Pharmacokinetic Study of Cefditoren Pivoxil in Breast Milk and Blood of Lactating Women.

ObjectiveTo determine the transfer of the monoclonal antibody natalizumab into breastmilk and to evaluate drug and serum neurofilament light chain ((s)NfL) levels in natalizumab exposed pregnancies and lactation periods.MethodsEleven women with relapsing remitting multiple sclerosis treated with natalizumab during pregnancy and lactation were included in this study. Breastmilk samples were collected up to 302 days after delivery and analyzed for natalizumab concentration and NfL. Additionally, maternal drug levels and sNfL were determined preconceptually, in each trimester, at delivery and postpartum. Clinical and radiological disease activity was systemically assessed across pregnancy and postpartum period.ResultsThe mean average natalizumab concentration in breast milk was low at 0.06 µg/ml [standard deviation (SD) 0.05] in the eight patients who provided serial breastmilk samples with an estimated mean absolute infant dose of 0.007 mg/kg/d (SD 0.005). The relative infant dose (RID), a metric comparing the infant with maternal drug exposure was low as well with a mean of 0.04% (SD=0.03). Most patients had a maximum concentration in breast milk at one to eight days after infusion. Pregnancy was associated with a non-significant decline of the median natalizumab serum concentration. All patients exposed to natalizumab prior (n=10) and during pregnancy (n=11) kept free of disease activity during gestation. While pregnancy was associated with low sNfL levels in patients treated with natalizumab prior and during pregnancy, the postpartum period was linked to a transient sNfL increase in some patients without any evidence of clinical or radiological disease activity. NfL was detectable in the majority of breastmilk samples with a median concentration of 1.7 pg/ml (range 0.004-18.1).ConclusionWe determined transfer of natalizumab into breastmilk with an RID far below the threshold of concern of 10%. Studies including childhood development assessment are needed in order to gain safety data about natalizumab-exposed breastfeeding. SNfL assessment might be a useful adjunct to monitor silent disease activity and therapeutic response during pregnancy and postpartum period. However, further investigations regarding transient postpartum sNfL increases are required to determine its association to parturition per se or to a silent disease activity in people with multiple sclerosis.

The risk of infant exposure to dextromethorphan (DM) and its active metabolite, dextrorphan (DX), through breast milk has not been evaluated. In this study, bound and unbound DM and DX concentrations in breast milk and plasma at 2hours post-dose were measured in 20 lactating women (n=20) following a single 30 mg oral dose of DM. The DM and DX concentrations in breast milk were positively correlated with their respective plasma concentrations. The breast milk-to-plasma (M/P) ratios of 1.0 and 1.6 and the unbound M/P ratios of 1.1 and 2.0 for DM and DX, respectively, suggested that DM and DX are extensively distributed into breast milk. The infant exposure following a single dose of 30 mg DM was estimated using breast milk concentrations of 0.33±0.32 and 1.8±1.0μg/kg/day for DM and DX, respectively. The steady-state infant exposure was estimated using the M/P ratios and previously reported area under the concentration-time curve (AUC) of DM and DX following repeated dosing of DM 60mg orally, twice daily, to be 0.64±0.22 and 1.23±0.38μg/kg/day, respectively. Based on these estimated infant doses, the relative infant doses (RIDs) were estimated to be <1%, suggesting the infant is only exposed to a minor fraction of adult dose through breast milk; however, one nursing infant developed an erythematous rash during this study, which warrants additional research to fully elucidate the risks of infant exposure to DM and DX through breast milk.

Maternal Diet and Exercise: Effects on Long-Chain Polyunsaturated Fatty Acid Concentrations in Breast Milk

More than half of women take medications during breastfeeding, predisposing their infants to medication exposure via breast milk. As a result, adverse drug reactions may emerge in the infant, although they are rarely reported. Disposition of maternal drugs in breast milk is described with several key parameters, which include relative infant dose (RID): infant drug intake via milk (weight- and time-adjusted) expressed as a percentage of the similarly adjusted mother's dose. Most drugs show RID values of <10%, indicating that drug concentrations in infant serum do not reach a level known to be therapeutic in adults unless drug clearance is markedly lower than the adult level on a weight basis. RID is a function of milk-to-(maternal) plasma drug concentration ratio (MP ratio) and maternal drug clearance. Therefore, MP ratio between drugs must be interpreted not by itself but with maternal drug clearance of each drug. This is why some drugs such as phenobarbital show an MP ratio of <1 but an RID as high as 50-70%, while morphine shows an MP ratio of 2 but an RID in the range of 5%. Using RID, we interpreted case reports of infant adverse outcomes, and we observed cases with relatively low infant serum concentrations of drug, consistent with low RID, as well as those with near- or above-adult therapeutic serum concentrations, with or without increased drug intake (i.e. high RID). It is important to consider both pharmacokinetic and pharmacodynamic factors in interpreting adverse outcomes in infants breastfed by a mother taking medications.

Many women need to use medications during breastfeeding. Very few medications have been adequately monitored, tested and labelled with safety information for this use. Prednisolone is one of these drugs. We aim to conduct a multicentre low-intervention clinical trial to determine the concentration of prednisolone in plasma of breastfed infants of lactating women treated with prednisolone. In addition, we will measure the concentration in maternal plasma and breast milk and calculate the daily infant dose (DID) and relative infant dose (RID). Infant cortisol levels will be analysed as a measure of clinical effects in the infants. The study will be conducted at departments of obstetrics and gynaecology and specialist maternity and paediatric outpatient clinics in Sweden. We aim to include 30 lactating women treated with prednisolone and their breastfed infants. Breast milk and blood will be collected merely to study the secretion of prednisolone into breast milk and transfer to the infant. Participants will be treated with prednisolone according to their physician's prescription. Study visits take place when the infant is approximately 6-8 weeks old. Milk and blood sampling of the mother will be performed at 1 hour after drug intake, in conjunction with the infant being fed. Blood sampling of the infant will be performed 2 hours after the feed. Breast milk and plasma will be biobanked for future research. Recruitment was initiated in 2024 and is ongoing. Patient representatives from the Swedish Rheumatism Association were involved in the planning of the study, and the organisation is providing information about the study on their website. The clinical trial was approved by the Swedish Medical Product Agency (Dnr. 5.1.1-2023-104170). The results will be published in peer-reviewed scientific journals and disseminated at scientific meetings and through patient organisations' websites. The clinical trial protocol is available via the Clinical Trial Information System at the European Medicines Agency (No. 2023-508913-18-00). It is also registered and publicly accessible at the EU PAS Register (EUPAS 1000000059).

Cetirizine is an antihistamine commonly used to treat allergic rhinitis and other allergic conditions. Cetirizine is often prescribed to breastfeeding mothers although there is limited information on infant exposure via breast milk. The aim of this study was to develop a popPK model based on data from a lactation study to predict cetirizine breast milk concentrations and estimate the relative infant dose (RID) in a breastfed infant. A popPK model was developed in NONMEM on data from a human lactation study including 35 women using cetirizine or levocetirizine while breastfeeding. Serial samples of breast milk were collected (n = 205) and the cetirizine concentrations quantified using a validated LC–MS/MS method. A one‐compartment model of cetirizine in breast milk was developed and employed to calculate the relative infant dose (RID). Covariates related to the maternal characteristics and breastfeeding patterns were evaluated in the model; only milk sampling pumping duration was found to be a significant covariate, with an increasing pumping duration leading to an increased apparent milk volume of distribution (Vm). The mean RID was 1.99% with the highest RID being 3.36% at Cmax. PopPK modelling could be used to estimate infant exposure to cetirizine via breast milk. The low predicted exposure in infants supports that cetirizine is compatible with breastfeeding.

Background: Belimumab is a recombinant human immunoglobulin G1 lambda monoclonal antibody that binds soluble B lymphocyte stimulator protein with high affinity and inhibits its biological activity. Belimumab is not recommended for breastfeeding women due to insufficient data about its excretion into breast milk. In this study, we measured belimumab concentrations in the breast milk of one nursing mother diagnosed with mixed connective tissue disease (MCTD) and evaluated the health of her breastfed infant. Materials and Methods: Maternal serum and breast milk belimumab concentrations were collected three times (2 weeks after the first dose, the day after the second dose, and 7 weeks after the second dose) after ethical approval and informed consent. An enzyme-linked immunosorbent assay was used to detect belimumab in serum and breast milk samples. Case Report: A 39-year-old para 4 female was diagnosed with MCTD. The serum concentrations at three times were 29.45, 76.82, and 33.95 mcg/mL. The concentrations in breast milk were 0.12, 0.17, and 0.12 mcg/mL. The milk-to-serum concentration ratios at each sampling point were 0.0041, 0.0022, and 0.0035, respectively. Her infant experienced no health problems. Routine vaccinations were administered without any adverse effects such as infection or immunoreaction. Discussion and Conclusions: Breast milk levels of belimumab ranged from 1/200 to 1/500 of those in serum, and no harmful effect occurred in her infant. This is the first study reporting belimumab concentrations in human breast milk. Further studies are needed to elucidate the impact of exposure on breastfeeding infants.

We present a case of a 27-year-old woman in whom idiopathic hypersomnolence was diagnosed in adolescence with adequate symptomatic control on daily dosage of 250 mg of modafinil. She maintained this dosage throughout her pregnancy and during the peripartum period, but did not breastfeed her newborn because of a lack of information on the transmission of modafinil in human breast milk. Samples of her breast milk were obtained at various times over a 24-hour period and analyzed using liquid chromatography mass spectrometry. The relative infant dose was calculated to be 5.3%, below the threshold of concern for drug passage via breast milk. This is the first reported case of modafinil transfer into human breast milk. Given the drug's use in a variety of sleep disorders, the results of this case can be used to advise breastfeeding mothers prescribed modafinil.

Methylprednisolone Concentrations in Breast Milk and Serum of Patients with Multiple Sclerosis Treated with IV Pulse Methylprednisolone

Atenolol lactation information is limited, and controversy exists over the safety of its use during breastfeeding. In this study, important parameters including milk-to-plasma ratio, ratio of infant plasma to maternal plasma, infant daily dosage, and relative infant dose were investigated. The findings from this study add information to existing data about atenolol transfer in human milk. This may help guide health professionals in decision making regarding the safety of beta blockers used by mothers during breastfeeding. Research aim: The aims of the study were to quantify concentrations of atenolol in human plasma and milk, to evaluate atenolol pharmacokinetics in lactating women, and to investigate subsequent infant exposure to atenolol via mother's milk. In this prospective, longitudinal observational study, participants were lactating mothers ( N = 3), 1 to 4 months postpartum, who had been taking atenolol for therapeutic reasons, and one 4-month-old breastfed infant. Eight milk samples were collected over 24 hr at different time points, together with a single blood sample from each lactating mother and the infant, and quantified using a new sensitive liquid chromatography mass spectrometry method developed for this study. Peak milk concentrations of atenolol were observed in the women at 4 hr (Tmax) after oral administration. The dose-normalized maximum concentrations (Cmax) of all patients were similar. The mean milk-to-plasma ratio of the patients who were taking 25 to 100 mg of atenolol was 8.57%. In the mother-infant pair study, the ratio (%) of infant plasma drug concentration to maternal plasma drug concentration observed (18.87%) was similar to the relative infant dose estimated (18.20%). The relative infant dose values (13.96%-18.20%) for all patients were within 10% to 25% of maternal dosage. Atenolol use during breastfeeding should be undertaken with some precaution. If clinically indicated, an alternate beta blocker may be preferred.

This study investigated the concentration of total mercury (THg) in maternal blood, cord blood, and breast milk, and its association with dietary factors. A total of 127 pregnant women in Busan, Korea were recruited. Maternal blood, cord blood, and breast milk were collected at 36 weeks of gestation, at delivery, and at one week after birth, respectively. Information about dietary habits and other factors were obtained from each subject. The mean THg concentrations in maternal blood, cord blood, and breast milk were 3.12±1.36 μg/L, 5.46±2.41 μg/L, and 0.91±2.08 μg/L, respectively. Positive correlations were found between log-transformed THg concentrations in maternal blood and cord blood (r=0.829, p<0.001), and between maternal blood and breast milk (r=0.296, p=0.001). Multiple linear regression analysis showed that the log-transformed concentration of THg in maternal blood was positively correlated with fish consumption (β=0.345, p<0.0001) and negatively correlated with bean consumption (β=-0.055, p=0.048). Fish consumption (β=0.482, p<0.0001) and maternal age (β=0.025, p=0.033) were positively associated with the concentration of THg in cord blood, while negative correlations were found for bean consumption (β=-0.134, p=0.027) and parity (β=-0.172, p=0.015). Beef consumption (β=0.031, p=0.007) was positively associated with log-transformed THg concentrations in breast milk, while negative correlations were found for bean consumption (β=-0.019, p=0.003) and maternal age (β=-0.083, p=0.004). Our study found that both the dietary and demographic factors differently affected to THg concentrations among samples of maternal blood, cord blood, and breast milk.

Zuranolone is a positive allosteric modulator of both synaptic and extrasynaptic γ-aminobutyric acid type A receptors and a neuroactive steroid approved as an oral, once-daily, 14-day treatment course for adults with postpartum depression in the United States. This study assessed zuranolone transfer into breast milk. Healthy, nonpregnant, lactating adult female participants received once-daily 30 mg zuranolone from day (D)1 through D5 in this phase 1 open-label study. The relative infant dose (RID; weight-adjusted proportion of the maternal dose in breast milk over 24 hours) for 30 mg zuranolone was assessed at D5. An RID for 50 mg zuranolone was estimated using a simulation approach across a range of infant ages and weights. Of 15 enrolled participants (mean age, 30.1 years), 14 completed the study. The mean RID for 30 mg zuranolone at D5 was 0.357%; the mean steady-state milk volume over D3 to D5 decreased from baseline by 8.3%. Overall unbound zuranolone in plasma was low (≤0.49%). Plasma concentrations peaked at D5 before decreasing in a biexponential manner. There was strong concordance between the temporal profiles of zuranolone concentrations in plasma and breast milk. The estimated mean RID for 50 mg zuranolone based on a milk intake of 200 mL/kg per day was 0.984%. All treatment-emergent adverse events reported by participants were mild, the most common being dizziness (n = 3). Zuranolone transfer into the breast milk of healthy, nonpregnant, lactating adult female participants was low; the estimated RID for 50 mg zuranolone was <1%, well below the <10% threshold generally considered compatible with breastfeeding.

ABSTRACTBackgroundDHA (22:6n–3) is essential for neurodevelopment in children, and its concentration in human breast milk is historically high in Japan. Dietary patterns in Japan might affect the fatty acid (FA) composition among lactating mothers.ObjectivesThis study aimed to characterize the composition of milk FAs and to identify any dietary and sociodemographic factors associated with the variability of DHA concentration in breast milk in the Japanese population.MethodsThis cross-sectional study was performed as part of the Japanese Human Milk Study. Milk FAs were analyzed by GC at 1–6 mo postpartum, and maternal diet was estimated using an FFQ, including 11 types and cooking methods of seafoods, and the use of DHA supplements. The association of milk DHA with maternal diet and sociodemographic factors was investigated.ResultsMilk FA concentrations were measured in 78 mothers, including 24 who routinely used DHA supplements. The DHA concentration in milk (overall median: 0.62%; IQR: 0.47%–0.78%) was higher in women who took DHA supplements than in women who had never used DHA supplements (0.74%compared with 0.55%; P = 0.011). A linear regression model showed the association of milk DHA concentration with maternal dietary intake of grilled fish (β ± SE: 0.006 ± 0.003; standardized β: 0.234; r2 = 0.232, P = 0.036) after adjustment for DHA supplementation status, maternal and infant age, maternal BMI, and infant birth weight. Other FA concentrations were consistent, whereas caproic acid (6:0), undecylic acid (11:0), pentadecylic acid (15:0), palmitoleic acid (16:1n–7), and vaccenic acid (18:1n–7) varied by DHA supplementation status.ConclusionsThe DHA concentration in human milk may be influenced by maternal grilled fish consumption and frequent DHA supplementation in lactating Japanese women. Milk DHA concentrations may reflect a dietary habit in Japanese mothers.This trial was registered at www.umin.ac.jp/ctr as UMIN000015494.

Limited information is available on breastmilk transfer and subsequent infant systemic exposure to dolutegravir (DTG), tenofovir alafenamide (TAF), and tenofovir (TFV). We evaluated concentrations of DTG, TAF, and TFV in maternal and infant plasma and breastmilk from participants of IMPAACT 2010, a clinical trial that enrolled women initiating either a DTG-containing or an efavirenz-containing antiretroviral treatment (ART) regimen in pregnancy. Time-matched postpartum maternal and infant samples were collected at 6 weeks postpartum. Validated assays quantitated concentrations of DTG, TAF, and TFV. Relative infant dose (RID) was estimated using an average milk intake of 150 mL/kg/day and observed breastmilk concentrations. Data were available from 192 postpartum lactating women and their breastfed infants. Median maternal plasma concentrations of DTG, TAF, and TFV were 2810, 0.0, and 96 ng/mL, respectively. For DTG, median (interquartile range; IQR) concentrations in breastmilk and infant plasma were 91 ng/mL (67-123) and 69 ng/mL (41-95), respectively. TAF was below the quantitative limit (BQL) in nearly all breastmilk and infant samples. For TFV, median (IQR) concentrations in breastmilk were 8 ng/mL (6-12), and nearly all infant samples were BQL. The median RIDs of DTG, TAF, and TFV from breastfeeding were 1.9%, 0.00%, and 0.03%, respectively. Breastmilk transfer of DTG, TAF, and TFV is low and results in minimal systemic exposure in breastfed infants. The clinical relevance of infant exposure to low concentrations of these antiretrovirals - particularly DTG - is unknown but should be considered in the context of the risk of drug resistance in infants who acquire HIV.

Duloxetine is an efficacious antidepressant; however, its safety during the perinatal period is uncertain. The objective of this study was to assess the transfer across the placenta and provide data on infant exposure to duloxetine via breast milk. A multiparous 31-year-old woman with recurrent melancholic depression had responded poorly to previous antidepressants, but had a full remission on duloxetine. She elected to remain on duloxetine for her third pregnancy and while breastfeeding. She gave birth to a healthy term infant and there were no adverse events noted for the infant exposed to duloxetine. Duloxetine concentration was measured chromatographically in maternal and infant serum collected at birth, and in maternal milk and plasma and infant plasma 18 days later, (C/M) concentration ratio was calculated. Absolute and relative infant doses via milk were estimated and the percent drug in infant versus mother's plasma was calculated. Cord/maternal serum concentration ratio for duloxetine was 0.12. Absolute infant dose via milk was 7.6 μg/L and relative infant dose was 0.81%. The ratio of drug in the infant's plasma to that in maternal plasma during lactation also gave a 0.82% infant exposure estimate. The low C/M ratio suggests a limited transfer across the placenta. The relative infant dose via milk was low by comparison to most other antidepressants, and this estimate confirmed the amount of drug in infant plasma during lactation. Our data suggest that duloxetine may be used in pregnancy and lactation for selected patients in whom other antidepressants have not been successful.