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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft guidance.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 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
1  Guidance for Industry1 
Pharmacokinetics in Pregnancy   
2 
Study Design, Data Analysis, and  
3 
Impact on Dosing and Labeling 
4 
5   
6   
7   
8   
9  This draft guidance, when finalized, will represent the Food and Drug Administrations (FDAs) current 
10  thinking on this topic.  It does not create or confer any rights for or on any person and does not operate to 
11  bind FDA or the public.  You can use an alternative approach if the approach satisfies the requirements of 
12  the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA 
13  staff responsible for implementing this guidance.  If you cannot identify the appropriate FDA staff, call 
14  the appropriate number listed on the title page of this guidance.   
15   
16   
17   
18   
19  I.  INTRODUCTION  
20   
21  This guidance describes a basic framework for designing and conducting PK/PD studies in 
22  pregnant women.  It provides recommendations to sponsors on how to assess the influence of 
23  pregnancy on the pharmacokinetics (PK), and where appropriate, the pharmacodynamics (PD) of 
24  drugs or biologic products.2  Additionally, this guidance provides recommendations to primary 
25  investigators, clinical researchers, and clinical pharmacologists about issues to consider when 
26  designing and conducting PK studies in pregnant women. 
27   
28  The Agency recommends using this guidance in conjunction with other FDA and ICH guidances, 
29  and pharmacological and clinical literature, on the design, conduct, and interpretation of 
30  pharmacokinetic studies.  Because the conduct of studies in pregnant women requires specialized 
31  knowledge in a variety of areas, investigators designing such studies are encouraged to obtain 
32  advice from experts in fields such as obstetrics, pediatrics, pharmacology, clinical pharmacology, 
33  pharmacometrics, statistics, and other applicable disciplines.  Although this guidance provides 
34  recommendations on when PK studies in pregnant women are appropriate, it does not address 
35  ways to assess efficacy of a drug in pregnancy or how to assess whether the drug causes adverse 
36  pregnancy or neonatal outcomes. 
37   
                                                 
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.  
  1 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
38  FDAs guidance documents, including this guidance, do not establish legally enforceable 
39  responsibilities.  Instead, guidances describe the Agencys current thinking on a topic and should 
40  be viewed only as recommendations, unless specific regulatory or statutory requirements are 
41  cited.  The use of the word should in Agency guidances means that something is suggested or 
42  recommended, but not required. 
43   
44   
45  II.  BACKGROUND 
46   
47  Ideally, pharmacologic agents would not be needed during pregnancy; however, some women 
48  enter pregnancy with medical conditions that require ongoing or episodic treatment (e.g., asthma, 
49  epilepsy, hypertension).  During pregnancy, new medical problems can also develop, and old 
50  ones can be exacerbated (e.g., migraine headaches), requiring pharmacologic therapy.  Studies 
51  have shown that most pregnant women do use either prescribed or over-the-counter medications 
52  during pregnancy (Bonati 1990, De Vigan 1999, Lacroix 2000, Mitchell 2001).  Interviews of 
53  approximately 20,000 U.S. and Canadian women conducted over 25 years reported a mean of 2.3 
54  medications used during pregnancy, excluding vitamins and minerals (Mitchell 2001).  Of the 
55  women interviewed, 28 percent reported using more than four medications during pregnancy, 
56  and medication use increased with maternal age.  In addition, the mean number of medications 
57  taken, in successive 5-year intervals, progressively increased from 2.7 to 4.4, indicating secular 
58  patterns of medication use by pregnant women.  A comparison of therapeutic drug use during 
59  pregnancy in Europe showed that 64 percent of women used at least one drug during pregnancy 
60  (De Vigan 1999), while in France, pregnant women were prescribed an average of five drugs 
61  during the first trimester (Lacroix 2000).   
62   
63  Generally, the safety and efficacy of a drug are established for a particular dosage regimen or 
64  range of dosage regimens in late phase (Phase 3) clinical trials involving relatively typical 
65  representatives from the target patient population.  Pregnant women are actively excluded from 
66  these trials, and, if pregnancy does occur, the usual procedure is to discontinue treatment and 
67  drop the patient from the study.  Consequently, at the time of a drugs initial marketing, except 
68  for products developed to treat conditions specific to pregnancy (e.g., oxytocics, cervical 
69  ripening agents), there are seldom human data on the appropriate dosage and frequency of 
70  administration during pregnancy.  Even after years of marketing, data in product labels regarding 
71  PK and dose adjustments during pregnancy rarely provide more information for appropriate 
72  prescribing in pregnancy than was available at the time of initial marketing.     
73   
74  The few data to address appropriate dosage and frequency of administration in pregnancy are not 
75  usually supported by a full understanding of the alterations of the PK of the drug in pregnancy.  
76  For example, the majority of published PK studies of anti-infective drug products during 
77  pregnancy were conducted at the time of abortion or delivery (usually via cesarean section) and 
78  were done to determine the transplacental passage of drug.  In the absence of data, the usual 
79  adult dose is typically prescribed for pregnant women.  Because of the physiologic changes 
80  inherent in pregnancy, the result can be substantial under dosing, or, in some cases, excessive 
81  dosing.   
82   
  2 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
83  Extrapolation of PK data from studies performed in nonpregnant adults fails to take into account 
84  the impact of the many physiologic changes that occur during pregnancy.  Most of the 
85  physiologic changes manifest during the first trimester and peak during the second trimester of 
86  pregnancy.  Physiologic changes are not fixed throughout pregnancy but rather reflect a 
87  continuum of change as pregnancy progresses, with return to baseline at various rates in the 
88  postpartum period.  The physiologic changes have the potential to alter the PK and/or PD of 
89  drugs.  Some of these changes include: 
90   
91    Changes in total body weight and body fat composition.   
92    Delayed gastric emptying and prolonged gastrointestinal transit time.   
93    Increase in extra cellular fluid and total body water. 
94    Increased cardiac output, increased stroke volume, and elevated maternal heart rate.  
95    Decreased albumin concentration with reduced protein binding. 
96    Increased blood flow to the various organs (e.g., kidneys, uterus). 
97    Increased glomerular filtration rate. 
98    Changed hepatic enzyme activity, including phase I CYP450 metabolic pathways (e.g., 
99  increased CYP2D6 activity), xanthine oxidase, and phase II metabolic pathways (e.g., N-
100  acetyltransferase).  
101   
102  A significant amount of pharmacologic research has been conducted to improve the quality and 
103  quantity of data available for other altered physiologic states (e.g., in patients with renal and 
104  hepatic disease) and for other patient subpopulations (e.g., pediatric patients).3  The need for 
105  PK/PD studies in pregnancy is no less than for these populations, nor is the need for the 
106  development of therapeutic treatments for pregnant women. 
107   
108   
109  III.  DECIDING WHETHER TO CONDUCT A PHARMACOKINETIC STUDY IN 
110  PREGNANT WOMEN 
111   
112  Ethical issues are important when considering studying drugs in pregnant women.  Given the 
113  large number of pregnant women who need prescription medicines to maintain their health, some 
114  have argued that it is unethical not to obtain dosing information in this subpopulation (Faden 
115  2000).  Others recommend that only pregnant women who need a drug for therapeutic reasons be 
116  included in clinical studies, citing that drug studies cannot be done in normal pregnant 
117  volunteers (Stika 2001).   
118   
                                                 
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 Agencys current thinking on these issues. 
 
  3 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
119  All studies in pregnant women must conform to all applicable regulations, including human 
120  subject protection.4  The Agency recommends that all studies in pregnant women have 
121  Institutional Review Board (IRB) review and informed consent for all study participants.  
122   
123  Pregnant women may be involved in PK studies if the following conditions are met (45 CFR 
124  Subpart B 46.204):  
125   
126    Preclinical studies, including studies on pregnant animals, and clinical studies, including 
127  studies on nonpregnant women, have been conducted and provide data for assessing 
128  potential risk to pregnant women and fetuses; and 
129    The risk to the fetus is not greater than minimal and the purpose of the research is the 
130  development of important biomedical knowledge which cannot be obtained by any other 
131  means.  
132   
133  The definition of minimal risk is broad.  The fetal risk is considered minimal when the estimated 
134  risk to the fetus is no more than that from established procedures routinely used in an 
135  uncomplicated pregnancy or in a pregnancy with complications comparable to those being 
136  studied.5  Although PK studies in pregnancy can be considered in Phase 3 development programs 
137  depending on anticipated use in pregnancy and the results of reproductive toxicity studies, the 
138  FDA anticipates that most PK studies in pregnant women will occur in the postmarketing period 
139  and will be conducted using pregnant women who have already been prescribed the drug as 
140  therapy by their own physician.  An example of a minimal risk study would be one to determine 
141  PK/PD of an antihypertensive medication in pregnant women who are taking that medication to 
142  treat hypertension during pregnancy.  The decision to use the antihypertensive medication is 
143  made by the patient and her physician independent of participation in the PK/PD study. 
144   
145  Information on human pregnancy experiences and exposures will emerge during the 
146  postmarketing phase for virtually all drug products.  Sponsors are requested to explicitly address 
147  positive or negative experiences during pregnancy or lactation as one of the safety issues in the 
148  Overall Safety Evaluation section of the Periodic Safety Update Report.6  This source of 
149  information is valuable in determining whether to conduct PK studies in pregnant women.  Other 
150  important sources of information include publications concerning safety (e.g., reports that 
151  describe the use of the drug in pregnancy) or efficacy in pregnancy and information from 
152  medical specialty groups.  These types of postmarketing exposure and safety data on drug 
153  products provide the basis for determining the need for PK assessment of a drug in pregnant 
154  women.  
155   
156  This guidance recommends that PK studies be conducted in pregnant women in any of the 
157  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.  
  4 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
158    
159    The drug is known to be prescribed in or used by pregnant women, especially in the 
160  second and third trimesters. 
161    For a new drug or indication, if there is anticipated or actual use of the drug in pregnancy.   
162    Use is expected to be rare, but the consequences of uninformed dosages are great (e.g., 
163  narrow therapeutic range drugs, cancer chemotherapy).  Drugs of this type can normally 
164  be studied in pregnant patients. 
165    Pregnancy is likely to alter significantly the PK of a drug (e.g., renally excreted drug) and 
166  any of the above apply. 
167   
168  PK studies in pregnant women are not recommended if the drug is not used in pregnant women 
169  or the drug has known or highly suspect fetal risk.  
170   
171  For approved products, consider whether a study in pregnant women must be conducted under 
172  the investigational new drug (IND) regulations (21 CFR 312.2).  If there is a concern for 
173  significantly increasing the risk (or decreasing the acceptability of the risks) in a patient 
174  population (i.e., the mother or fetus), an IND would be needed (21 CFR 312.2(b)(iii)).  Also, 
175  according to the IND regulations, if a different route of administration or dosage level is used, an 
176  IND would be needed.  
177   
178   
179  IV.  STUDY DESIGN  
180   
181  Study design considerations are important when conducting a study in pregnant women to 
182  determine if the PK and/or PD are altered enough to require an adjustment from the established 
183  dosage.  Ideally, PK studies in pregnancy would be done pre-pregnancy (for baseline 
184  comparison) and during all three trimesters, especially for chronically administered drugs.  Given 
185  the constraints of a study design that enrolls women prior to pregnancy, an alternative can be to 
186  determine PK/PD in the second and third trimesters, with the baseline assessment for comparison 
187  to the pregnant state done in the postpartum period.  The Agency recommends care be taken to 
188  select the most appropriate postpartum time for PK/PD determination, if known.  Cardiovascular 
189  and renal changes do not return to the pre-pregnancy state until 3 months postpartum.  Optimally, 
190  postpartum PK/PD assessments for comparative purposes to PK/PD in pregnancy would be done 
191  when the woman is neither pregnant nor lactating.  
192   
193  The PK and/or PD study can also be nested within a larger clinical study on safety, efficacy, and 
194  outcomes of interest (e.g., Prevost et al. performed a study on the PK of nifedipine on a small 
195  subset of patients who were participating in a larger clinical study to assess treatment for 
196  pregnancy-induced hypertension (Prevost 1992)). 
197   
198  A.  Longitudinal Design 
199   
200  For drugs that are administered chronically or given for several treatment cycles during 
201  pregnancy, a longitudinal study design is most clinically meaningful.  This allows for intensive 
202  PK studies in pregnant women conducted serially so that each woman serves as her own control, 
  5 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
203  avoiding the common criticism that PK/PD studies in pregnant women are flawed because of the 
204  comparison group employed (Reynolds 1991; Little 1999).  Such a study would focus on 
205  comparing each pregnant woman enrolled at one trimester of pregnancy to the same patient at a 
206  different trimester as well as during the postpartum period.  We recommend that the rationale for 
207  which trimesters are chosen be stated clearly in the study protocol.  This longitudinal design 
208  minimizes interindividual variability across gestational ages; however, intraindividual variability 
209  would be taken into account when determining the sample size.  It is important that the analytical 
210  plan take into consideration the repeat measures characteristics of a longitudinal design. 
211   
212  Because physiologic changes are continuous throughout pregnancy, and abrupt changes do not 
213  necessarily coincide with each trimester shift, the Agency recommends that investigators 
214  consider narrowing the time of sampling from trimester to a window of time during each 
215  trimester.  For example, 4-week windows can be selected for second trimester (e.g., 24-28 
216  weeks) and third trimester assessments (e.g., 34-38 weeks).  
217   
218  The Agency recommends that each woman serve as her own control and have PK/PD 
219  determinations performed at different trimesters and in the postpartum period.  For certain drugs 
220  that are given acutely (e.g., single dose or short course of therapy) it can be difficult to 
221  implement a longitudinal design using the same subjects throughout and after pregnancy.  For 
222  example, in certain circumstances drug therapy may no longer be medically essential in the 
223  postpartum period.  In these situations, a multi-arm study can be designed to compare different 
224  pregnant subjects at different trimesters and in the postpartum period. 
225   
226  B.  Population PK Design 
227   
228  A population PK approach with nonlinear mixed effects modeling techniques can be used as an 
229  alternate way to enroll pregnant women in PK studies and minimize the number of blood draws 
230  and PD assessments.  The population PK approach can assess the impact on the PK of a drug on 
231  various covariates, such as maternal characteristics (e.g., age, gravity, parity, race, weeks or 
232  trimester of gestation), concomitant medications, and underlying medical conditions.  For 
233  example, a measure of pregnancy status such as weeks gestation can be one of the covariates, 
234  making it possible to model the relationship between gestational age of pregnancy and PK 
235  parameters such as the apparent clearance of the drug (CL/F). 
236   
237  In principle, a population PK study design and analysis might detect PK differences large enough 
238  to warrant dosage adjustment if the study has enough pregnant and nonpregnant women enrolled 
239  with sufficient representation of second and third trimesters (with a continuum of gestational 
240  ages from 13 to 40 weeks).  Typically, each patient is only sparsely sampled to obtain plasma 
241  drug concentration data and/or PD data.  Due to the intrinsic characteristics of a population PK 
242  study, the controls for this study design can differ from other study designs and can potentially 
243  include matched healthy nonpregnant female volunteers.  To ensure the ability to determine the 
244  inter-occasion variability and prevent a parallel group trial design, a cohort of study subjects 
245  would have data collected from all trimesters and the postpartum period.  Considering the 
246  number of subjects in the study and the key objective of the study, efforts can be made to reduce 
247  the number of influential covariates such as concomitant medication. 
  6 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
248   
249  Some investigators have proposed conducting a population PK study as a preliminary step and to 
250  subsequently conduct a standard intensive PK/PD study if the population PK study suggests 
251  changes between the pregnant and nonpregnant women (Stika 2000).  For further information 
252  about the population PK approach, see the Guidance for Industry Population Pharmacokinetics.7   
253   
254   
255  V.  OTHER DESIGN CONSIDERATIONS 
256   
257  A.  Study Participants 
258   
259  Study participants should be representative of a typical patient population for the drug to be 
260  studied including race, ethnicity, and trimester of pregnancy.  Factors with significant potential 
261  to affect the PK of a drug to be studied (e.g., age, weight, diet, smoking, concomitant 
262  medications, ethnicity, renal function, other medical conditions) can be considered depending on 
263  the pharmacologic properties of the drug.  The FDA recommends that uniform diagnostic 
264  measures be applied to all pregnant women to ensure similarity of diagnosis for the treatment 
265  being given and to reduce disease-specific variability in PK.  The FDA recommends that 
266  measures used for dating the pregnancy be stated clearly in the study protocol and consistently 
267  applied throughout the study.  Inclusion and exclusion criteria can be tailored to the study. 
268   
269  For drugs that are metabolized by enzymes known to exhibit genetic polymorphism (e.g., 
270  CYP2D6 or CYP2C19), the FDA recommends that the investigator consider the metabolic status 
271  of the enrolled subjects when analyzing the results of the study.  Genotype has been shown to 
272  have an effect on pregnancy-related changes in metabolism (Wadelius 1997).  
273   
274  B.  Postpartum Assessments 
275   
276  Physiology changes rapidly at delivery but can take from weeks to months to return to the pre-
277  pregnancy state.  The Agency recommends that drugs used only during the peripartum period 
278  (e.g., labor and delivery) be studied only at that time.  In the peripartum period, PK and receptor 
279  sensitivity related to PD can change, so PK/PD studies for drugs used in the peripartum period 
280  are important. 
281   
282  A womans own postpartum PK/PD assessments can serve as a control or comparator for the 
283  pregnant state.  For women to whom drugs are administered chronically and for whom a 
284  pregnancy on the medication of interest is planned, the pre-pregnancy PK/PD assessment can 
285  serve as the comparison.  For drugs used throughout pregnancy and the postpartum period, PK 
286  studies can be performed during the postpartum period to serve as the comparator or control 
287  group.  Postpartum assessments can potentially be done longitudinally (e.g., at 2, 4, 6, and 8 
288  weeks postpartum) to determine the time course for PK changes to return to the nonpregnant 
289  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. 
  7 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
290  pharmacologic therapy is no longer needed in the postpartum period (e.g., some cases of 
291  pregnancy-induced hypertension or gestational diabetes).  In this scenario women can participate 
292  in a single-dose PK/PD study in the postpartum period.  If a drug possesses linear kinetics, the 
293  single-dose PK data can be extrapolated to the multiple-dose steady state kinetics and then 
294  compared with steady state kinetics obtained during pregnancy when the drug was administered 
295  chronically. 
296   
297  If subjects are breast-feeding during the postpartum portion of the study, the FDA recommends 
298  that the study incorporate appropriate safety precautions concerning drug excretion into breast 
299  milk and the effects of the drug on the breast-fed infant.  The study design should take into 
300  account data concerning the pediatric pharmacology and adverse effects of the drug.  A lactation 
301  study might be performed in conjunction with postpartum sampling.  
302   
303  C.  Sample Size 
304   
305  The objective and design of a study are determining factors in deciding adequate sample size.  
306  The number of subjects enrolled in a study should be sufficient to detect PK differences large 
307  enough to warrant dosage adjustments.  Sample size considerations include PK and PD 
308  variability for the drug being studied, the study design (i.e., single-dose versus multiple-dose), 
309  and the physiologic changes inherent in pregnancy.  For a population PK approach,8 sparse 
310  sampling with a larger number of subjects that span the gestational time periods of interest is 
311  encouraged. 
312   
313  As a practical matter, it is prudent that the final number of subjects enrolled be in excess of that 
314  originally determined by standard sample size calculations to take into account withdrawal of 
315  subjects from the study.  Even if data for a subject are missing for one trimester, the Agency 
316  suggests that the subject be retained in the study for the postpartum assessments.   
317   
318  D.  Drug Administration 
319   
320  In single-dose studies, the same dose can usually be administered to all women in the study.  
321  Lower or less frequent doses can be considered to minimize fetal risk in pregnant women who 
322  volunteer to take the medication for study purposes, even if it is expected to pose minimal risk at 
323  standard doses.  The dosage regimen can be adjusted based on the best available pre-study 
324  estimates of the PK of the drug and its active metabolites and what is known about drug 
325  elimination.  A concentration-controlled study design or a dosage adjustment based on the 
326  patients response are alternative methods to consider.  For example, the study might be 
327  conducted to achieve a specific target concentration using therapeutic drug monitoring 
328  procedures.  When studying pregnant patients who need the study drug, the dose can be 
329  modified, either increased or decreased as pregnancy progresses, to achieve the appropriate 
330  response (e.g., lowering of blood pressure, or to decrease adverse events such as hypotensive 
331  episodes with antihypertensive therapy). 
                                                 
8 Guidance for Industry Population Pharmacokinetics, http://www.fda.gov/cder/guidance/1852fnl.pdf, issued 
February 1999.  
 
  8 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
332   
333  E.  Sample Collection and Analysis 
334   
335  The Agency recommends that plasma or whole blood samples and urine samples be analyzed for 
336  the parent drug and any metabolites with known or suspected activity, therapeutic or adverse.  It 
337  is recommended that the frequency and duration of plasma sampling and urine collection be 
338  sufficient to estimate accurately the relevant PK parameters for the parent drug and its active 
339  metabolites (see Section VI, Data Analysis). 
340   
341  Plasma protein binding, like renal function, is often altered in pregnancy.9  For example, albumin 
342  and alpha-1-acid glycoprotein levels are reduced in pregnancy, consequently the protein binding 
343  of drugs can be affected.  With systemically active drugs and metabolites, the unbound 
344  concentrations are generally believed to determine the rate and extent of delivery to the sites of 
345  action.  For drugs and metabolites with a relatively low extent of plasma protein binding (e.g., 
346  the extent of binding is less than 80 percent), alterations in binding due to pregnancy are small in 
347  relative terms.  In such cases, description and analysis of the PK in terms of total concentrations 
348  would be sufficient.  For drugs where the extent of protein binding is greater than 80 percent, 
349  primarily to albumin, it is recommended that the PK be described and analyzed with respect to 
350  the unbound concentrations of the drug and active metabolites.  Although unbound 
351  concentrations should be measured in each plasma sample, if the binding is concentration-
352  independent and unaffected by metabolites or other time-varying factors, the fraction unbound 
353  can be determined using a limited number of samples or even a single sample from each patient 
354  during each trimester.  The unbound concentration in each sample should then be estimated by 
355  multiplying the total concentration by the fraction unbound for the individual patient.  
356   
357  F.  Studies with No Intended Therapeutic Benefit 
358   
359  It is possible to study drugs that have no intended direct therapeutic benefit to the pregnant 
360  woman provided that the risk to the fetus is minimal (45 CFR 46).  For example, probe substrates 
361  can be used to investigate drug metabolism (e.g., cytochrome P-450 activity) or drug transporter 
362  status (e.g., p-glycoprotein).  Data from these studies offer generalizable information to other 
363  pregnant women but do not offer direct therapeutic benefit to study participants.  The Agency 
364  encourages sponsors or investigators to explore additional safeguards for human subject 
365  protection for this type of study.  To minimize exposure to a nontherapeutic drug, each pregnant 
366  woman can be exposed to the drug once during pregnancy and in the postpartum period 
367  employing a nonlongitudinal design (e.g., one cohort of women sampled in second trimester and 
368  postpartum and another cohort of women sampled in third trimester and postpartum).  Examples 
369  of additional safeguards include administering only products with a long or known record of 
370  safety in pregnancy, administering products using only a single dose of the drug, using lower 
371  doses of the drug, decreasing the number of drugs (probe substrates) used in any study subject, 
372  and limiting study participants to pregnant women only in second or third trimester. 
373   
                                                 
9 Guidance for Industry Pharmacokinetics in Patients with Impaired Renal Function, 
http://www.fda.gov/cder/guidance/1449fnl.pdf, issued May 1998.   
  9 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
374  G.  Pharmacodynamic Assessments 
375   
376  PK studies are usually enhanced by including PD assessments as part of the study.  The Agency 
377  encourages sponsors to discuss the selection of the PD endpoints with the appropriate FDA 
378  review staff.  Endpoints would be based on the pharmacological characteristics of the drug and 
379  metabolites (e.g., the behavior of other drugs in the same pharmacological class), and include 
380  consideration of relevant biomarkers.10  Fetal PD endpoints can warrant study as well (e.g., fetal 
381  heart rate and rhythm response to maternal administration of an antiarrhythmic drug). 
382   
383   
384  VI.  DATA ANALYSIS 
385   
386  The primary intent of the data analysis is to assess whether dosage adjustment is needed for 
387  pregnant patients, and, if so, to develop dosing recommendations for such patients based on 
388  gestational age or trimester.  The analysis, specifically modeling and dosing recommendations, 
389  will depend on the study design characteristics.  The categorization of pregnancy status, either as 
390  nominal (e.g., trimester) or continuous (e.g., week of gestation) data will direct the type of 
391  analysis performed.  The Agency encourages giving special analytical considerations to 
392  longitudinal study designs and the baseline (e.g., postpartum) comparisons.  The data analysis 
393  typically consists of the following steps: 
394   
395    Estimation of PK parameters 
396    Development of dosing recommendations 
397   
398  A.  Parameter Estimation 
399   
400  The Agency recommends that total and unbound plasma concentration data (and urinary 
401  excretion data if collected) be used to estimate PK parameters of the parent drug and 
402  metabolite(s).  Standard PK parameters of a drug include the area under the plasma concentration 
403  curve (AUC), peak concentration (C ), plasma clearance (CL ) or apparent oral clearance 
max T
404  (CL/F), renal clearance (CL ), apparent volume of distribution (V /F or V /F), and terminal 
R Z ss
405  half-life (t ).  It is recommended that PK parameters be expressed in terms of total and unbound 
1/2
406  concentrations and when applicable (e.g., oral and renal clearance, expressed in terms of body 
407  weight, L/hr/kg).  For drugs and metabolites with a relatively low extent of plasma protein 
408  binding (e.g., extent of binding less than 80 percent), description and analysis of the PK in terms 
409  of total concentrations can be sufficient.  Noncompartmental and/or compartmental modeling 
410  approaches to parameter estimation can be employed. 
411   
412   
413   
                                                 
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. 
 
  10 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
414  B.  Development of Dosing Recommendations 
415   
416  Specific dosing recommendations should be constructed based on study results.  Typically the 
417  dose should be adjusted to produce a comparable range of unbound plasma concentrations of 
418  drug or active metabolites in both controls and pregnant patients.  Simulations are encouraged as 
419  a means to identify doses and dosing intervals that achieve that goal for pregnant patients at 
420  different trimesters or gestational ages. 
421   
422  One approach might be for the sponsor to recommend, prior to the conduct of the studies, 
423  specific no effect boundaries for the ratio of a PK measurement from pregnant patients and 
424  controls, such as (AUCu,pregnant/AUCu,control) or (Dpregnant/Dcontrol).  If the 90 percent 
425  confidence interval for the ratio of PK measurements falls within these boundaries, the sponsor 
426  might claim no effect of pregnancy on PK, and it would be reasonable to conclude that no dosage 
427  adjustment is needed for pregnancy.  The sponsor might determine no effect boundaries from 
428  population or individual PK/PD relationships, dose-finding studies and/or dose-response studies 
429  which are conducted as part of drug development. 
430   
431  Another approach might be for the sponsor to assume no effect boundaries of 80-125 percent for 
432  C  and AUC without further justification, recognizing that the small sample sizes in pregnancy 
max
433  studies coupled with high intersubject variability can preclude meeting the 80-125 percent no 
434  effect boundaries. 
435   
436  For some drugs, pregnancy may not alter PK sufficiently to warrant dosage adjustment.  A 
437  sponsor might make this claim by providing an analysis of the study data to show that the PK 
438  measurements most relevant to therapeutic outcome in pregnant patients are similar or equivalent 
439  to those in the comparator group. 
440   
441   
442  VII.  LABELING 
443   
444  The Agency recommends that labeling reflect the data from PK/PD studies in pregnancy and, if 
445  known, dosing recommendations during pregnancy.  The labeling would reflect the data 
446  pertaining to the effect of pregnancy on the PK and PD obtained from studies conducted.  If no 
447  studies were conducted, the Agency recommends that the labeling indicate that the impact of 
448  pregnancy was not studied.  If the PK/PD is altered during pregnancy, the appropriate description 
449  of such and recommendations for dosing should be stated in labeling. 
450   
451  The various permutations of intrinsic drug characteristics and the effect of pregnancy on drug 
452  performance preclude precise specification of how such drugs would be labeled.  The following 
453  comments offer general suggestions on labeling. 
454   
455   
456   
457   
  11 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
458  A.  Clinical Pharmacology 
459   
460  1.  Pharmacokinetics Subsection  
461   
462  It is recommended that this section include information pertinent to pregnancy such as: 
463   
464    Disposition of parent drug and metabolites, if applicable 
465    Effects of pregnancy on protein binding of parent drug and metabolites, if applicable 
466    Effects of changes in urinary pH or other special situations (e.g., tubular secretion 
467  inhibited by probenecid) 
468   
469  2.  Special Populations Subsection 
470   
471  It is recommended that this section recapitulate, in brief, the PK changes found in pregnancy and, 
472  if needed, dosing adjustments for pregnant patients.  This information should be based on the 
473  studies performed as described in this guidance.  Reference should be made to the 
474  PRECAUTIONS/PREGNANCY and the DOSAGE AND ADMINISTRATION sections.  The 
475  following text provides examples of possible wording for these sections. 
476   
477  The simplest situation involves drugs for which pregnancy has little or no effect on PK: 
478   
479  The disposition of [Drug X] was studied in [number of] pregnant patients [in y trimester 
480  or from a through b weeks gestation].  Pregnancy has little or no influence on [Drug X] 
481  pharmacokinetics and no dosing adjustment is needed. 
482   
483  This should be followed by a brief summary of the PK/PD data (e.g., mean, range). 
484   
485  Similarly, for drugs whose PK is influenced by pregnancy, the statement similar to the following 
486  can be modified as appropriate and in accordance with what is known about the drug (e.g., active 
487  or toxic metabolite) and from the studies performed in accordance with this guidance: 
488   
489  The disposition of [Drug X] was studied in [number of] pregnant patients [in y trimester 
490  or from a through b weeks gestation].  Elimination of the drug (and metabolite, if 
491  applicable) is significantly changed during pregnancy.  Total body clearance of 
492  (unbound, if applicable) [Drug X]/metabolite was reduced/increased in pregnant patients 
493  compared to [healthy postpartum women, the same women prior to pregnancy or c weeks 
494  postpartum].  The terminal half-life of [Drug X]/metabolite is [prolonged/decreased] by 
495  Y-, and Z- fold in second and third trimesters, respectively.  Protein binding of [Drug 
496  X]/metabolite [is/is not] affected by pregnancy.  The [drug/metabolite accumulates/does 
497  not accumulate] in pregnant patients on chronic administration resulting in 
498  increased/decreased plasma levels of drug/metabolite.  The pharmacologic response 
499  [is/is not] affected by pregnancy.  The dosage/dosing interval should be 
500  [decreased/increased] in pregnant patients receiving [Drug X] (see DOSAGE AND 
501  ADMINISTRATION). 
502   
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Draft  Not for Implementation 
 
503  B.  Precautions/Pregnancy 
504   
505  In addition to standard labeling for use in pregnancy, including Pregnancy Category, a brief 
506  statement regarding PK/PD in pregnancy would be included in the 
507  PRECAUTIONS/PREGNANCY section with cross reference to DOSAGE AND 
508  ADMINISTRATION and CLINICAL PHARMACOLOGY sections.  If PK studies in pregnancy 
509  were not conducted, the Agency recommends that the labeling indicate that. 
510   
511  C.  Dosage and Administration 
512   
513  As appropriate, the following information could be included: 
514    
515    A statement describing the relationship between the drugs clearance and pregnancy 
516    A statement describing how the dose would be adjusted during pregnancy, for example:  
517   
518  The dose of [Drug X] should be [increased/decreased by _____%] during pregnancy. 
519   
520    A statement describing how the dose would be adjusted in the postpartum time period in 
521  nonlactating women, specifying the time period studied (e.g., 2 weeks postpartum) 
522    The dosing adjustment regimen can alternatively be represented in tabular format, for 
523  example: 
524   
525   
Group  Dosage (mg)  Frequency 
1st trimester  x  Every y hours 
2nd trimester     
3rd trimester     
Postpartum      
(specify time) 
Standard adult dose     
526   
527    If no dose adjustment is necessary the following statement is suggested: 
528   
529  The influence of pregnancy on [Drug X] pharmacokinetics is sufficiently small that no 
530  dosing adjustment is needed. 
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Draft  Not for Implementation 
 
531  REFERENCES 
532   
533  Bonati, M, R Bortulus, F Marchetti, M Romero, and G Tognoni, 1990, Drug Use in Pregnancy:  
534  An Overview of Epidemiological (Drug Utilization) Studies, Eur J Clin Pharmacol, 
535  38:325-8. 
536   
537  De Vigan, C, HEK De Walle, S Cordier et al., 1999, Therapeutic Drug Use During Pregnancy:  
538  A Comparison in Four European Countries, J Clin Epidemiol, 52(10):977-82. 
539   
540  Faden, R, 2000, Ethics of Studying Pregnant Women, FDA/NICHD Conference:  Clinical 
541  Pharmacology During Pregnancy:  Addressing Clinical Needs Through Science, Internet:  
542  http://www.fda.gov/cder/present/clinpharm2000/1205preg.txt. 
543   
544  Lacroix, I, C Damase-Michel, M Lapeyre-Mestre, and JL Montastruc, 2000, Prescription of 
545  Drugs During Pregnancy in France, Lancet, 356:1735-6. 
546   
547  Little, BB, 1999, Pharmacokinetics During Pregnancy:  Evidence-Based Maternal Dose 
548  Formulation, Obstet Gynecol, 93:858-68. 
549   
550  Mitchell, AA, S Hernandez-Diaz, C Louik, and MM Werler, 2001, Medication Use in Pregnancy, 
551  Pharmacoepidemiology and Drug Safety,10:S146. 
552   
553  Prevost, RR, SA Akl, WD Whybrew, and B Sibai, 1992, Oral Nifedipine Pharmacokinetics in 
554  Pregnancy-induced Hypertension, Pharmacother, 12:174-177. 
555   
556  Reynolds, F, 1991, Pharmacokinetics, In:  Hytten, F and  G Chamberlain (editors), Clinical 
557  Physiology in Obstetrics, Boston, MA:  Blackwell Scientific Publications, 224-240. 
558   
559  Stika, CE, 2000, Industry Experience:  Design and Conduct of a Pregnancy PK Study, 
560  FDA/NICHD Conference:  Clinical Pharmacology During Pregnancy:  Addressing 
561  Clinical Needs Through Science, Internet:  
562  http://www.fda.gov/cder/present/clinpharm2000/Stika/index.htm. 
563   
564  Stika, CE and MC Frederiksen, 2001, Drug Therapy in Pregnant and Nursing Women, In:  
565  Atkinson, AJ Jr., CE Daniels, RL Dedrick et al. (editors), Principles of Clinical 
566  Pharmacology, New York:  Academic Press, 277-291. 
567   
568  Wadelius, M, E Darj, G Frenne, and A Rane, 1997, Induction of CYP2D6 in Pregnancy, Clin 
569  Pharmacol Ther, 62:400-7. 
570   
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