A population pharmacokinetic model for sertraline in women during the perinatal period-A contribution from the ConcePTION project.

AIMS: Sertraline is frequently prescribed for mental health conditions in both pregnant and breastfeeding women. According to the limited available data, only small amounts of sertraline are transferred into human milk, yet with a large amount of unexplained interindividual variability. This study aimed to develop a population pharmacokinetic (popPK) model to describe the pharmacokinetics of sertraline during the perinatal period and explain interindividual variability. METHODS: Pregnant women treated with sertraline were enrolled in the multicenter prospective cohort SSRI-Breast Milk study. A popPK model for sertraline maternal plasma and breast milk concentrations was developed and allowed estimating the milk-to-plasma ratio (MPR). An additional fetal compartment allowed cord blood concentrations to be described. Several covariates were tested for significance. Ultimately, model-based simulations allowed infant drug exposure through placenta and breast milk under various conditions to be predicted. RESULTS: Thirty-eight women treated with sertraline were included in the study and provided 89 maternal plasma, 29 cord blood and 107 breast milk samples. Sertraline clearance was reduced by 42% in CYP2C19 poor metabolizers compared to other phenotypes. Doubling milk fat content increased the MPR by 95%. Simulations suggested a median daily infant dosage of 6.9 µg kg-1 after a 50 mg maternal daily dose, representing 0.95% of the weight-adjusted maternal dose. Median cord blood concentrations could range from 3.29 to 33.23 ng mL-1 after maternal daily doses between 25 and 150 mg. CONCLUSIONS: Infant exposure to sertraline, influenced by CYP2C19 phenotype and breast milk fat content, remains low, providing reassurance regarding the use of sertraline during pregnancy and breastfeeding.

A population pharmacokinetic model for escitalopram and its major metabolite in depressive patients during the perinatal period: Prediction of infant drug exposure through breast milk.

BACKGROUND AND OBJECTIVES: Escitalopram (SCIT) is frequently prescribed to breastfeeding women. Available information on SCIT excretion into breast milk is based on heterogeneous and incomplete data. A population pharmacokinetic model that aimed to better characterize maternal and infant exposure to SCIT and its metabolite was developed. METHODS: The study population was composed of women treated by SCIT or racemic citalopram and enrolled in the multicenter prospective cohort study SSRI-Breast Milk study (ClinicalTrial.gov NCT01796132). A joint structural model was first built for SCIT and S-desmethylcitalopram (SDCIT) in plasma using NONMEM and the milk-to-plasma ratio (MPR) was estimated by adding the drug breast milk concentrations. The effect of different influential covariates was tested and the average drug exposure with variability through breastfeeding was predicted under various conditions by simulation. RESULTS: The study enrolled 33 patients treated with SCIT or racemic citalopram who provided 80 blood and 104 milk samples. Mean MPR for both parent drug and metabolite was 1.9. Increased milk fat content was significantly associated with an increased drug transfer into breast milk (+28% for SCIT and +18% for SDCIT when fat amount doubles from 3.1 to 6.2 g/100 mL). Simulations suggested that an exclusively breastfed infant would ingest daily through breast milk 3.3% of the weight-adjusted maternal SCIT dose on average. CONCLUSION: The moderate between-subject variability in milk concentration of SCIT and the limited exposure to escitalopram through breast milk observed provide reassurance for treated mothers of breastfed healthy infants.

Safety of Drugs during Pregnancy and Breastfeeding in Cystic Fibrosis Patients.

Health management of cystic fibrosis (CF) patients should be maximized during pregnancy and breastfeeding because of its significant impact on the maternal and newborn outcomes. Thus, numerous drugs will have to be continued during pregnancy and lactation. Most of the drugs representing CF treatment lines cross the placenta or are excreted into human milk. Research addressing the risks and benefits of drugs used in CF patients during pregnancy and lactation is often incomplete or challenged by limited methodology, which often leads to conflicting or inconclusive results. Yet, potential treatment benefits for CF pregnant patients most often outbalance potential risks for the unborn child.

[SSRI antidepressant use during pregnancy and the assessment of the risk-benefit ratio]. / Bon usage des antidépresseurs ISRS durant la grossesse--le défi de l'évaluation de la balance bénéfice-risque.

Studies report that between 6 and 13% of women experience symptoms of depression during pregnancy and the postpartum period. The abundant data available make selective serotonin reuptake inhibitors (SSRIs) the first line treatment in pregnancy when a pharmacological treatment is required. Risks associated with the use of SSRIs during pregnancy are limited (moderate effect size) and are often not distinguishable from those inherent to the mother's disease. Yet, several questions regarding the SSRI safety profile for the unborn child are still under debate or require additional epidemiological data. The decision of SSRI use during pregnancy needs an individual evaluation of the risk-benefit balance.

[Pharmacokinetic alterations in pregnancy and use of therapeutic drug monitoring]. / Médicaments et grossesse : modifications pharmacocinétiques et place du suivi thérapeutique pharmacologique.

Following the thalidomide tragedy, pharmacological research in pregnant women focused primarily on drug safety for the unborn child and remains only limited regarding the efficacy and safety of treatment for the mother. Significant physiological changes during pregnancy may yet affect the pharmacokinetics of drugs and thus compromise its efficacy and/or safety. Therapeutic drug monitoring (TDM) would maximize the potential effectiveness of treatments, while minimizing the potential risk of toxicity for the mother and the fetus. At present, because of the lack of concentration-response relationship studies in pregnant women, TDM can rely only on individual assessment (based on an effective concentration before pregnancy) and remains reserved only to unexpected situations such as signs of toxicity or unexplained inefficiency.

Infant exposure to Fluvoxamine through placenta and human milk: a case series - A contribution from the ConcePTION project.

Introduction: Fluvoxamine is widely used to treat depression during pregnancy and lactation. However, limited data are available on its transfer to the fetus or in human milk. This case series provides additional information on the infant exposure to fluvoxamine during pregnancy and lactation. Case presentation: Two women, aged 38 and 34 years, diagnosed with depression were treated with 50 mg fluvoxamine during pregnancy and lactation. At delivery a paired maternal and cord blood sample was collected for each woman. The first mother exclusively breastfed her child for 4 months and gave one foremilk and one hindmilk sample at 2 days and 4 weeks post-partum, whereas the second mother did not breastfeed. Results: The cord to plasma concentration ratios were 0.62 and 0.48, respectively. At 2 weeks post-partum, relative infant doses (RID) were 0.47 and 0.57% based on fluvoxamine concentrations in foremilk and hindmilk, respectively. At 4 weeks post-partum, the RIDs were 0.35 and 0.90%, respectively. The child from the first mother was born healthy and showed a normal development at the 6th, 18th and 36th month follow-ups. One of the twins from the second woman was hospitalized for hypoglycemia that was attributed to gestational diabetes and low birth weight. The second one was born healthy. Conclusion: These results suggest a minimal exposure to fluvoxamine during lactation which is in accordance with previously published data. Larger clinical and pharmacokinetic studies assessing the long-term safety of this drug during lactation and the variability of its exposure through breastmilk are warranted.

Risk-benefit balance assessment of SSRI antidepressant use during pregnancy and lactation based on best available evidence - an update.

Introduction: Depression affects 300 million individuals worldwide. While selective serotonin reuptake inhibitors (SSRI) are one of the first-line pharmacological treatments of major depression in the general population, there is still uncertainty regarding their potential benefits and risks during pregnancy. Areas covered: Outcomes requisite for a proper risk/benefit assessment of SSRI in pregnancy and lactation were considered: (a) potential risks associated with untreated depression, (b) effectiveness of different treatment options of depression, (c) potential risks associated with SSRI. Expert opinion: Despite the growing amount of literature on SSRI use during pregnancy, no new trials assessing the benefits of SSRIs on maternal depression were found. In the light of new data regarding the potential risks, depressed SSRI-treated pregnant women and their children seem at increased risk for several complications (mostly of small absolute risk). The interpretation of these findings remains quite similar to our previous review as the available methodology does not allow to disentangle the potential effect of SSRIs from those of the disease itself or/and of its unmeasured associated risk factors. Thus, in pregnant or lactating women who require a pharmacological treatment, SSRIs can still be considered as appropriate when effective as the abundant data support their relative safety.

Infant Exposure to Methylphenidate and Duloxetine During Lactation.

BACKGROUND: Duloxetine and methylphenidate are commonly prescribed for the management of depression and attention-deficit/hyperactivity disorder (ADHD), respectively. However, little information is available concerning their safety during lactation. The purpose of this case series was to provide additional information to the medical literature concerning infant exposure to methylphenidate and duloxetine through breast milk. METHOD: Bioanalytical method (liquid chromatography coupled to mass spectrometry) was developed and validated before its use to determine the concentrations of both medications in breast milk samples. CASES: Case 1: A 30-year-old woman with depression and ADHD took duloxetine 90 mg daily and methylphenidate 36 mg daily during pregnancy and breastfeeding. The newborn was found to have a congenital pulmonary airway malformation. The breastfeeding status was nonexclusive. At week 4 postpartum, the concentration found in the milk was 32.8 ng/mL of duloxetine and 7.9 ng/mL of methylphenidate (estimated relative infant dose [RID] of 0.3% and 0.2%, respectively). Case 2: A 41-year-old women with depression took duloxetine 60 mg daily during pregnancy and lactation. She gave birth to a healthy child. The breastfeeding status was nonexclusive. Cord to maternal plasma concentration ratio was 0.4. At day 6 postpartum, the concentration of duloxetine was 23.6 ng/mL in the foremilk and 14.3 ng/mL in the hindmilk (RID of 0.4% and 0.2%, respectively). At week 6 postpartum, the concentration was 25.2 ng/mL in the foremilk and 29.3 ng/mL in the hindmilk (RID of 0.4% and 0.4%, respectively). CONCLUSION: In accordance with previously published data, this case series suggests a minimal exposure to duloxetine and methylphenidate through breast milk. Thus, these drugs are likely compatible with lactation. However, large cohort studies are necessary to evaluate their long-term impact on the exposed infants.

Simultaneous determination of selective serotonin reuptake inhibitors and their main metabolites in human breast milk by liquid chromatography-electrospray mass spectrometry.

A bioanalytical method by high performance liquid chromatography coupled to electrospray mass spectrometry (HPLC-ESI-MS), adapted from a previously published method in plasma, was validated in breast milk for the simultaneous quantification of all antidepressants belonging to the class of selective serotonin reuptake inhibitors (citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline) and their major metabolites (desmethylcitalopram and norfluoxetine). Milk samples (250µl) first underwent protein precipitation followed by solid-phase extraction on a reversed phase/cation exchange sorbent. Analytes were thereafter separated on a XBridge C18 column (2.1mm×100mm; 3.5µm) using a mobile phase composed of ammonium acetate buffer (pH 8.1; 50mM) and acetonitrile in gradient mode. Detection was performed by a single quadrupole mass spectrometer running in selected ion monitoring in positive ionization mode. Method validation covered a wide concentration range of 2-500ng/ml for citalopram, desmethylcitalopram and paroxetine, 5-500ng/ml for sertraline, and 2-1000ng/ml for fluoxetine, norfluoxetine and fluvoxamine. Validation performances such as trueness (90.3-111.6%), repeatability (0.8-9.3%) and intermediate precision (0.9-9.5%) were in agreement with criteria from international guidelines and matrix effects for the analyte/internal standard ratios ranged from 92% to 110% (relative standard deviation <15%). Accuracy profiles (total error of trueness and precision) were lying within the limits of ±30% accepted in bioanalysis. Finally, the method was successfully applied to patient samples collected in a clinical pharmacokinetic study of nursing mothers taking an antidepressant treatment.

Stereoselective determination of citalopram and desmethylcitalopram in human plasma and breast milk by liquid chromatography tandem mass spectrometry.

A high performance liquid chromatography (HPLC) tandem mass spectrometry (MS/MS) method was developed for the simultaneous, stereoselective quantification of the antidepressant citalopram and its active metabolite desmethylcitalopram in human plasma and breast milk. Sample preparation was performed by a two-step approach, including generic protein precipitation with acetonitrile followed by solid phase extraction. Enantiospecific separation of analytes was achieved on a Phenomenex® Lux Cellulose-2 column (4.6mm×150mm; 5µm), using reversed phase chromatography conditions characterized by a gradient elution of ammonium acetate buffer (pH 9.0; 20mM) and acetonitrile at a flow rate of 0.6ml/min. The compounds were detected by a tandem quadrupole mass spectrometer equipped with an electrospray ionization source and operating in multiple reaction monitoring mode. The method was fully validated in both biological fluids over a large concentration range of 0.1-100ng/ml for S-(+)- and R-(-)-citalopram, and 0.3-100ng/ml for S-(+)- and R-(-)-desmethylcitalopram. Trueness (90.0-113.3% and 97.1-103.6%), repeatability (0.9-15.9% and 0.9-8.4%) and intermediate precision (1.3-17.8% and 0.9-9.6%) in plasma and breast milk, respectively, meet international guidelines for method validation. Internal standard-normalized matrix effects ranged between 99 and 101% and 98-105%, respectively. The accuracy profiles (total error of trueness and precision) were mostly within the acceptance limits for biological samples defined as ±30%. The method was successfully applied to patient samples in a clinical trial setting.

Risk-benefit balance assessment of SSRI antidepressant use during pregnancy and lactation based on best available evidence.

INTRODUCTION: Psychiatric disorders are among the leading causes of disability in Western societies. Selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed antidepressant drugs during pregnancy and the postpartum period. Over the last decade, conflicting findings regarding the safety of SSRI drugs during pregnancy and lactation have questioned whether such treatments should be used during this period. AREAS COVERED: We discuss the main criteria that should be considered in the risk/benefit assessment of SSRI treatment in pregnant and/or breastfeeding patients (i.e., risks associated with SSRI use and with untreated depression as well as therapeutic benefits of SSRI and some alternative treatment strategies). For each criterion, available evidence has been synthesized and stratified by methodological quality as well as discussed for clinical impact. EXPERT OPINION: Currently, it is impossible for most of the evaluated outcomes to distinguish between the effects related to the mother's underlying disease and those inherent to SSRI treatment. In women suffering from major depression and responding to a pharmacological treatment, introduction or continuation of an SSRI should be encouraged in order to prevent maternal complications and to preserve maternal-infant bonding. The choice of the right drug depends above all on individual patient characteristics such as prior treatment response, diagnoses and comorbid conditions.