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Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Emerging Research Paradigm for Infant Drug Exposure Through Breast Milk

Author(s): Shinya Ito*

Volume 25 , Issue 5 , 2019

Page: [528 - 533] Pages: 6

DOI: 10.2174/1381612825666190318165932

Price: $65


Background: Information on drug secretion into milk is insufficient due to the exclusion of lactating women from clinical trials and drug development processes. As a result, non-adherence to the necessary drug therapy and discontinuation of breastfeeding occur, even if the predicted level of infant exposure is low. In contrast, inadvertent infant exposure to drugs in breast milk continues to happen due to lack of rational risk assessment, resulting in serious toxicity cases including death. This problem is multifactorial, but one of the key elements is the lack of pharmacokinetic information on drug secretion into milk and resultant infant exposure levels, the first line of evidence for risk assessment.

Methods: Basic PK principles in drug excretion into milk were explained. The literature was scanned to identify approaches for PK data acquisition in this challenging field.

Results: This review describes the feasibility to develop such approaches, and the knowledge gaps that still exist. A combination of population pharmacokinetics approach (to estimate averages and variations of drug concentration profiles in milk) and physiologically-based pharmacokinetics modeling of infants (to predict the population profiles of infant drug exposure levels) appears useful.

Conclusions: In order to facilitate participant enrollment and PK data acquisition in a timely manner, networks of investigators become crucial.

Keywords: Human milk, drugs, breastfeeding, MP ratio, PBPK modeling, population pharmacokinetics, input drug exposure.

Breastfeeding and the use of human milk. Pediatrics 2012; 129(3): e827-41.
Cunningham AS, Jelliffe DB, Jelliffe EFP. Breast-feeding and health in the 1980s: A global epidemiologic review. J Pediatr 1991; 118(5): 659-66.
Carpenter RG, Gardner A, Jepson M, et al. Prevention of unexpected infant death. Evaluation of the first seven years of the Sheffield Intervention Programme. Lancet 1983; 1(8327): 723-7.
Ruiz-Palacios GM, Calva JJ, Pickering LK, et al. Protection of breast-fed infants against Campylobacter diarrhea by antibodies in human milk. J Pediatr 1990; 116(5): 707-13.
Koletzko S, Sherman P, Corey M, Griffiths A, Smith C. Role of infant feeding practices in development of Crohn’s disease in childhood. BMJ 1989; 298(6688): 1617-8.
Mayer EJ, Hamman RF, Gay EC, Lezotte DC, Savitz DA, Klingensmith GJ. Reduced risk of IDDM among breast-fed children. The Colorado IDDM Registry. Diabetes 1988; 37(12): 1625-32.
Kramer MS, Aboud F, Mironova E, et al. Breastfeeding and child cognitive development: new evidence from a large randomized trial. Arch Gen Psychiatry 2008; 65(5): 578-84.
Belfort MB, Anderson PJ, Nowak VA, et al. Breast Milk Feeding, Brain Development, and Neurocognitive Outcomes: A 7-Year Longitudinal Study in Infants Born at Less Than 30 Weeks’. Gestation J Pediatr 2016; 177: 133-139.e1.
Verhasselt V, Milcent V, Cazareth J, et al. Breast milk-mediated transfer of an antigen induces tolerance and protection from allergic asthma. Nat Med 2008; 14(2): 170-5.
Liu B, Zupan B, Laird E, et al. Maternal hematopoietic TNF, via milk chemokines, programs hippocampal development and memory. Nat Neurosci 2014; 17(1): 97-105.
Yang L, Jacobsen KH. A systematic review of the association between breastfeeding and breast cancer. J Womens Health (Larchmt) 2008; 17(10): 1635-45.
Lord SJ, Bernstein L, Johnson KA, et al. Breast cancer risk and hormone receptor status in older women by parity, age of first birth, and breastfeeding: A case-control study. Cancer Epidemiol Biomarkers Prev 2008; 17(7): 1723-30.
Huo D, Adebamowo CA, Ogundiran TO, et al. Parity and breastfeeding are protective against breast cancer in Nigerian women. Br J Cancer 2008; 98(5): 992-6.
Danforth KN, Tworoger SS, Hecht JL, Rosner BA, Colditz GA, Hankinson SE. Breastfeeding and risk of ovarian cancer in two prospective cohorts. Cancer Causes Control 2007; 18(5): 517-23.
Matheson I. Drugs taken by mothers in the puerperium. Br Med J (Clin Res Ed) 1985; 290(6481): 1588-9.
Schirm E, Schwagermann MP, Tobi H, de Jong-van den Berg LTW. Drug use during breastfeeding. A survey from the Netherlands. Eur J Clin Nutr 2004; 58(2): 386-90.
Stultz EE, Stokes JL, Shaffer ML, Paul IM, Berlin CM. Extent of medication use in breastfeeding women. Breastfeed Med 2007; 2(3): 145-51.
Saha MR, Ryan K, Amir LH. Postpartum women’s use of medicines and breastfeeding practices: A systematic review. Int Breastfeed J 2015; 10(1): 28.
Ito S, Koren G, Einarson TR. Maternal noncompliance with antibiotics during breastfeeding. Ann Pharmacother 1993; 27(1): 40-2.
Lee A, Moretti ME, Collantes A, et al. Choice of breastfeeding and physicians’ advice: A cohort study of women receiving propylthiouracil. Pediatrics 2000; 106(1 Pt 1): 27-30.
Ito S, Moretti M, Liau M, Koren G. Initiation and duration of breast-feeding in women receiving antiepileptics. Am J Obstet Gynecol 1995; 172(3): 881-6.
Ito S. Drug therapy for breast-feeding women. N Engl J Med 2000; 343(2): 118-26.
Ito S, Lee A. Drug excretion into breast milk--overview. Adv Drug Deliv Rev 2003; 55(5): 617-27.
Koren G, Cairns J, Chitayat D, Gaedigk A, Leeder SJ. Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet 2006; 368(9536): 704.
Kwok B, Yamauchi A, Rajesan R, et al. Carnitine/xenobiotics transporters in the human mammary gland epithelia, MCF12A. Am J Physiol Regul Integr Comp Physiol 2006; 290(3): R793-802.
Wu AM, Yang M, Dalvi P, et al. Role of STAT5 and epigenetics in lactation-associated upregulation of multidrug transporter ABCG2 in the mammary gland. Am J Physiol Endocrinol Metab 2014; 307(7): E596-610.
Wu AM, Dedina L, Dalvi P, et al. Riboflavin uptake transporter Slc52a2 (RFVT2) is upregulated in the mouse mammary gland during lactation. Am J Physiol Regul Integr Comp Physiol 2016; 310(7): R578-85.
Alcorn J, Lu X, Moscow JA, McNamara PJ. Transporter gene expression in lactating and nonlactating human mammary epithelial cells using real-time reverse transcription-polymerase chain reaction. J Pharmacol Exp Ther 2002; 303(2): 487-96.
Oo CY, Kuhn RJ, Desai N, McNamara PJ. Active transport of cimetidine into human milk. Clin Pharmacol Ther 1995; 58(5): 548-55.
Jonker JW, Merino G, Musters S, et al. The breast cancer resistance protein BCRP (ABCG2) concentrates drugs and carcinogenic xenotoxins into milk. Nat Med 2005; 11(2): 127-9.
van Herwaarden AE, Wagenaar E, Merino G, et al. Multidrug transporter ABCG2/breast cancer resistance protein secretes riboflavin (vitamin B2) into milk. Mol Cell Biol 2007; 27(4): 1247-53.
Koshimichi H, Ito K, Hisaka A, Honma M, Suzuki H. Analysis and prediction of drug transfer into human milk taking into consideration secretion and reuptake clearances across the mammary epithelia. Drug Metab Dispos 2011; 39(12): 2370-80.
Ito N, Ito K, Ikebuchi Y, et al. Prediction of drug transfer into milk considering breast cancer resistance protein (BCRP)-mediated transport. Pharm Res 2015; 32(8): 2527-37.
Miyake K, Mickley L, Litman T, et al. Molecular cloning of cDNAs which are highly overexpressed in mitoxantrone-resistant cells: demonstration of homology to ABC transport genes. Cancer Res 1999; 59(1): 8-13.
Doyle LA, Yang W, Abruzzo LV, et al. A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci USA 1998; 95(26): 15665-70.
Leslie EM, Deeley RG, Cole SP. Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol Appl Pharmacol 2005; 204(3): 216-37.
Wilson JT, Brown RD, Cherek DR, et al. Drug excretion in human breast milk: Principles, pharmacokinetics and projected consequences. Clin Pharmacokinet 1980; 5(1): 1-66.
Bennett PN. Drugs and human lactation: A guide to the content and consequences of drugs, micronutrients, radiopharmaceuticals, and environmental and occupational chemicals in human milk New York. USA: Elsevier 1988.
Larsen ER, Damkier P, Pedersen LH, et al. Use of psychotropic drugs during pregnancy and breast-feeding. Acta Psychiatr Scand Suppl 2015; (445): 1-28.
Lam J, Baello S, Iqbal M, et al. The ontogeny of P-glycoprotein in the developing human blood-brain barrier: implication for opioid toxicity in neonates. Pediatr Res 2015; 78(4): 417-21.
Wang J, Johnson T, Sahin L, et al. Evaluation of the safety of drugs and biological products used during lactation: Workshop summary. Clin Pharmacol Ther 2017; 101(6): 736-44.
Panchaud A, Garcia-Bournissen F, Csajka C, et al. Prediction of infant drug exposure through breastfeeding: Population PK modeling and simulation of fluoxetine exposure. Clin Pharmacol Ther 2011; 89(6): 830-6.
Tanoshima R, Bournissen FG, Tanigawara Y, et al. Population PK modelling and simulation based on fluoxetine and norfluoxetine concentrations in milk: A milk concentration-based prediction model. Br J Clin Pharmacol 2014; 78(4): 918-28.
Delaney SR, Malik PRV, Stefan C, Edginton AN, Colantonio DA, Ito S. Predicting escitalopram exposure to breastfeeding infants: integrating analytical and in silico techniques. Clin Pharmacokinet 2018; 57(12): 1603-11.
Ilett KF, Paech MJ, Page-Sharp M, et al. Use of a sparse sampling study design to assess transfer of tramadol and its O-desmethyl metabolite into transitional breast milk. Br J Clin Pharmacol 2008; 65(5): 661-6.
Barrett JS, Della Casa Alberighi O, Läer S, Meibohm B. Physiologically based pharmacokinetic (PBPK) modeling in children. Clin Pharmacol Ther 2012; 92(1): 40-9.
Edginton AN, Schmitt W, Willmann S. Development and evaluation of a generic physiologically based pharmacokinetic model for children. Clin Pharmacokinet 2006; 45(10): 1013-34.
Maharaj AR, Barrett JS, Edginton AN. A workflow example of PBPK modeling to support pediatric research and development: case study with lorazepam. AAPS J 2013; 15(2): 455-64.

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