Modeling drug passage into human milk

Anderson, Philip O.; Sauberan, Jason

doi:10.1002/cpt.377

Cited by 95 publications

(119 citation statements)

References 71 publications

(135 reference statements)

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“…Drugs in the interstitial compartment get in contact with mammary gland epithelia. There are multiple mechanisms of drug secretion into milk, which include, but are not limited to, passive and facilitated diffusion and active transport . Clinical observations of drug concentrations in milk and maternal plasma indicate that a combined model of diffusion and active transport, particularly breast cancer–resistant protein (BCRP)‐mediated efflux into milk, may explain the milk disposition patterns of many drugs …”

Section: Mechanism Of Drug Transfer Into Milkmentioning

confidence: 99%

“…Milk intake of an infant is usually assumed to be 150 mL/(kg·day) (∼0.1 mL/[kg·min]) . Therefore,

RID (%) = EI (%) = MP ratio \times 10 / CL

where EI is exposure index, and a unit of CL is mL/(kg·min).…”

Section: Mechanism Of Drug Transfer Into Milkmentioning

confidence: 99%

“…There are multiple mechanisms of drug secretion into milk, which include, but are not limited to, passive and facilitated diffusion and active transport. 25 Clinical observations of drug concentrations in milk and maternal plasma indicate that a combined model of diffusion and active transport, particularly breast cancer-resistant protein (BCRP)-mediated efflux into milk, may explain the milk disposition patterns of many drugs. 26,27 BCRP is highly expressed in tissues with a barrier function, including vascular endothelial cells in the brain (ie, blood-brain barrier), placental syncitiotrophoblast, and intestinal epithelia, as an efflux transporter reducing exposures of brain, fetus, and host organs to drugs and toxins.…”

Section: Mechanism Of Drug Transfer Into Milkmentioning

confidence: 99%

“…The MP ratio is defined as a ratio of the area under the concentration-time curve (AUC, or average concentrations) between milk and maternal plasma. 25 Because of the difficulty in obtaining AUC data, the MP ratio is often estimated from a single data point as a surrogate, which may or may not reflect AUC-based MP ratio values because concentration-time profiles may be different between milk and maternal plasma. Although MP ratio is a concept easy to understand, it is sometimes overinterpreted as a sole determinant of the infant drug exposure level.…”

Section: Parameters Of Drug Transfer Into Breast Milkmentioning

confidence: 99%

“…Milk intake of an infant is usually assumed to be 150 mL/(kg·day) (ß0.1 mL/[kg·min]). 25,33 Therefore,…”

Section: Pharmacokinetic Principlesmentioning

confidence: 99%

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Opioids in Breast Milk: Pharmacokinetic Principles and Clinical Implications

Itô

2018

The Journal of Clinical Pharma

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Safety of maternal drug therapy during breastfeeding may be assessed from estimated levels of drug exposure of the infant through milk. Pharmacokinetic (PK) principles predict that the lower the clearance is, the higher the infant dose via milk will be. Drugs with low clearance (<1 mL/[kg·min]) are likely to cause an infant exposure level greater than 10% of the weight‐adjusted maternal dose even if the milk‐to‐plasma concentration ratio is 1. Most drugs cause relatively low‐level exposure below 10% of the weight‐adjusted maternal dose, but opioids require caution because of their potential for severe adverse effects. Furthermore, substantial individual variations of drug clearance exist in both mother and infant, potentially causing drug accumulation over time in some infants even if an estimated dose of the drug through milk is small. Such PK differences among individuals are known not only for codeine and tramadol through pharmacogenetic variants of CYP2D6 but also for non‐CYP2D6 substrate opioids including oxycodone, indicating difficulties of eliminating PK uncertainty by simply replacing an opioid with another. Overall, opioid use for pain management during labor and delivery and subsequent short‐term use for 2‐3 days are compatible with breastfeeding. In contrast, newly initiated and prolonged maternal opioid therapy must follow a close monitoring program of the opioid‐naive infants. Until more safety data become available, treatment duration of newly initiated opioids in the postpartum period should be limited to 2‐3 days in unsupervised outpatient settings. Opioid addiction treatment with methadone and buprenorphine during pregnancy may continue into breastfeeding, but infant conditions must be monitored.

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Section: Mechanism Of Drug Transfer Into Milkmentioning

confidence: 99%

“…Milk intake of an infant is usually assumed to be 150 mL/(kg·day) (∼0.1 mL/[kg·min]) . Therefore,

RID (%) = EI (%) = MP ratio \times 10 / CL

where EI is exposure index, and a unit of CL is mL/(kg·min).…”

Section: Mechanism Of Drug Transfer Into Milkmentioning

confidence: 99%

Section: Mechanism Of Drug Transfer Into Milkmentioning

confidence: 99%

Section: Parameters Of Drug Transfer Into Breast Milkmentioning

confidence: 99%

“…Milk intake of an infant is usually assumed to be 150 mL/(kg·day) (ß0.1 mL/[kg·min]). 25,33 Therefore,…”

Section: Pharmacokinetic Principlesmentioning

confidence: 99%

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Opioids in Breast Milk: Pharmacokinetic Principles and Clinical Implications

Itô

2018

The Journal of Clinical Pharma

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Antiepileptic Drug Exposure in Infants of Breastfeeding Mothers With Epilepsy

et al. 2020

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There is limited information on infant drug exposure via breastfeeding by mothers who are receiving antiepileptic drug therapy.OBJECTIVE To provide direct, objective information on antiepileptic drug exposure through breast milk.DESIGN, SETTING, AND PARTICIPANTS This prospective cohort study was conducted between December 2012 to October 2016, with follow-up in children until 6 years of age at 20 sites across the United States. Data were collected via an observational multicenter investigation (Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs [MONEAD]) of outcomes in pregnant mothers with epilepsy and their children. Pregnant women with epilepsy who were aged 14 to 45 years, had pregnancies that had progressed to less than 20 weeks' gestational age, and had measured IQ scores of more than 70 points were enrolled and followed up through pregnancy and 9 postpartum months. Their infants were enrolled at birth. Data were analyzed from May 2014 to August 2019.EXPOSURES Antiepileptic drug exposure in infants who were breastfed. MAIN OUTCOMES AND MEASURESThe percentage of infant-to-mother concentration of antiepileptic drugs. Antiepileptic drug concentrations were quantified from blood samples collected from infants and mothers at the same visit, 5 to 20 weeks after birth. Concentrations of antiepileptic drugs in infants at less than the lower limit of quantification were assessed as half of the lower limit. Additional measures collected were the total duration of all daily breastfeeding sessions and/or the volume of pumped breast milk ingested from a bottle.RESULTS A total of 351 women (of 865 screened and 503 eligible individuals) were enrolled, along with their 345 infants (179 female children [51.9%]; median [range] age, 13 [5-20] weeks). Of the 345 infants, 222 (64.3%) were breastfed; the data collection yielded 164 matching infant-mother concentration pairs from 138 infants. Approximately 49% of all antiepileptic drug concentrations in nursing infants were less than the lower limit of quantification. The median percentage of infant-to-mother concentration for all 7 antiepileptic drugs and 1 metabolite (carbamazepine, carbamazepine-10,11-epoxide, levetiracetam, lamotrigine, oxcarbazepine, topiramate, valproate, and zonisamide) ranged from 0.3% (range, 0.2%-0.9%) to 44.2% (range, 35.2%-125.3%). In multiple linear regression models, maternal concentration was a significant factor associated with lamotrigine concentration in infants (Pearson correlation coefficient, 0.58; P < .001) but not levetiracetam concentration in infants.CONCLUSIONS AND RELEVANCE Overall, antiepileptic drug concentrations in blood samples of infants who were breastfed were substantially lower than maternal blood concentrations. Given the well-known benefits of breastfeeding and the prior studies demonstrating no ill effects when the mother was receiving antiepileptic drugs, these findings support the breastfeeding of infants by mothers with epilepsy who are taking antiepileptic drug therapy.

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Pharmacokinetics of Drugs in Pregnancy and Lactation

Steinberg

2019

Cardiac Problems in Pregnancy, 4th Edition

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Modeling drug passage into human milk

Cited by 95 publications

References 71 publications

Opioids in Breast Milk: Pharmacokinetic Principles and Clinical Implications

Opioids in Breast Milk: Pharmacokinetic Principles and Clinical Implications

Antiepileptic Drug Exposure in Infants of Breastfeeding Mothers With Epilepsy

Pharmacokinetics of Drugs in Pregnancy and Lactation

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