Pharmacokinetics of Sertraline Across Pregnancy and Postpartum

Transcription

Original Contribution
Pharmacokinetics of Sertraline Across
Pregnancy and Postpartum
Marlene P. Freeman, MD,*y Paul E. Nolan Jr, PharmD,z Melinda F. Davis, PhD,x
Marietta Anthony, PhD,k Karen Fried, BA,z Martha Fankhauser, MS Pharm,z
Raymond L. Woosley, MD ,PhD,k and Francisco Moreno, MDy
Abstract: Insufficient data inform dosing of antidepressants and
clinical monitoring for Major Depressive Disorder (MDD) during
the perinatal period. The objectives were to assess the pharmacokinetics of sertraline (SER) across pregnancy and postpartum. Participants treated with SER for MDD underwent serial sampling to
measure steady-state concentrations of SER and norsertraline during
the second and third trimesters and postpartum (total of 3 assessments). Blood was drawn before observed SER administration and
0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours after administration. A sensitive high-performance liquid chromatography/mass spectrometric
method for simultaneous determination of serum concentrations of
SER and norsertraline was developed and validated. For each sampling period for SER, area under the serum concentration versus
time curve, maximal serum concentration (Cmax), and the time at
which Cmax occurred (Tmax) were determined. Of 11 women initially
enrolled, 6 completed second- and third-trimester assessments, and 3
completed all 3 assessments (including the postpartum assessment).
Mean changes on all pharmacokinetic parameters were nonsignificant between assessments, although there was a marked heterogeneity among individuals. Results were not significantly altered by
incorporation of body weights into the analyses. The range of
pharmacokinetic changes between individuals was broad, indicating
heterogeneity regarding the impact of pregnancy on SER metabolism. Overall, lowest observed SER area under the curve and Cmax
occurred in the third trimester (observed in 5 of 6 participants).
Despite nonsignificant mean pharmacokinetic changes, the range of
pharmacokinetic changes across pregnancy warrants careful monitoring of depressive symptoms in women with MDD in late
pregnancy and further study.
*Departments of Psychiatry and Obstetrics and Gynecology, Women’s
Mental Health Center, University of Texas Southwestern Medical Center
at Dallas, Dallas, TX; and yDepartment of Psychiatry, University of
Arizona College of Medicine; zDepartment of Pharmacy Practice and
Science, University of Arizona College of Pharmacy; xDepartment of
Pediatrics, University of Arizona College of Medicine; and kThe Critical
Path Institute, Tucson, AZ.
Received January 26, 2008; accepted after revision August 25, 2008.
This study was funded by the US Food and Drug Administration Office of
Women’s Health 223-03-8723, task order no. 1, and the National Institute
of Mental Health K23 MH66265 (for the principal investigator’s time).
Address correspondence and reprint requests to Marlene P. Freeman, MD,
Department of Psychiatry, Massachusetts General Hospital, Simches
Research Building, Floor 2, 185 Cambridge St, Boston, MA 02114,
617-724-8020. E-mail: [email protected].
Copyright * 2008 by Lippincott Williams & Wilkins
ISSN: 0271-0749/08/2806-0646
DOI: 10.1097/JCP.0b013e31818d2048
646
(J Clin Psychopharmacol 2008;28:646–653)
M
ajor depressive disorder (MDD) is common during
pregnancy and postpartum, and antidepressants are
often used during these periods.1–4 The assessment of the
risks and benefits of antidepressants during pregnancy are
complicated, and a growing body of literature supports the
need to carefully consider both the risks of untreated MDD
and antidepressant medication exposure.5–7 Once a decision
is made to commence or continue an antidepressant during
pregnancy, there is a paucity of data to inform appropriate
dosing and clinical monitoring. Factors that may impact
pharmacokinetics during pregnancy include increased plasma
volume, total body water, and extracellular fluid space; decreased concentration of plasma albumin; increased regional
blood flow changes; changes in hepatic metabolism of some
drugs; and gastrointestinal changes.8,9 Some medications are
well known to require monitoring and frequent dose adjustments to maintain therapeutic benefit during pregnancy. For
example, pregnant women treated with lithium or lamotrigine
may require increased doses late in pregnancy to maintain
therapeutic drug blood levels and clinical benefits.10 It is unclear what dose changes or monitoring, if any, are required
with antidepressants.
A limited amount of data have been published in the
area of antidepressant dosing requirements throughout pregnancy. Most studies suggest a possible need for higher dosing
in late pregnancy, although the studies have generally been
limited by small numbers of subjects and single blood draws
after the subject has taken the antidepressant. In 1 study by
Wisner et al,11 pregnant women (N = 8) with histories of
good response to tricyclic antidepressants were followed up,
and doses were adjusted based on clinical need. Serum samples were collected 12 to 18 hours after drug administration
after the dose was stable for at least 1 week. The investigators
observed that dosing requirements during the third trimester
ranged from 1.3 to 2 times the dose that the patients required
when they were not pregnant. Serum levels substantiated that
higher dosing in late pregnancy was required to maintain
therapeutic levels. Dose requirements escalated in the third
trimester from earlier in pregnancy. Similarly, Altshuler and
Hendrick12 reported 2 cases in which tricyclic antidepressant
blood levels were lower in the second half of pregnancy and
Journal of Clinical Psychopharmacology Volume 28, Number 6, December 2008
Copyright @ 2008 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
correlated with increased need for higher doses clinically for
the treatment of MDD. Klier et al13 reported a case (N = 1) in
which values of venlafaxine and quetiapine area under the
curve (AUC) were reduced in a pregnant patient as compared
with her AUC values postpartum.
In the case of selective serotonin reuptake inhibitor
(SSRI) use in pregnancy, a limited amount of data suggests that
escalating doses may be required to maintain efficacy as the
pregnancy progresses.14 In 1 study, fluoxetine (in typically
prescribed dosage ranges) was demonstrated to result in relatively low serum levels during pregnancy, likely because
of a more rapid metabolism of the drug.15 The rate of metabolism of fluoxetine to norfluoxetine, its major metabolite,
was 2.4-fold higher in late pregnancy than at 2 months postpartum. Sit et al16 assessed pharmacokinetics and dosing requirements across pregnancy and during the postpartum in 3
women who were treated with citalopram, 2 treated with
escitalopram, and 6 treated with sertraline (SER). Blood samples were collected 8 to 15 hours postdose. The investigators
found that dose requirements were higher in late pregnancy
as compared with earlier in gestation and postpartum.
We sought to determine the pharmacokinetics of SER
across pregnancy with a rigorous approach using serial blood
levels after observed dosage administration in the second
trimester, third trimester, and postpartum. In this study, we
elected to monitor women who were receiving treatment with
SER, which was selected based on wide utilization, data demonstrating low levels of exposure via breast milk to breastfed infants, and lack of adverse events in breast-feeding
infants.17–21 Maternal SER use was previously observed to
produce the lowest ratios of cord blood concentrations to
maternal serum relative to other SSRIs.22 At the time the
protocol was developed, SER (brand Zoloft) was the most
prescribed antidepressant in the United States.
METHODS
Subjects
We used a longitudinal design, allowing for women to
serve as their own controls during the postpartum year, as
recommended by the US Food and Drug Administration (FDA)
for pharmacokinetic studies in pregnant women. (Guidance for
Industry Pharmacokinetics in Pregnancy—Study Design, Data
Analysis, and Impact on Dosing and Labeling [2004]; 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; available at: http://www.fda.gov/cder/guidance/
5917dft.htm).
Pregnant women who were currently receiving treatment
with SER, aged 18 to 45 years, were recruited in their first or
second trimester of pregnancy. Women were eligible if they
were currently taking SER (at least 2 weeks on a stable daily
dose), able to provide written informed consent, and had a history of MDD, as defined by Diagnostic and Statistical Manual
of Mental Disorders, Fourth Edition criteria, verified using the
Structured Clinical Interview for Diagnostic and Statistical
Manual of Mental Disorders, Fourth Edition (SCID).
SER Pharmacokinetics—Pregnancy/Postpartum
Exclusion criteria were as follows: current active suicidal or homicidal ideation; active substance abuse as per
history at intake; concurrent medication that would require
continuation during the 2 weeks preceding each assessment in
the General Clinical Research Center (GCRC), with the exception of thyroid hormone medications, prenatal vitamins,
and iron supplements; and Bhigh-risk[ pregnancy as defined
by the subject’s obstetrical provider, excluding uncomplicated
Badvanced maternal age.[ Referrals were made to the study by
health care providers. Initial target enrollment was 20.
Protocol
The study was approved by the institutional review
board at the University of Arizona and the Research Involving Human Subjects Committee of the US FDA. Subjects
provided written and verbal consent for participation. The
study was implemented through the Women’s Mental Health
Program, a specialty clinic within the Department of Psychiatry, and the GCRC at the University of Arizona College
of Medicine.
Participants came to the GCRC for serial blood sampling to measure SER and its major metabolite, norsertraline (NOR), at steady-state concentrations at multiple time
points after dosing (at least 14 days on a constant dose) for up
to 3 visits during the pregnancy and postpartum periods: (1)
second trimester 22 to 26 weeks’ gestation, (2) third trimester: 30 to 34 weeks’ gestation, and (3) postpartum: 12 to
52 weeks postpartum. Blood samples were obtained according to the following schedule: 0 hours (before the dose of
SER) and at 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours after
observed administration of SER. To assess the nonpregnant
state pharmacokinetics, the third GCRC visit occurred to
assess maternal SER and NOR levels between 12 and 52
weeks postpartum after the mother had ceased breast-feeding.
Postpartum women therefore served as their own controls for
the nonpregnant state to allow for comparison with results
generated during their pregnancies.
For the safety of the subjects, we obtained a complete
blood count before each GCRC visit. Contraindications for
blood draws were as follows: hemoglobin level of less than
8 g/dL; baseline heart rate greater than 120 beats/min; orthostatic symptoms; and orthostatic changes on vital signs. If
any of these were present on the day of a scheduled GCRC
visit, the visit was rescheduled to ensure patient safety.
For each GCRC visit, participants fasted for at least
2 hours before the time of observed SER administration.
Participants received their usual oral dose of SER with 200 mL
of water in the GCRC, and they were allowed to receive food
and drink beginning 2 hours after drug administration. Participants refrained from caffeine-containing beverages for at
least 4 hours after SER administration. Participants were asked
to avoid consumption of grapefruit juice at least 1 full week
before and during each GCRC visit because of possible
inhibition of the cytochrome P450 (CYP) 3A/4 isoenzymes, which can alter SER metabolism (ie, increase SER
concentrations).23
After placement of a peripheral venous catheter, the
patency of which was maintained via hourly injections of
normal saline, blood samples (approximately 8 mL each) were
* 2008 Lippincott Williams & Wilkins
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Freeman et al
TABLE 1. SER Doses, Body Weights, and Depression Status
SER Daily Dose, mg
Weight, kg
2nd Trimester
3rd Trimester
Postpartum
2nd Trimester
3rd Trimester
Postpartum
Met Criteria for MDD at Intake
Ms A
100
150
150
92.8
93.7
87.8
Yes
Ms B
50
50
50
66.2
71.7
55.9
No
Ms C
100
100
NA
94.2
99.8
n/a
No
Ms D
50
100
200
133.9
135.8
137.5
Yes
Ms E
50
50
NA
62.0
70.6
NA
No
Ms F
150
150
NA
74.6
78.0
NA
No
Ms G
Ms H
200
25
NA
NA
NA
NA
79.2
64.8
NA
NA
NA
NA
No
No
NA indicates not available.
collected into serum tubes immediately (0 hours) before the
patient’s usual daily dose of SER was administered and then at
fixed times after dosing. Blood was drawn at the following
sample times: predose (time 0) and 0.5, 1, 2, 4, 6, 8, 10, 12, and
24 hours after dosing. Serum samples were kept frozen at
j20-C until analyzed. Laboratory measures were obtained at
B0 hours[ for serum albumin and protein, as SER is highly
protein bound; liver function tests were also obtained, as SER
undergoes extensive hepatic metabolism.
A sensitive high-performance liquid chromatography
method for the simultaneous determination of serum concentrations of SER and its major metabolite NOR was developed
and validated in the Bioanalytical Core Lab of the University
of Arizona Health Science Center. The separations were
achieved on a silica column with a polar organic mobile
phase consisting of acetonitrile and methanol at a flow rate of
0.5 mL/min. The concentrations were measured using mass
spectroscopy detection. Because a suitable internal standard
was not found, none was used.
Sample preparation consisted of a simple liquid-liquid
procedure. Briefly, 200 HL of patient serum or spiked drug-
free serum for calibration standards was made alkaline by the
addition of 1 mol/L sodium hydroxide. Sertraline and NOR
were extracted into a mixture of diethyl ether–hexane, 80:20
(vol/vol), by vortex mixing. The ether extracts were evaporated to dryness before they were reconstituted into 200 HL of
0.5% acetic acid in acetonitrile (vol/vol) and transferred into
a 200-HL polypropylene autosampler vial. For analysis, an
80-HL aliquot of the reconstituted extract was introduced
onto the Agilent 1100 liquid chromatography/mass spectroscopy detection chromatographic system consisting of the
following modules: a vacuum degasser, a binary pump, an
autosampler, a thermostated column compartment, and a
mass selective detector supplied with atmospheric pressure
ionization electrospray. The detector was set in selective ion
mode for each compound of interest, 306 m/z for SER and
275 m/z for its desmethyl metabolite NOR.
Calibration curves, where y represents the peak area of
SER or NOR calibration standards in nanograms per milliliter, were generated by least squares linear regression. Both
curves were linear through their full range, 5 through 160
ng/mL for SER and 10 through 320 ng/mL for NOR, with
TABLE 2. Pharmacokinetic Parameters of SER Across the Perinatal Period: Dose Normalized
Ms A
Ms B
Ms C
Ms D
Ms E
Ms F
Ms G
Ms H
2nd Trimester
0.43
0.62
0.41
0.63
1.33
0.89
0.37
0.53
3rd Trimester
0.60
0.51
0.32
0.54
1.21
0.77
NA
NA
Postpartum
0.37
0.77
NA
1.25
NA
NA
NA
2nd Trimester
4.91
8.33
4.03
9.80
20.30
14.69
5.16
9.06
3rd Trimester
8.20
7.25
2.80
8.17
17.23
12.79
NA
NA
6.16
11.38
NA
22.98
NA
NA
NA
NA
2nd Trimester
5.88
20.50
10.98
21.76
74.96
24.81
11.23
28.80
3rd Trimester
10.73
36.55
8.10
17.01
70.85
36.38
NA
NA
6.40
36.80
NA
46.59
NA
NA
NA
NA
Cmax, ng/mL per mg
SER AUC (0–24 h), (ng/mL) h per mg
Postpartum
NOR AUC (0–24 h), (ng/mL) h per mg
Postpartum
All SER values were dose normalized.
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TABLE 3. Pharmacokinetic Parameters of SER Across the Perinatal Period (Not Dose Normalized)
Ms A
Ms B
Ms C
Ms D
Ms E
Ms F
Ms G
Ms H
SER Cmax, ng/mL
2nd Trimester
42.6
31.1
40.5
31.6
66.4
133.2
73.4
13.2
3rd Trimester
Postpartum
89.7
55.4
25.6
38.5
31.5
NA
53.7
249.8
60.6
NA
115.5
NA
NA
NA
NA
NA
SER AUC (0–24 h), (ng/mL) h
2nd Trimester
490.61
416.27
402.74
489.77
1014.80
2202.99
1032.63
226.48
3rd Trimester
1230.31
362.40
279.70
816.51
333.00
1918.89
NA
NA
923.57
569.01
NA
4596.08
NA
NA
NA
NA
Postpartum
NOR AUC (0–24 h), (ng/mL) h
2nd Trimester
588.28
1025.16
1097.79
1087.93
3747.88
3721.79
2245.22
226.48
3rd Trimester
Postpartum
1609.75
959.32
1827.57
1840.13
810.32
NA
1700.92
9318.89
3542.25
NA
5457.21
NA
NA
NA
NA
NA
correlation coefficients of r2 Q 0.99. Quality control
standards at 3 levels, low (8/16 ng/mL, SER/NOR), medium
(32/64 ng/mL, SER/NOR), and high (128/256 ng/mL, SER/
NOR), were run in replicates for interday and intraday
variability; for intraday, the percent coefficient of variation
was 7.3 or less (n = 5) for both SER and NOR, whereas the
value of percent coefficient of variation for interday
variability was 12.7 or less (n = 15) for both SER and
NOR. A standard curve and a set of quality control
standards, in triplicate, were analyzed along with each batch
of patient samples.
For each sampling period for SER, area under the serum
concentration versus time curve (AUC), maximal serum
concentration (Cmax), and the time at which Cmax occurred
(Tmax) were determined using the noncompartmental pharmacokinetic model provided by WinNonlin version 5.1
(Pharsight Corporation, Mountain View, Calif). For NOR,
AUC and the NOR/SER AUC ratios were also calculated.
Sertraline AUC, Cmax, and NOR AUC were dose normalized
(ie, values divided by the patient’s dose at the time of sampling), because of varying doses within and between subjects.
Dose normalizing was required, because dose changes made
by prescribing physicians outside the study as part of clinical
treatment were common.
At each visit, the following were completed: Structured
Interview Guide for the Hamilton Depression Rating Scale—
Seasonal Affective Disorder version, which incorporates the
well-validated and highly used 21-item Hamilton Rating
Scale for Depression as well as a set of questions designed to
assess atypical symptoms of depression; Edinburgh Postnatal
Depression Scale, a 10-item, patient-completed rating scale
of depressive symptoms that is frequently used in the obstetric population; the Zung Self-Rating Anxiety Scale; and
Clinical Global Impression Scale.24–27
Paired-samples t tests were used to compare SER AUC
between the second and third trimesters. Paired-samples
t tests were used to compare normalized and nonnormalized
results. Normalized and nonnormalized SER AUCs were
compared between the second and third trimesters using
paired-samples t tests. Nonparametric analyses were also performed in case the underlying population distributions were
not normal.
RESULTS
Subjects
Eleven patients were enrolled into the study, of which
8 completed 1 GCRC visit (the second-trimester assessment),
6 completed 2 GCRC visits (second- and third-trimester assessments), and 3 completed all 3 GCRC visits (the 2 pregnancy and
postpartum assessments). All of the participants who completed
at least 1 GCRC visit (n = 8) were white and non-Hispanic. One
Hispanic subject discontinued because of ineligibility of highrisk pregnancy, after her obstetrician determined by ultrasound
that she was carrying twins, and 1 fetus was found by ultrasound
to have hydrocephalus. The other women who did not complete
the study were all white and had normal singleton pregnancies
without medical complications.
FIGURE 1. SER AUC dose normalized.
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Freeman et al
T1
FIGURE 2. SER Cmax dose normalized.
FIGURE 4. Serum SER and NOR levels by trimester for Ms A.
Because the objective of the study was to determine
pharmacokinetic changes across pregnancy and postpartum,
and because patients served as their own controls, we focused
our results on those who completed at least 2 of the scheduled
GCRC visits (n = 6). Of the eight subjects who completed at
least 1 GCRC visit, 2 met the criteria for a major depressive
episode at enrollment. These 2 subjects were among the 3 to
complete all assessments. Three subjects who completed at
least 2 GCRC visits required dose increases from the second
trimester to the third trimester, based on the clinical judgment
of the prescriber and independent of study participation. The
women ranged in age from 23 to 36 years, with an average age
of 30.5 years (SD, 4.0 years). Seven of the 8 women were
married; the eighth was living with her boyfriend. All of
the women had at least a high school education, and 4 had
a bachelor’s degree or higher. Half of the women were employed or attending school full time. The 3 women with
children were either full-time homemakers or worked part
time. Two women met the criteria for current MDD at intake,
and they were the only women in the study who had more
than 1 child (refer to Table 1 for patient SER doses, body
weights, and MDD status at baseline [presence or absence of
current MDD]).
FIGURE 3. NOR/SER ratio.
FIGURE 5. Serum SER and NOR levels by trimester for Ms B.
650
Pharmacokinetic Results
The pharmacokinetic measures in full are shown in
Tables 2 and 3. We used dose-normalized assessment of pharmacokinetic data to account for the dose changes that occurred throughout the trial for individual participants. Dose
normalizing was required, because dose changes made by
prescribing physicians outside the study as part of clinical
treatment were common. Data are presented both with and
without normalizing for dose in Tables 2 and 3, and in the
accompanying figures.
Considerations of the Changes From the Second
to the Third Trimester
Paired-comparisons t tests were used to examine the
changes in SER and NOR AUC from second to third trimester for the 6 women who had 2 clinic visits. The non–
dose-adjusted serum concentrations were examined first.
Sertraline AUC rose from 836.20 to 911.53 [(ng/mL) h],
with an average increase of 75.34 [(ng/mL) h] (SE, 157.28).
third trimester and postpartum assessments. Dose-normalized
SER AUC increased from the third trimester to the postpartum visit by a mean of 4.4% (a statistically nonsignificant change), although only 3 participants completed the
postpartum visit. In 2 of 3 participants, the dose-corrected
SER AUC and SER Cmax increased postpartum, compared
with the third trimester, although mean changes were not
statistically significant (Figs. 1–3). Figures 4–6 represent
serum SER and NOR (not dose normalized) versus time
curves for the 3 participants who completed all pharmacokinetic assessments.
Body Weights
FIGURE 6. Serum SER and NOR levels by trimester for Ms D.
The increase was not significant (t5 = 0.48, P = 0.65).
Norsertraline AUC rose from 1878.14 to 2491.34 [(ng/mL) h], with an average increase of 613.20 [(ng/mL) h] (SE,
313.24). This did not reach significance, possibly because of
the small sample size (t5 = 1.96, P = 0.11). Two of the women
increased their dosage of SER between the second and third
trimesters; higher serum concentrations would be expected
from the increased dosages alone. To remove the effect of
dose changes, we examined dose-normalized serum concentrations. Dose-normalized SER AUC decreased from 10.34 to
9.41 [(ng/mL) h per mg], with an average difference of
0.93 [(ng/mL) h per mg] (SE, 2.19), which was not
significant (t5 = j1.05, P = 0.34). Dose-normalized
NOR AUC increased from 26.48 to 29.94 [(ng/mL) h
per mg]. The average difference was 3.45 [(ng/mL) h per
mg] (SE, 8.84), which was also not significant (t5 = 0.96,
P = 0.38).
Overall, changes from the second- to third-trimester
GCRC visits included a mean apparent increase in the oral
clearance of SER by 15.7% from the second to the third
trimester, as evidenced by decreases in SER AUC during the
third trimester. The general pattern of decreased SER AUC
(ie, increased SER oral clearance) in the third trimester was
observed in 5 of 6 women. However, in 1 case, an individual
demonstrated decreased clearance from the second to third
trimester (corresponding to increased SER AUC). As regards
the SER Cmax, a similar pattern was observed in 5 of 6
women, with SER Cmax tending to decline from the second to
third trimester. In the same individual in whom SER AUC
increased, Cmax also increased. The ratio of NOR to SER
from second to third trimester was highly variable between
individuals and across time points, likely reflecting interindividual and intraindividual differences in SER metabolism.
The AUC for NOR was also highly variable, among individuals and across trimesters.
Postpartum Data
Three subjects completed postpartum visits that occurred between 12 and 52 weeks postpartum after cessation of
breast-feeding. One patient had a dose increase between the
We measured body weights at all GCRC assessments.
Body weight increased modestly but significantly as determined by paired t tests from the second to third trimester
(P < 0.01). Pharmacokinetic analyses were repeated with the
variable of body weight added, and this addition did not
significantly alter pharmacokinetic outcomes.
Nonparametric analyses were also performed in case
the underlying population distributions were not normal.
Similar nonsignificant results were obtained. No visits needed
to be rescheduled based on laboratory or clinical indications,
such as complete blood count or abnormal vital signs. Overall, a broad range was noted, indicating heterogeneity in the
influence of pregnancy on the metabolism of SER.
DISCUSSION
This study adds to the small body of literature on antidepressant pharmacokinetics in pregnancy and postpartum
and, in conjunction with other studies, may help to develop
strategies for antidepressant dosing and clinical monitoring of
MDD during pregnancy and postpartum. We observed a
general mean decrease in SER serum levels as pregnancy
progressed that was not statistically significant, with lowest
dose-adjusted levels observed in the third trimester compared
with the second trimester and postpartum for the majority of
this small sample. Although the overall mean change in SER
AUC during the third trimester was modest, the range of
observed changes between patients was large and needs to be
considered as potentially clinically relevant for some women.
Notable heterogeneity was observed in pharmacokinetics of
SER during pregnancy and in the doses prescribed across
pregnancy. Intraindividual and interindividual differences in
dose requirements are likely impacted by course of illness,
metabolic effects of pregnancy, and genetically determined
individual differences in metabolism.28–30
Our methods were more rigorous than those of other
published studies on this topic, in terms of observed administration of study drug and serial blood level sampling, but our
results are consistent with previously published findings.
Previous studies have included usually only a single blood draw
after medication administration, and medication administration
was not reported as observed in previous protocols. Our
findings therefore provide detailed data about the pharmacokinetics of SER at precise increments of time after observed administration of the drug, allowing for a more
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Freeman et al
comprehensive picture of the pharmacokinetics, with substantiated adherence to the protocol.
Treatment guidelines for the acute and maintenance
treatment of MDD during pregnancy and postpartum are
urgently needed. Much of the focus to date has been on safety
of in utero exposure to the baby, but data are also necessary
to inform dosing of medication, efficacy of antidepressants,
and monitoring guidelines. If patients are to be treated with
antidepressant medication, it is prudent to use the lowest
possible dose to minimize risks of exposure to the baby, but
not to the extent of sacrificing optimal outcomes with regard
to maternal depression treatment.
Our results support that additional clinical monitoring
is advisable for women treated with antidepressants during
pregnancy, especially in the third trimester, as serum concentrations are likely to decrease somewhat for most women.
Although many women may not experience clinically important pharmacokinetic changes in late pregnancy, the heterogeneity of such changes we observed suggests that individual
women may indeed experience changes that necessitate careful monitoring of clinical condition and appropriate treatment
modifications.
At this time, there is a substantial need for evidencebased guidelines to inform the treatment of major depression
in women during pregnancy and postpartum. Similar to the
increased frequency of obstetric visits in late pregnancy based
on medical need, women with MDD should have mood assessments with increased frequency as pregnancy progresses.
In fact, it would be prudent and convenient to consider assessing depressive symptoms in coordination with prenatal
care visits, which generally increase in frequency during late
pregnancy, overlapping with the observed points with greatest
likelihood of diminished antidepressant serum levels.
We observed a substantial degree of heterogeneity in
pharmacokinetic data between individuals. We suspect that
genetically determined factors pertaining to drug metabolism
were involved in the observed heterogeneity. Sertraline is
extensively metabolized, and multiple CYP isozymes are involved in the metabolism of SER including the polymorphically distributed isozymes CYP2D6, CYP2C9, CYP2B6,
CYP2C19, and CYP3A4.31–34 Calculating the contribution
from specific isoforms onto the clearance of SER has proven
a complicated task. Metabolism and clearance of SER are
consistent with a high hepatic extraction. The initial pathway
involves N-demethylation to the active metabolite, NOR.
Norsertraline has a plasma elimination half-life of 62 to 104
hours. Both SER and NOR undergo oxidative deamination,
followed by reduction, hydroxylation, and glucuronide conjugation. Genetic assessments may be important in future
studies of pharmacokinetics in pregnant and postpartum
women. Pregnancy is a condition characterized by high serum
estrogen concentrations, which may affect the activity of various CYP isoforms potentially affecting clearance.35 Therefore, future studies might also explore the relationship of
estrogen and SER levels during the third trimester and the
mediating role of CYP2D6.
The foremost limitation of this study is the small sample
size. We initially intended to include 20 women, but enrolled
11. Six women completed at least 2 GCRC visits, allowing us
652
to collect serial blood samples under controlled conditions
for 2 points of comparison during pregnancy. We found
several factors contributed to difficult recruitment and retention. Over the course of the study, new information regarding potential risks of SSRIs was reported, and the US FDA
(the sponsor of this study) issued warnings about the use
of antidepressants during pregnancy, including a black-box
warning. Subsequent to the labeling change, health care providers in our community were increasingly uncomfortable
prescribing antidepressants for pregnant women. In addition,
many of the women who participated in the study found the
lengthy GCRC visits prohibitive to continuing participation,
although we were able to reimburse participants for their
time and additionally for child care if necessary. Also, our
protocol prohibited concurrent medications with few exceptions. There were interested potential participants who could
not enroll in the study because of concurrent psychotropic
medication use or high-risk pregnancies.
Other groups of investigators have experienced similar
challenges as we did in recruitment and retention of pregnant
and postpartum women. In recent treatment studies in pregnant and postpartum women with MDD, researchers in this
area have found that enrollment and retention are challenging
in this population.36,37 In a longitudinal study by Sit et al,16
single blood samples were obtained longitudinally during
pregnancy and postpartum. In their study, of 11 subjects
enrolled, the protocol required single blood draws at 7 points
(20, 30, and 36 weeks during pregnancy, at delivery, and at 2,
4, 5, 6, and 12 weeks postpartum). None of the participants
completed all of the sampling times, and 5 of 11 did not have
the final 12-week blood draw data. The study by Sit et al16
represents the largest longitudinal study to date on this topic,
and the authors found that most women using SSRIs in that
study experienced decreased mean dose plasma concentrations in late pregnancy. Similar to our findings, this was not
universally observed for all participants, and there may be
individual differences in the impact of pregnancy on the
pharmacokinetics of antidepressants.
An important limitation in the interpretation of pharmacodynamic data was the heterogeneity of course of MDD.
We did not require that participants meet the criteria for a
current major depressive episode nor be in remission at the
time of intake. Therefore, the course of the disorder between
patients and correlated with pharmacokinetic data is difficult
to compare across study visits.
Future directions of study are required to advise dosing
and monitoring of antidepressants during pregnancy and postpartum. Further study is required, and additional data are
needed to include the role of genetics, implications of polypharmacy, and the clinical implications of pharmacokinetic
changes associated with pregnancy.
AUTHOR DISCLOSURE INFORMATION
Marlene P. Freeman, MD: US FDA, research support
(for investigator-initiated trials) from GlaxoSmithKline, Lilly,
Forest; honoraria for CME development from Chatham
Institute (grant from KV Pharmaceuticals). Karen Fried, BA,
Marietta Anthony, PhD, Raymond L. Woosley, MD, PhD, report
nothing to disclose. Melinda F. Davis, PhD: research support
from National Science Foundation, WOMB Foundation
(Watching Over Mothers and Babies), CDC, McKnight Associates, consulting firm subcontracting for CDC). Martha
Fankhauser, MS Pharm: speakers’ bureau at Forest Pharmaceuticals Inc, AstraZeneca Pharmaceuticals LP. Francisco
Moreno, MD: research funding, consulting, and speaking
honoraria from Cyberonics Inc; speaker and consultant for
Bristol-Myers Squibb and Otsuka Pharmaceuticals; consultant for Forest; contract (clinical trial) with Novartis;
pending contracts for research with CORCEPT, Pfizer, and
Sepracor. Paul E. Nolan Jr, PharmD: research support from
Medical Carbon Research Institute, NovoNordisk, Medicure,
Inc, Syncardia Systems, Inc, and ThromboVision, Inc; honoraria or travel support for consulting from Syncardia
Systems, Inc, Abiomed, Inc, CV Therapeutics, and Abbott
Laboratories.
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Pharmacokinetics of Sertraline Across Pregnancy and Postpartum

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