Guidance for Industry 

Pharmacokinetics in Pregnancy — 

Study Design, Data Analysis, 

and Impact on Dosing and Labeling

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only. 

Comments and suggestions regarding this draft document should be submitted within 60 days of 

publication in the Federal Register of the notice announcing the availability of the draft guidance. 

Submit comments to the Division of Dockets Management (HFA-305), Food and Drug 

Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be 

identified with the docket number listed in the notice of availability that publishes in the Federal 

Register. 

For questions regarding this draft document contact (CDER) Kathleen Uhl 301-443-5157. 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

October 2004 

Clinical Pharmacology 

J:\!GUIDANC\5917dftcln2.doc 

10/22/2004
Guidance for Industry 

Pharmacokinetics in Pregnancy — 

Study Design, Data Analysis, 

and Impact on Dosing and Labeling

Additional copies are available from: 

Office of Training and Communications

Division of Drug Information, HFD-240

Center for Drug Evaluation and Research

Food and Drug Administration 

5600 Fishers Lane 

Rockville, MD 20857

(Tel) 301-827-4573

http://www.fda.gov/cder/guidance/index.htm 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

October 2004 

Clinical Pharmacology 
TABLE OF CONTENTS 

I. INTRODUCTION............................................................................................................. 1

II. BACKGROUND ............................................................................................................... 2

III. DECIDING WHETHER TO CONDUCT A PHARMACOKINETIC STUDY IN 

PREGNANT WOMEN..................................................................................................... 3

IV. STUDY DESIGN............................................................................................................... 5

A. Longitudinal Design.......................................................................................................................5

B. Population PK Design....................................................................................................................6

V. OTHER DESIGN CONSIDERATIONS ........................................................................ 7

A. Study Participants..........................................................................................................................7

B. Postpartum Assessments...............................................................................................................7

C. Sample Size.....................................................................................................................................8

D. Drug Administration .....................................................................................................................8

E. Sample Collection and Analysis....................................................................................................9

F. Studies with No Intended Therapeutic Benefit ...........................................................................9

G. Pharmacodynamic Assessments.................................................................................................10

VI. DATA ANALYSIS.......................................................................................................... 10

A. Parameter Estimation..................................................................................................................10

B. Development of Dosing Recommendations................................................................................11

VII. LABELING ..................................................................................................................... 11

A. Clinical Pharmacology.................................................................................................................12

1. Pharmacokinetics Subsection ........................................................................................................12

2. Special Populations Subsection .....................................................................................................12

B. Precautions/Pregnancy................................................................................................................13

C. Dosage and Administration.........................................................................................................13

REFERENCES............................................................................................................................ 14
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Guidance for Industry1 1 

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Pharmacokinetics in Pregnancy — 

Study Design, Data Analysis, and 

Impact on Dosing and Labeling 

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This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current 

thinking on this topic. It does not create or confer any rights for or on any person and does not operate to 

bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of 

the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA 

staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call 

the appropriate number listed on the title page of this guidance. 

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I. INTRODUCTION 

This guidance describes a basic framework for designing and conducting PK/PD studies in 

pregnant women. It provides recommendations to sponsors on how to assess the influence of 

pregnancy on the pharmacokinetics (PK), and where appropriate, the pharmacodynamics (PD) of 

drugs or biologic products.2

 Additionally, this guidance provides recommendations to primary 

investigators, clinical researchers, and clinical pharmacologists about issues to consider when 

designing and conducting PK studies in pregnant women. 

The Agency recommends using this guidance in conjunction with other FDA and ICH guidances, 

and pharmacological and clinical literature, on the design, conduct, and interpretation of 

pharmacokinetic studies. Because the conduct of studies in pregnant women requires specialized

knowledge in a variety of areas, investigators designing such studies are encouraged to obtain 

advice from experts in fields such as obstetrics, pediatrics, pharmacology, clinical pharmacology, 

pharmacometrics, statistics, and other applicable disciplines. Although this guidance provides 

recommendations on when PK studies in pregnant women are appropriate, it does not address 

ways to assess efficacy of a drug in pregnancy or how to assess whether the drug causes adverse 

pregnancy or neonatal outcomes. 

1

 This guidance has been prepared by the PK in Pregnancy Working Group of the Pregnancy Labeling Task Force, 

Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration. 

2

 Throughout this document, the term medical product or drug means drug and biological products, including

vaccines. 

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FDA’s guidance documents, including this guidance, do not establish legally enforceable 

responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should 

be viewed only as recommendations, unless specific regulatory or statutory requirements are 

cited. The use of the word should in Agency guidances means that something is suggested or 

recommended, but not required. 

II. BACKGROUND 

Ideally, pharmacologic agents would not be needed during pregnancy; however, some women 

enter pregnancy with medical conditions that require ongoing or episodic treatment (e.g., asthma, 

epilepsy, hypertension). During pregnancy, new medical problems can also develop, and old 

ones can be exacerbated (e.g., migraine headaches), requiring pharmacologic therapy. Studies 

have shown that most pregnant women do use either prescribed or over-the-counter medications 

during pregnancy (Bonati 1990, De Vigan 1999, Lacroix 2000, Mitchell 2001). Interviews of 

approximately 20,000 U.S. and Canadian women conducted over 25 years reported a mean of 2.3 

medications used during pregnancy, excluding vitamins and minerals (Mitchell 2001). Of the 

women interviewed, 28 percent reported using more than four medications during pregnancy, 

and medication use increased with maternal age. In addition, the mean number of medications 

taken, in successive 5-year intervals, progressively increased from 2.7 to 4.4, indicating secular 

patterns of medication use by pregnant women. A comparison of therapeutic drug use during 

pregnancy in Europe showed that 64 percent of women used at least one drug during pregnancy 

(De Vigan 1999), while in France, pregnant women were prescribed an average of five drugs 

during the first trimester (Lacroix 2000). 

Generally, the safety and efficacy of a drug are established for a particular dosage regimen or 

range of dosage regimens in late phase (Phase 3) clinical trials involving relatively typical 

representatives from the target patient population. Pregnant women are actively excluded from

these trials, and, if pregnancy does occur, the usual procedure is to discontinue treatment and 

drop the patient from the study. Consequently, at the time of a drug’s initial marketing, except 

for products developed to treat conditions specific to pregnancy (e.g., oxytocics, cervical 

ripening agents), there are seldom human data on the appropriate dosage and frequency of 

administration during pregnancy. Even after years of marketing, data in product labels regarding 

PK and dose adjustments during pregnancy rarely provide more information for appropriate 

prescribing in pregnancy than was available at the time of initial marketing. 

The few data to address appropriate dosage and frequency of administration in pregnancy are not 

usually supported by a full understanding of the alterations of the PK of the drug in pregnancy. 

For example, the majority of published PK studies of anti-infective drug products during 

pregnancy were conducted at the time of abortion or delivery (usually via cesarean section) and 

were done to determine the transplacental passage of drug. In the absence of data, the usual 

adult dose is typically prescribed for pregnant women. Because of the physiologic changes 

inherent in pregnancy, the result can be substantial under dosing, or, in some cases, excessive 

dosing. 

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Extrapolation of PK data from studies performed in nonpregnant adults fails to take into account 

the impact of the many physiologic changes that occur during pregnancy. Most of the 

physiologic changes manifest during the first trimester and peak during the second trimester of 

pregnancy. Physiologic changes are not fixed throughout pregnancy but rather reflect a 

continuum of change as pregnancy progresses, with return to baseline at various rates in the 

postpartum period. The physiologic changes have the potential to alter the PK and/or PD of 

drugs. Some of these changes include: 

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• Changes in total body weight and body fat composition. 

• Delayed gastric emptying and prolonged gastrointestinal transit time. 

• Increase in extra cellular fluid and total body water. 

• Increased cardiac output, increased stroke volume, and elevated maternal heart rate. 

• Decreased albumin concentration with reduced protein binding. 

• Increased blood flow to the various organs (e.g., kidneys, uterus). 

• Increased glomerular filtration rate. 

• Changed hepatic enzyme activity, including phase I CYP450 metabolic pathways (e.g., 

increased CYP2D6 activity), xanthine oxidase, and phase II metabolic pathways (e.g., Nacetyltransferase). 

A significant amount of pharmacologic research has been conducted to improve the quality and 

quantity of data available for other altered physiologic states (e.g., in patients with renal and 

hepatic disease) and for other patient subpopulations (e.g., pediatric patients).3

 The need for 

PK/PD studies in pregnancy is no less than for these populations, nor is the need for the 

development of therapeutic treatments for pregnant women. 

III. DECIDING WHETHER TO CONDUCT A PHARMACOKINETIC STUDY IN 

PREGNANT WOMEN 

Ethical issues are important when considering studying drugs in pregnant women. Given the 

large number of pregnant women who need prescription medicines to maintain their health, some

have argued that it is unethical not to obtain dosing information in this subpopulation (Faden 

2000). Others recommend that only pregnant women who need a drug for therapeutic reasons be 

included in clinical studies, citing that drug studies cannot be done in “normal pregnant 

volunteers” (Stika 2001). 

3 Guidance for Industry Pharmacokinetics in Patients with Impaired Renal Function,

http://www.fda.gov/cder/guidance/1449fnl.pdf, issued May 1998. Guidance for Industry Pharmacokinetics in

Patients with Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling, 

http://www.fda.gov/cder/guidance/3625fnl.pdf, issued May 2003. Draft Guidance for Industry General 

Considerations for Pediatric Pharmacokinetic Studies for Drugs and Biological Products, 

http://www.fda.gov/cder/guidance/1970dft.pdf, issued November 1998. Draft guidances, when finalized, will 

represent the Agency’s current thinking on these issues. 

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All studies in pregnant women must conform to all applicable regulations, including human 

subject protection.

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4

 The Agency recommends that all studies in pregnant women have 

Institutional Review Board (IRB) review and informed consent for all study participants.

Pregnant women may be involved in PK studies if the following conditions are met (45 CFR 

Subpart B 46.204): 

• Preclinical studies, including studies on pregnant animals, and clinical studies, including

studies on nonpregnant women, have been conducted and provide data for assessing 

potential risk to pregnant women and fetuses; and 

• The risk to the fetus is not greater than minimal and the purpose of the research is the 

development of important biomedical knowledge which cannot be obtained by any other 

means. 

The definition of minimal risk is broad. The fetal risk is considered minimal when the estimated 

risk to the fetus is no more than that from established procedures routinely used in an 

uncomplicated pregnancy or in a pregnancy with complications comparable to those being 

studied.5

 Although PK studies in pregnancy can be considered in Phase 3 development programs 

depending on anticipated use in pregnancy and the results of reproductive toxicity studies, the 

FDA anticipates that most PK studies in pregnant women will occur in the postmarketing period 

and will be conducted using pregnant women who have already been prescribed the drug as 

therapy by their own physician. An example of a minimal risk study would be one to determine 

PK/PD of an antihypertensive medication in pregnant women who are taking that medication to 

treat hypertension during pregnancy. The decision to use the antihypertensive medication is 

made by the patient and her physician independent of participation in the PK/PD study. 

Information on human pregnancy experiences and exposures will emerge during the 

postmarketing phase for virtually all drug products. Sponsors are requested to explicitly address 

positive or negative experiences during pregnancy or lactation as one of the safety issues in the 

Overall Safety Evaluation section of the Periodic Safety Update Report.6

 This source of 

information is valuable in determining whether to conduct PK studies in pregnant women. Other 

important sources of information include publications concerning safety (e.g., reports that 

describe the use of the drug in pregnancy) or efficacy in pregnancy and information from 

medical specialty groups. These types of postmarketing exposure and safety data on drug 

products provide the basis for determining the need for PK assessment of a drug in pregnant 

women. 

This guidance recommends that PK studies be conducted in pregnant women in any of the 

following situations: 

4 45 CFR 46, Protection of Human Subjects, http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm. 

5

 Office of Human Research Protections, http://ohrp.osophs.dhhs.gov

6 Guidance for Industry E2C Clinical Safety Data Management: Periodic Safety Update Reports for Marketed 

Drugs, http://www.fda.gov/cder/guidance/1351fnl.pdf, issued May 1997. 

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• The drug is known to be prescribed in or used by pregnant women, especially in the 

second and third trimesters. 

• For a new drug or indication, if there is anticipated or actual use of the drug in pregnancy. 

• Use is expected to be rare, but the consequences of uninformed dosages are great (e.g., 

narrow therapeutic range drugs, cancer chemotherapy). Drugs of this type can normally 

be studied in pregnant patients. 

• Pregnancy is likely to alter significantly the PK of a drug (e.g., renally excreted drug) and 

any of the above apply. 

PK studies in pregnant women are not recommended if the drug is not used in pregnant women 

or the drug has known or highly suspect fetal risk. 

For approved products, consider whether a study in pregnant women must be conducted under 

the investigational new drug (IND) regulations (21 CFR 312.2). If there is a concern for 

significantly increasing the risk (or decreasing the acceptability of the risks) in a patient 

population (i.e., the mother or fetus), an IND would be needed (21 CFR 312.2(b)(iii)). Also, 

according to the IND regulations, if a different route of administration or dosage level is used, an 

IND would be needed. 

IV. STUDY DESIGN 

Study design considerations are important when conducting a study in pregnant women to 

determine if the PK and/or PD are altered enough to require an adjustment from the established 

dosage. Ideally, PK studies in pregnancy would be done pre-pregnancy (for baseline 

comparison) and during all three trimesters, especially for chronically administered drugs. Given 

the constraints of a study design that enrolls women prior to pregnancy, an alternative can be to 

determine PK/PD in the second and third trimesters, with the baseline assessment for comparison 

to the pregnant state done in the postpartum period. The Agency recommends care be taken to 

select the most appropriate postpartum time for PK/PD determination, if known. Cardiovascular 

and renal changes do not return to the pre-pregnancy state until 3 months postpartum. Optimally, 

postpartum PK/PD assessments for comparative purposes to PK/PD in pregnancy would be done 

when the woman is neither pregnant nor lactating.

The PK and/or PD study can also be nested within a larger clinical study on safety, efficacy, and 

outcomes of interest (e.g., Prevost et al. performed a study on the PK of nifedipine on a small 

subset of patients who were participating in a larger clinical study to assess treatment for 

pregnancy-induced hypertension (Prevost 1992)). 

A. Longitudinal Design 

For drugs that are administered chronically or given for several treatment cycles during

pregnancy, a longitudinal study design is most clinically meaningful. This allows for intensive 

PK studies in pregnant women conducted serially so that each woman serves as her own control, 

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avoiding the common criticism that PK/PD studies in pregnant women are flawed because of the 

comparison group employed (Reynolds 1991; Little 1999). Such a study would focus on 

comparing each pregnant woman enrolled at one trimester of pregnancy to the same patient at a 

different trimester as well as during the postpartum period. We recommend that the rationale for 

which trimesters are chosen be stated clearly in the study protocol. This longitudinal design 

minimizes interindividual variability across gestational ages; however, intraindividual variability 

would be taken into account when determining the sample size. It is important that the analytical 

plan take into consideration the repeat measures characteristics of a longitudinal design. 

Because physiologic changes are continuous throughout pregnancy, and abrupt changes do not 

necessarily coincide with each trimester shift, the Agency recommends that investigators 

consider narrowing the time of sampling from trimester to a window of time during each 

trimester. For example, 4-week windows can be selected for second trimester (e.g., 24-28 

weeks) and third trimester assessments (e.g., 34-38 weeks). 

The Agency recommends that each woman serve as her own control and have PK/PD 

determinations performed at different trimesters and in the postpartum period. For certain drugs 

that are given acutely (e.g., single dose or short course of therapy) it can be difficult to 

implement a longitudinal design using the same subjects throughout and after pregnancy. For 

example, in certain circumstances drug therapy may no longer be medically essential in the 

postpartum period. In these situations, a multi-arm study can be designed to compare different 

pregnant subjects at different trimesters and in the postpartum period. 

B. Population PK Design 

A population PK approach with nonlinear mixed effects modeling techniques can be used as an 

alternate way to enroll pregnant women in PK studies and minimize the number of blood draws 

and PD assessments. The population PK approach can assess the impact on the PK of a drug on 

various covariates, such as maternal characteristics (e.g., age, gravity, parity, race, weeks or 

trimester of gestation), concomitant medications, and underlying medical conditions. For 

example, a measure of pregnancy status such as weeks gestation can be one of the covariates, 

making it possible to model the relationship between gestational age of pregnancy and PK 

parameters such as the apparent clearance of the drug (CL/F).

In principle, a population PK study design and analysis might detect PK differences large enough 

to warrant dosage adjustment if the study has enough pregnant and nonpregnant women enrolled 

with sufficient representation of second and third trimesters (with a continuum of gestational 

ages from 13 to 40 weeks). Typically, each patient is only sparsely sampled to obtain plasma

drug concentration data and/or PD data. Due to the intrinsic characteristics of a population PK 

study, the controls for this study design can differ from other study designs and can potentially 

include matched healthy nonpregnant female volunteers. To ensure the ability to determine the 

inter-occasion variability and prevent a parallel group trial design, a cohort of study subjects 

would have data collected from all trimesters and the postpartum period. Considering the 

number of subjects in the study and the key objective of the study, efforts can be made to reduce 

the number of influential covariates such as concomitant medication. 

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Some investigators have proposed conducting a population PK study as a preliminary step and to 

subsequently conduct a standard intensive PK/PD study if the population PK study suggests 

changes between the pregnant and nonpregnant women (Stika 2000). For further information 

about the population PK approach, see the Guidance for Industry Population Pharmacokinetics.

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V. OTHER DESIGN CONSIDERATIONS 

A. Study Participants 

Study participants should be representative of a typical patient population for the drug to be 

studied including race, ethnicity, and trimester of pregnancy. Factors with significant potential 

to affect the PK of a drug to be studied (e.g., age, weight, diet, smoking, concomitant 

medications, ethnicity, renal function, other medical conditions) can be considered depending on 

the pharmacologic properties of the drug. The FDA recommends that uniform diagnostic 

measures be applied to all pregnant women to ensure similarity of diagnosis for the treatment 

being given and to reduce disease-specific variability in PK. The FDA recommends that 

measures used for dating the pregnancy be stated clearly in the study protocol and consistently 

applied throughout the study. Inclusion and exclusion criteria can be tailored to the study. 

For drugs that are metabolized by enzymes known to exhibit genetic polymorphism (e.g., 

CYP2D6 or CYP2C19), the FDA recommends that the investigator consider the metabolic status

of the enrolled subjects when analyzing the results of the study. Genotype has been shown to 

have an effect on pregnancy-related changes in metabolism (Wadelius 1997). 

B. Postpartum Assessments 

Physiology changes rapidly at delivery but can take from weeks to months to return to the prepregnancy state. The Agency recommends that drugs used only during the peripartum period 

(e.g., labor and delivery) be studied only at that time. In the peripartum period, PK and receptor 

sensitivity related to PD can change, so PK/PD studies for drugs used in the peripartum period 

are important. 

A woman’s own postpartum PK/PD assessments can serve as a control or comparator for the 

pregnant state. For women to whom drugs are administered chronically and for whom a 

pregnancy on the medication of interest is planned, the pre-pregnancy PK/PD assessment can 

serve as the comparison. For drugs used throughout pregnancy and the postpartum period, PK 

studies can be performed during the postpartum period to serve as the comparator or control 

group. Postpartum assessments can potentially be done longitudinally (e.g., at 2, 4, 6, and 8 

weeks postpartum) to determine the time course for PK changes to return to the nonpregnant 

state. Some pregnancy-related medical conditions rapidly improve after delivery such that 

7 Guidance for Industry Population Pharmacokinetics, http://www.fda.gov/cder/guidance/1852fnl.pdf, issued

February 1999. 

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pharmacologic therapy is no longer needed in the postpartum period (e.g., some cases of 

pregnancy-induced hypertension or gestational diabetes). In this scenario women can participate 

in a single-dose PK/PD study in the postpartum period. If a drug possesses linear kinetics, the 

single-dose PK data can be extrapolated to the multiple-dose steady state kinetics and then 

compared with steady state kinetics obtained during pregnancy when the drug was administered 

chronically. 

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If subjects are breast-feeding during the postpartum portion of the study, the FDA recommends 

that the study incorporate appropriate safety precautions concerning drug excretion into breast 

milk and the effects of the drug on the breast-fed infant. The study design should take into 

account data concerning the pediatric pharmacology and adverse effects of the drug. A lactation 

study might be performed in conjunction with postpartum sampling.

C. Sample Size 

The objective and design of a study are determining factors in deciding adequate sample size. 

The number of subjects enrolled in a study should be sufficient to detect PK differences large 

enough to warrant dosage adjustments. Sample size considerations include PK and PD 

variability for the drug being studied, the study design (i.e., single-dose versus multiple-dose), 

and the physiologic changes inherent in pregnancy. For a population PK approach,8

 sparse 

sampling with a larger number of subjects that span the gestational time periods of interest is 

encouraged.

As a practical matter, it is prudent that the final number of subjects enrolled be in excess of that 

originally determined by standard sample size calculations to take into account withdrawal of 

subjects from the study. Even if data for a subject are missing for one trimester, the Agency 

suggests that the subject be retained in the study for the postpartum assessments. 

D. Drug Administration 

In single-dose studies, the same dose can usually be administered to all women in the study. 

Lower or less frequent doses can be considered to minimize fetal risk in pregnant women who 

volunteer to take the medication for study purposes, even if it is expected to pose minimal risk at 

standard doses. The dosage regimen can be adjusted based on the best available pre-study 

estimates of the PK of the drug and its active metabolites and what is known about drug 

elimination. A concentration-controlled study design or a dosage adjustment based on the 

patient’s response are alternative methods to consider. For example, the study might be 

conducted to achieve a specific target concentration using therapeutic drug monitoring 

procedures. When studying pregnant patients who need the study drug, the dose can be 

modified, either increased or decreased as pregnancy progresses, to achieve the appropriate 

response (e.g., lowering of blood pressure, or to decrease adverse events such as hypotensive 

episodes with antihypertensive therapy). 

8 Guidance for Industry Population Pharmacokinetics, http://www.fda.gov/cder/guidance/1852fnl.pdf, issued

February 1999. 

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E. Sample Collection and Analysis 

The Agency recommends that plasma or whole blood samples and urine samples be analyzed for 

the parent drug and any metabolites with known or suspected activity, therapeutic or adverse. It 

is recommended that the frequency and duration of plasma sampling and urine collection be 

sufficient to estimate accurately the relevant PK parameters for the parent drug and its active 

metabolites (see Section VI, Data Analysis). 

Plasma protein binding, like renal function, is often altered in pregnancy.9

 For example, albumin 

and alpha-1-acid glycoprotein levels are reduced in pregnancy, consequently the protein binding 

of drugs can be affected. With systemically active drugs and metabolites, the unbound 

concentrations are generally believed to determine the rate and extent of delivery to the sites of 

action. For drugs and metabolites with a relatively low extent of plasma protein binding (e.g., 

the extent of binding is less than 80 percent), alterations in binding due to pregnancy are small in 

relative terms. In such cases, description and analysis of the PK in terms of total concentrations 

would be sufficient. For drugs where the extent of protein binding is greater than 80 percent, 

primarily to albumin, it is recommended that the PK be described and analyzed with respect to 

the unbound concentrations of the drug and active metabolites. Although unbound 

concentrations should be measured in each plasma sample, if the binding is concentrationindependent and unaffected by metabolites or other time-varying factors, the fraction unbound 

can be determined using a limited number of samples or even a single sample from each patient

during each trimester. The unbound concentration in each sample should then be estimated by 

multiplying the total concentration by the fraction unbound for the individual patient. 

F. Studies with No Intended Therapeutic Benefit 

It is possible to study drugs that have no intended direct therapeutic benefit to the pregnant 

woman provided that the risk to the fetus is minimal (45 CFR 46). For example, probe substrates 

can be used to investigate drug metabolism (e.g., cytochrome P-450 activity) or drug transporter 

status (e.g., p-glycoprotein). Data from these studies offer generalizable information to other 

pregnant women but do not offer direct therapeutic benefit to study participants. The Agency 

encourages sponsors or investigators to explore additional safeguards for human subject 

protection for this type of study. To minimize exposure to a nontherapeutic drug, each pregnant 

woman can be exposed to the drug once during pregnancy and in the postpartum period 

employing a nonlongitudinal design (e.g., one cohort of women sampled in second trimester and 

postpartum and another cohort of women sampled in third trimester and postpartum). Examples 

of additional safeguards include administering only products with a long or known record of 

safety in pregnancy, administering products using only a single dose of the drug, using lower 

doses of the drug, decreasing the number of drugs (probe substrates) used in any study subject, 

and limiting study participants to pregnant women only in second or third trimester. 

9 Guidance for Industry Pharmacokinetics in Patients with Impaired Renal Function,

http://www.fda.gov/cder/guidance/1449fnl.pdf, issued May 1998. 

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PK studies are usually enhanced by including PD assessments as part of the study. The Agency 

encourages sponsors to discuss the selection of the PD endpoints with the appropriate FDA 

review staff. Endpoints would be based on the pharmacological characteristics of the drug and 

metabolites (e.g., the behavior of other drugs in the same pharmacological class), and include 

consideration of relevant biomarkers.10 Fetal PD endpoints can warrant study as well (e.g., fetal 

heart rate and rhythm response to maternal administration of an antiarrhythmic drug).

VI. DATA ANALYSIS 

The primary intent of the data analysis is to assess whether dosage adjustment is needed for 

pregnant patients, and, if so, to develop dosing recommendations for such patients based on 

gestational age or trimester. The analysis, specifically modeling and dosing recommendations, 

will depend on the study design characteristics. The categorization of pregnancy status, either as 

nominal (e.g., trimester) or continuous (e.g., week of gestation) data will direct the type of 

analysis performed. The Agency encourages giving special analytical considerations to 

longitudinal study designs and the baseline (e.g., postpartum) comparisons. The data analysis 

typically consists of the following steps: 

• Estimation of PK parameters 

• Development of dosing recommendations

A. Parameter Estimation

The Agency recommends that total and unbound plasma concentration data (and urinary 

excretion data if collected) be used to estimate PK parameters of the parent drug and 

metabolite(s). Standard PK parameters of a drug include the area under the plasma concentration

curve (AUC), peak concentration (Cmax), plasma clearance (CLT) or apparent oral clearance 

(CL/F), renal clearance (CLR), apparent volume of distribution (VZ/F or Vss/F), and terminal 

half-life (t1/2). It is recommended that PK parameters be expressed in terms of total and unbound 

concentrations and when applicable (e.g., oral and renal clearance, expressed in terms of body 

weight, L/hr/kg). For drugs and metabolites with a relatively low extent of plasma protein 

binding (e.g., extent of binding less than 80 percent), description and analysis of the PK in terms 

of total concentrations can be sufficient. Noncompartmental and/or compartmental modeling 

approaches to parameter estimation can be employed. 

10 Guidance for Industry Exposure-Response Relationships — Study Design, Data Analysis, and Regulatory 

Applications, http://www.fda.gov/cder/guidance/5341fnl.pdf, issued May 2003. 

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Specific dosing recommendations should be constructed based on study results. Typically the 

dose should be adjusted to produce a comparable range of unbound plasma concentrations of 

drug or active metabolites in both controls and pregnant patients. Simulations are encouraged as 

a means to identify doses and dosing intervals that achieve that goal for pregnant patients at 

different trimesters or gestational ages. 

One approach might be for the sponsor to recommend, prior to the conduct of the studies, 

specific no effect boundaries for the ratio of a PK measurement from pregnant patients and 

controls, such as (AUCu,pregnant/AUCu,control) or (Dpregnant/Dcontrol). If the 90 percent 

confidence interval for the ratio of PK measurements falls within these boundaries, the sponsor 

might claim no effect of pregnancy on PK, and it would be reasonable to conclude that no dosage 

adjustment is needed for pregnancy. The sponsor might determine no effect boundaries from

population or individual PK/PD relationships, dose-finding studies and/or dose-response studies 

which are conducted as part of drug development. 

Another approach might be for the sponsor to assume no effect boundaries of 80-125 percent for 

Cmax and AUC without further justification, recognizing that the small sample sizes in pregnancy 

studies coupled with high intersubject variability can preclude meeting the 80-125 percent no 

effect boundaries. 

For some drugs, pregnancy may not alter PK sufficiently to warrant dosage adjustment. A 

sponsor might make this claim by providing an analysis of the study data to show that the PK 

measurements most relevant to therapeutic outcome in pregnant patients are similar or equivalent 

to those in the comparator group.

VII. LABELING 

The Agency recommends that labeling reflect the data from PK/PD studies in pregnancy and, if 

known, dosing recommendations during pregnancy. The labeling would reflect the data 

pertaining to the effect of pregnancy on the PK and PD obtained from studies conducted. If no 

studies were conducted, the Agency recommends that the labeling indicate that the impact of 

pregnancy was not studied. If the PK/PD is altered during pregnancy, the appropriate description 

of such and recommendations for dosing should be stated in labeling. 

The various permutations of intrinsic drug characteristics and the effect of pregnancy on drug 

performance preclude precise specification of how such drugs would be labeled. The following 

comments offer general suggestions on labeling. 

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1. Pharmacokinetics Subsection 

It is recommended that this section include information pertinent to pregnancy such as: 

• Disposition of parent drug and metabolites, if applicable 

• Effects of pregnancy on protein binding of parent drug and metabolites, if applicable 

• Effects of changes in urinary pH or other special situations (e.g., tubular secretion 

inhibited by probenecid) 

2. Special Populations Subsection 

It is recommended that this section recapitulate, in brief, the PK changes found in pregnancy and, 

if needed, dosing adjustments for pregnant patients. This information should be based on the 

studies performed as described in this guidance. Reference should be made to the 

PRECAUTIONS/PREGNANCY and the DOSAGE AND ADMINISTRATION sections. The 

following text provides examples of possible wording for these sections. 

The simplest situation involves drugs for which pregnancy has little or no effect on PK: 

The disposition of [Drug X] was studied in [number of] pregnant patients [in y trimester 

or from a through b weeks gestation]. Pregnancy has little or no influence on

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pharmacokinetics and no dosing adjustment is needed.

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This should be followed by a brief summary of the PK/PD data (e.g., mean, range). 

Similarly, for drugs whose PK is influenced by pregnancy, the statement similar to the following 

can be modified as appropriate and in accordance with what is known about the drug (e.g., active 

or toxic metabolite) and from the studies performed in accordance with this guidance: 

The disposition of [Drug X] was studied in [number of] pregnant patients [in y trimester 

or from a through b weeks gestation]. Elimination of the drug (and metabolite, if 

applicable) is significantly changed during pregnancy. Total body clearance of 

(unbound, if applicable)

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[Drug X]/metabolite was reduced/increased in pregnant patients 

compared to [healthy postpartum women, the same women prior to pregnancy or c weeks 

postpartum]. The terminal half-life of

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[Drug X]/metabolite is [prolonged/decreased] by 

Y-, and Z- fold in second and third trimesters, respectively. Protein binding of

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[Drug

X]/metabolite [is/is not] affected by pregnancy. The [drug/metabolite accumulates/does 

not accumulate] in pregnant patients on chronic administration resulting in 

increased/decreased plasma levels of drug/metabolite. The pharmacologic response 

[is/is not] affected by pregnancy. The dosage/dosing interval should be 

[decreased/increased] in pregnant patients receiving

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[Drug X] (see DOSAGE AND 

ADMINISTRATION).

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In addition to standard labeling for use in pregnancy, including Pregnancy Category, a brief 

statement regarding PK/PD in pregnancy would be included in the 

PRECAUTIONS/PREGNANCY section with cross reference to DOSAGE AND 

ADMINISTRATION and CLINICAL PHARMACOLOGY sections. If PK studies in pregnancy 

were not conducted, the Agency recommends that the labeling indicate that. 

C. Dosage and Administration 

As appropriate, the following information could be included: 

 

• A statement describing the relationship between the drug’s clearance and pregnancy 

• A statement describing how the dose would be adjusted during pregnancy, for example: 

518 The dose of [Drug X] should be [increased/decreased by _____%] during pregnancy.

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• A statement describing how the dose would be adjusted in the postpartum time period in 

nonlactating women, specifying the time period studied (e.g., 2 weeks postpartum)

• The dosing adjustment regimen can alternatively be represented in tabular format, for 

example: 

Group Dosage (mg) Frequency

1st trimester x Every y hours 

2nd trimester

3rd trimester

Postpartum 

(specify time) 

Standard adult dose 

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• If no dose adjustment is necessary the following statement is suggested: 

The influence of pregnancy on [Drug X] pharmacokinetics is sufficiently small that no 

dosing adjustment is needed.

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REFERENCES 

Bonati, M, R Bortulus, F Marchetti, M Romero, and G Tognoni, 1990, Drug Use in Pregnancy: 

An Overview of Epidemiological (Drug Utilization) Studies, Eur J Clin Pharmacol,

38:325-8. 

De Vigan, C, HEK De Walle, S Cordier et al., 1999, Therapeutic Drug Use During Pregnancy: 

A Comparison in Four European Countries, J Clin Epidemiol, 52(10):977-82. 

Faden, R, 2000, Ethics of Studying Pregnant Women, FDA/NICHD Conference: Clinical 

Pharmacology During Pregnancy: Addressing Clinical Needs Through Science, Internet: 

http://www.fda.gov/cder/present/clinpharm2000/1205preg.txt. 

Lacroix, I, C Damase-Michel, M Lapeyre-Mestre, and JL Montastruc, 2000, Prescription of 

Drugs During Pregnancy in France, Lancet, 356:1735-6. 

Little, BB, 1999, Pharmacokinetics During Pregnancy: Evidence-Based Maternal Dose 

Formulation, Obstet Gynecol, 93:858-68. 

Mitchell, AA, S Hernández-Díaz, C Louik, and MM Werler, 2001, Medication Use in Pregnancy, 

Pharmacoepidemiology and Drug Safety,10:S146.

Prevost, RR, SA Akl, WD Whybrew, and B Sibai, 1992, Oral Nifedipine Pharmacokinetics in 

Pregnancy-induced Hypertension, Pharmacother, 12:174-177. 

Reynolds, F, 1991, Pharmacokinetics, In: Hytten, F and G Chamberlain (editors), Clinical 

Physiology in Obstetrics, Boston, MA: Blackwell Scientific Publications, 224-240. 

Stika, CE, 2000, Industry Experience: Design and Conduct of a Pregnancy PK Study, 

FDA/NICHD Conference: Clinical Pharmacology During Pregnancy: Addressing 

Clinical Needs Through Science, Internet: 

http://www.fda.gov/cder/present/clinpharm2000/Stika/index.htm. 

Stika, CE and MC Frederiksen, 2001, Drug Therapy in Pregnant and Nursing Women, In: 

Atkinson, AJ Jr., CE Daniels, RL Dedrick et al. (editors), Principles of Clinical 

Pharmacology, New York: Academic Press, 277-291. 

Wadelius, M, E Darj, G Frenne, and A Rane, 1997, Induction of CYP2D6 in Pregnancy, Clin 

Pharmacol Ther, 62:400-7.