patients with impaired elimination (renal or hepatic failure), the elderly, children, women and ethnic subgroups should be considered. Drug-drug interaction studies are important formany drugs; these are generally performed in phases beyond Phase I but studies in animals and in vitro studies of metabolism and potential interactions may lead to doing such studies earlier.

Question 6

3.1.3.1 Phase I (Most typical kind of study: Human Pharmacology)

c. Assessment of Pharmacodynamics

Answer 6

Depending on the drug and the endpoint studied, pharmacodynamic studies and studies relating drug blood levels to response (PK/PD studies) may be conducted in healthy volunteer subjects or in patients with the target disease. In patients, if there is an appropriate measure, pharmacodynamic data can provide early estimates of activity and potential efficacy and may guide the dosage and dose regimen in later
studies.

Question 7

3.1.3.1 Phase I (Most typical kind of study: Human Pharmacology)

d. Early Measurement of Drug Activity

Answer 7

Preliminary studies of activity or potential therapeutic benefit may be conducted in Phase I as a secondary objective. Such studies are generally performed in later phases but may be appropriate when drug activity is readily measurable with a short duration of drug exposure in patients at this early stage.