General Considerations for Pediatric Pharmacokinetic Studies for Drugs and Biological Products

Status: Draft

Date: November 1998

Released by: 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)

Target Audience: Developers of drugs/biologics

Laws and Regulations:

·59 FR 64240: aka the 1994 rule; FDA ruling asking manufacturers to include more information about the use of a drug in the pediatric population in the product labeling

·62 FR 43899: the 1997 FDA ruling mandating that new drugs and biologics include labeling on how to safely use medicines indicated for adults in the pediatric population

·FDA Modernization Act of 1997 revised the Federal Food, Drug, and Cosmetic Act and the Public Health Service Act to enhance the regulation of food, drugs, devices, and biological products

·21 U.S.C.: part of the FDA Modernization Act of 1997 that provides incentives such as market exclusivity to drug developers who conduct pediatric studies on drugs already approved in adults

·Department of Health and Human Services (DHHS), Policy for Protection of Human Research Subjects 45 CFR 46: regulations to protect human research subjects in clinical trials

·21 CFR 50: Informed consent regulation

·21 CFR 56: Institutional review board regulation

·Declaration of Helsinki: a series of recommendations and guidelines to direct the conduct of biomedical research involving human subjects, based on the principles of the Nuremberg Code

·21 CFR 312.120: regulation regarding when the results of foreign clinical studies not conducted under an investigational new drug (IND) application can be accepted as support for an IND or an application for marketing approval


Absorption: the movement of a drug into the bloodstream from the skin, lungs, stomach, intestinal tract, or muscle

ADME: absorption (A), distribution (D), metabolism (M), and elimination (E) of a drug within the body; pharmacokinetic measures

AUC: area under the curve; PK parameter indicating the quantity of a therapeutic agent present in the circulation in a time period, often 24 hrs

Clearance: the rate at which a substance is removed from the blood

Cmax: maximum concentration; PK parameter indicating the maximum plasma concentration of the drug

Distribution: the spread of a drug to body tissues after it enters the blood

Elimination: the act of removing something, such as a drug, from the body

Half-life: the amount of time it takes for the concentration of a specified chemical or drug to decrease to half its original concentration in the specified fluid or blood

Linear PK: constancy of PK parameters of a drug throughout a wide range of dosages, allowing for concentrations at the site of measurement to always be directly related to dose, both for single and multiple doses

Metabolism: process by which a set of chemical reactions modify a molecule into another for storage, or for immediate use in another reaction or as a byproduct

PD: pharmacodynamics; the study of the biochemical and physiological effects of drugs and the mechanisms of their actions, including the relationship of their actions and effects with their chemical structure

Pediatric: individuals aged <16 years

PK: pharmacokinetic(s); the science and study of the factors that determine the amount of chemical agents at their sites of biological effect at various times after the application of an agent or drug to biological systems; includes the study of the effect of ADME on a drug

Protein binding: the process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds

Volume of distribution: a hypothetical volume of body fluid that would be required to dissolve the total amount of drug needed to achieve the same concentration as that found in the blood


Many drugs on the market are indicated for use in adults. Many of these same drugs also may be useful in the pediatric population, with some possibly already being used off-label in this young population. However, without official trials that investigate the safety, efficacy, and appropriate dosing of drugs in the pediatric population, it is impossible to know how to appropriately use these drugs in the pediatric population—and if it is wise to do so at all.

In an effort to encourage drug manufacturers to investigate the effect of drugs and biologics in the pediatric population, the FDA has passed several rules and regulations such as 59 FR 64240, which asked manufacturers to include more information about the use of a drug in the pediatric population in the product labeling; 62 FR 43899, which mandated that new drugs and biologics include labeling on how to safely use these medicines in the pediatric population; and the FDA Modernization Act of 1997, which gave incentives to motivate sponsors to run pediatric trials (21 U.S.C. 355a).


This guidance is meant to help drug manufacturers perform pharmacokinetic studies in the pediatric population. It advises that pediatric PK studies be conducted in all age groups within the pediatric population to verify appropriate dosing and what dose adjustments should be made to the dosage regimen to ensure that pediatric patients will achieve a comparable systemic exposure to adults that is as safe and effective. This information should then be included in the product labeling of this drug or biologic. This guidance should only be considered for conditions with a similar disease course in adult and pediatric populations, as well as a similar association between dose/response.


The safety and efficacy of a drug is based on the achievement of a defined amount of systemic exposure of a drug within a therapeutic window. This systematic exposure is measured by the area under the curve (AUC) and concentration at the maximum (Cmax) from which the clearance, half-life, and volume of distribution of a drug is determined. PK studies show what the body does to a drug in terms of how it is absorbed, distributed, metabolized, and eliminated—all of which affect the AUC and Cmax of the drug. Drugs typically vary in PK measures between persons and within the same person. The many changes occurring in pediatric patients as they develop into adults can affect the way the body absorbs, distributes, metabolizes, and eliminates a drug.

The appropriate AUC and Cmax values that mean safe and efficacious use in children are generally different than those in adults. Therefore it is necessary to test the PK of a drug in different age groups, including a full range of ages within the pediatric population. This will help assess the systemic exposure of a drug in various age groups and determine appropriate dosing.

Resulting Recommendations:

1. Pediatric PK studies should assess the absorption, distribution, metabolism, elimination, and protein binding of a drug as these processes are affected by the changes occurring in the rapidly growing and developing bodies of pediatric patients.

2. In vitro plasma protein studies should be conducted.

3. PD studies should be conducted in the pediatric population to determine how blood concentration, efficacy, and toxicity of a drug relate to help better understand dose and/or concentration/response differences between pediatric and adult populations.

4. Pediatric PK studies should include the influence of body size (eg, height, weight, surface area) and age on a drug. Additional covariates should include, if relevant, gestational age, birth weight, lab tests on organs involved in drug elimination, and concomitant and recent drug therapy.

5. In the pediatric population, single-dose studies should be conducted for drugs with linear PK in adults and steady-state studies for drugs with nonlinear PK.

6. The population approach is preferred over the standard approach to PK studies in the pediatric population.

7. Samples such as blood should be collected with utmost safety, minimizing frequency and quantity.

8. Data derived from PK studies should be included in the labeling of the drug specific to use of the drug in the pediatric population. If available, data should be included in the following sections of the prescribing information (labeling): CLINICAL PHARMACOLOGY (eg, variations in absorption, distribution, metabolism, and/or elimination between adult and pediatric populations); PRECAUTIONS: Pediatric Use (eg, information on safety and what the drug does in the pediatric body according to age); and DOSAGE AND ADMINISTRATION (eg, dosing modifications for the pediatric population according to age and body weight).

9. The safety and rights of pediatric participants in any studies should be upheld in any trials involving these patients according to ethical standards.

10. Pediatric PK studies should be conducted in all age groups within the pediatric population to verify what dose adjustments should be made to the dosage regimen to ensure that pediatric patients achieve a comparable systemic exposure that is as safe and effective as in adults.


Studies in pediatric populations of drugs indicated for adults will allow drug developers to determine if their drugs can be safely and efficaciously used in pediatric patients. These studies will help determine what doses are safe and effective in the pediatric population, too. Conducting pediatric studies will help decrease the unsubstantiated off-label use of adult drugs in pediatric patients.