Modelling of the passage of drugs into milk

doi:10.1016/0163-7258(93)90072-L

Pharmacology & Therapeutics

Volume 59, Issue 3, 1993, Pages 301-310

https://doi.org/10.1016/0163-7258(93)90072-L Get rights and content

Abstract

Pharmacokinetic modelling of plasma to milk transfer of drugs has assisted our understanding of the milk to plasma ratio (M/P) and pitfalls associated with it. The most useful way of measuring M/P ratios is, however, by model independent analysis. Physiological models have been proposed to enable the prediction of M/P ratios. The most accurate in prospective performance is the log-transformed phase distribution model. This model, developed by stepwise multiple linear regression analysis, also assists in the understanding of the relative contribution of the various physiological factors involved in the distribution of drugs into milk.

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The development of an effective method for predicting the transfer of biologics from plasma into breast milk is important to ensure the safe use of medications during lactation. The aim of this study was to develop a regression model that could predict the transfer of monoclonal antibodies (mAbs) and Fc-fusion proteins from plasma into breast milk. By searching various databases, a list of eleven mAbs and Fc-fusion proteins with available information of presence in the breast milk was generated. Physicochemical properties such as the isoelectric point (pI), molecular weight (MW), dissociation constant (K_d), and pharmacokinetic (PK) parameters such as clearance (CL), volume of distribution (V_d), and half-life (T_1/2) were collected or calculated. A two-variable non-linear regression analysis and a multivariate regression analysis were employed to establish correlation of milk-to-plasma (M/P) ratios with different combinations of two physicochemical properties. The 3D isoelectric point (pI) of the Fv region and the buried surface area (BSA) between the light and heavy chains (LC_HC) were two factors that emerged as a promising predictor of the milk-to-plasma concentration ratio (M/P). The correlation between M/P ratio, 3D pI of Fv region, and BSA_LC_HC was found to be good with R² of 0.9058. Other combinations of the physicochemical properties did not show a statistically significant correlation. The multivariate regression model was used to predict the MP ratios for 79 different mAbs. We believe that this regression model could serve as a valuable tool to estimate the M/P ratios of mAbs and Fc-fusion proteins. Further model validation is necessary when the M/P ratios of additional biologics are available. This could inform clinical decision-making and improve the safety of large molecule drug use during lactation.
An in vitro human mammary epithelial cell permeability assay to assess drug secretion into breast milk
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Citation Excerpt :
Data from animal lactation studies are not very useful due to the large inter-species variability in protein and lipid contents of milk. Several in vitro mathematical models have been developed to predict drug transfer into milk, with both strengths and limitations (Fleishaker et al., 1987; Atkinson and Begg, 1988; Atkinson and Begg, 1990; Begg and Atkinson, 1993; Larsen et al., 2003; Koshimichi et al., 2011). Different physicochemical characteristics (i.e., lipophilicity, pKa, and protein binding) have been used in these models.
Determining the amount of a drug transferred into breast milk is critical for benefit-risk analysis of breastfeeding when a lactating mother takes medications. In this study, we developed a human mammary epithelial cell (MEC)-based permeability assay to assess drug permeability across the mammary epithelium. Human MEC cell MCF10F formed tight junctions when cultured on Transwells with culture medium containing insulin, hydrocortisone and epidermal growth factor (EGF). Formation of integral cell barrier and morphology of the cells were confirmed by assessing trans-epithelial electrical resistance (TEER), flux of fluorescent tracers and imaging with transmission electron microscopy (TEM). MCF10F cells showed consistent P-glycoprotein (P-gp) transporter expression when culturing on Transwell inserts versus on petri dish. A few P-gp transporter drug substrates were used to estimate the permeability from this assay. Human plasma and breast milk were used as incubation medium in basolateral and apical chambers respectively to mimic physiological conditions. The predicted milk to plasma (M/P) ratios were reasonably good. The current effort to develop the MEC-based permeability assay to facilitate M/P ratio prediction showed promising results. This assay may have a potential to be developed as a useful in vitro technique for determining the transfer of small-molecule therapeutic drugs into breast milk.
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The transfer of drugs and other xenobiotics to the infant via breast milk is a frequent cause for concern. Many women who require pharmacological therapy interrupt or stop breastfeeding, or fail to take the prescribed treatment regimen because of perceived risk to the suckling infant. However, maternal drug therapy should only very rarely preclude breastfeeding. Virtually all drugs (and xenobiotics) transfer into milk, with the extent varying widely between drugs usually in accordance with the principals of passive diffusion. Risk to the suckling infant should be assessed via consideration of the likely “dose” of drug that will be ingested via milk and the infant’s clearance, and the plasma concentration and possible pharmacological effects that result from these. For environmental chemicals, quantifying risk can be challenging due to factors such as inadequate study and uncontrolled “dosing.” For medicines it is usually possible to select an agent that safely treats maternal disease while posing minimal risk to the breastfeeding infant. It is only in very rare instances of severe potential toxicity, such as during maternal chemotherapy, that breastfeeding is best avoided even if the amount transferred into milk is small.
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Citation Excerpt :
Some drugs may have a local effect in the infant’s gastrointestinal tract and this should also be considered. Even if for many drugs the relative amounts secreted into milk may be estimated, the gold standard for maternal counseling remains direct sampling and pharmacokinetics measurement of the drug of interest and its metabolites in maternal plasma and milk.14–16 Variations in individual metabolism may be particularly relevant in cancer patients where impairment in renal and hepatic function are common.
An increasing number of women are diagnosed with cancer during pregnancy and lactation. Women are usually advised to interrupt breastfeeding during systemic anticancer treatment for fear of serious adverse effects to the nursed infant. However, the issue is poorly addressed in the literature and very few studies have evaluated the safety of breastfeeding during or after cytotoxic drugs or target agents administration. In this review we will analyze the available evidence that addresses the issue of anticancer drugs, targeted agents, antiemetics and growth-factors excretion in human milk. This could serve as a unique resource that may aid physicians in the management of breastfeeding cancer patients interested in maintaining lactation during treatment.
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Lactation and Contamination of Breast Milk with Xenobiotics
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The health, economic, and sociologic benefits of breastfeeding are substantial. As a result, women are encouraged to exclusively breastfeed their infants until they are around six months of age. However, the transfer of drugs and other xenobiotics to the infant via breast milk is a frequent cause of concern. Many women requiring drug therapy interrupt or stop breastfeeding, or fail to take the prescribed treatment regimen. All drugs, with the exception of very large molecules such as insulin, transfer into milk and may potentially pose risk. However, the extent of transfer varies widely between drugs, usually in accordance with the principles of passive diffusion of unionized and unbound drug. Risk to the suckling infant is best assessed via consideration of the likely ‘dose’ of drug that will be ingested via milk, the infant’s clearance, the plasma concentration that results from these, and the possible pharmacological effects. It is usually possible to select a drug that is safe and effective for the mother while posing minimal risk to her infant. Maternal drug therapy should rarely be a reason to avoid or interrupt breastfeeding. However, in rare instances such as during maternal chemotherapy, breastfeeding is best avoided.

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^†: Current address: Medical Director, Roche (NZ) Ltd, PO Box 12-492, Auckland, New Zealand.

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Modelling of the passage of drugs into milk

Abstract

J. Pharm. Sci.

J. Pharm. Sci.

Toxic. appl. Pharmac.

J. Diary Sci.

J. Pharm. Sci.

Drug use during breast-feeding

Clin. Pharmac.

Electrolyte and pH changes in human milk

Pediat. Res.

Prediction of drug concentrations in human skim milk from plasma protein binding and acid-base characteristics

Br. J. Clin. Pharmac.

Prediction of drug distribution into human milk from physicochemical characteristics

Clin. Pharmacokinet.

Drugs in human milk

Clin. Pharmacokinet.

Prospective evaluation of a model for the prediction of milk: plasma drug concentrations from physicochemical characteristics

Br. J. clin. Pharmac.

Excretion of paracetamol in human breast milk

Eur. J. clin. Pharmac.

Comparison of lipid-mediated blood-brain-barrier penetrability in neonates and adults

Am. J. Physiol.

Pharmacokinetics