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Current Pharmaceutical Design

Author(s): Domenico Ventrella, Monica Forni, Maria Laura Bacci and Pieter Annaert*

DOI: 10.2174/1381612825666190320165904

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Non-clinical Models to Determine Drug Passage into Human Breast Milk

Page: [534 - 548] Pages: 15

  • * (Excluding Mailing and Handling)

Abstract

Background: Successful practice of clinical perinatal pharmacology requires a thorough understanding of the pronounced physiological changes during lactation and how these changes affect various drug disposition processes. In addition, pharmacokinetic processes unique to lactation have remained understudied. Hence, determination of drug disposition mechanisms in lactating women and their babies remains a domain with important knowledge gaps. Indeed, lack of data regarding infant risk during breastfeeding far too often results in discontinuation of breastfeeding and subsequent loss of all the associated benefits to the breastfed infant. In the absence of age-specific toxicity data, human lactation data alone are considered insufficient to rapidly generate the required evidence regarding risks associated with medication use during lactation.

Methods: Systematic review of literature to summarize state-of-the art non-clinical approaches that have been developed to explore the mechanisms underlying drug milk excretion.

Results: Several studies have reported methods to predict (to some extent) milk drug excretion rates based on physicochemical properties of the compounds. In vitro studies with primary mammary epithelial cells appear excellent approaches to determine transepithelial drug transport rates across the mammary epithelium. Several of these in vitro tools have been characterized in terms of transporter expression and activity as compared to the mammary gland tissue. In addition, with the advent of physiology-based pharmacokinetic (PBPK) modelling, these in vitro transport data may prove instrumental in predicting drug milk concentration time profiles prior to the availability of data from clinical lactation studies. In vivo studies in lactating animals have proven their utility in elucidating the mechanisms underlying drug milk excretion.

Conclusion: By combining various non-clinical tools (physicochemistry-based, in vitro and PBPK, in vivo animal) for drug milk excretion, valuable and unique information regarding drug milk concentrations during lactation can be obtained. The recently approved IMI project ConcePTION will address several of the challenges outlined in this review.

Keywords: Pharmacokinetics, lactation, breast milk, milk/plasma ratio, mammary epithelial cells, animal model, physiology-based pharmacokinetic modelling, relative infant dose.

[1]
Bagci Bosi AT, Eriksen KG, Sobko T, Wijnhoven TMA, Breda J. Breastfeeding practices and policies in WHO European Region Member States. Public Health Nutr 2016; 19(4): 753-64.
[2]
Persson LÅ. Breastfeeding in low-resource settings: Not a “small matter”. PLoS Med 2018; 15(8): e1002646.
[3]
Rollins NC, Bhandari N, Hajeebhoy N, et al. Why invest, and what it will take to improve breastfeeding practices? Lancet 2016; 387(10017): 491-504.
[4]
LactMed® [Internet]. NIH U.S. National Library of Medicine. Available from: https://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm
[5]
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.
[6]
Anderson PO, Sauberan JB. Modeling drug passage into human milk. Clin Pharmacol Ther 2016; 100(1): 42-52.
[7]
Johnson TN, Rostami-Hodjegan A. Resurgence in the use of physiologically based pharmacokinetic models in pediatric clinical pharmacology: parallel shift in incorporating the knowledge of biological elements and increased applicability to drug development and clinical practice. Paediatr Anaesth 2011; 21(3): 291-301.
[8]
Zhang T. Physiologically based pharmacokinetic modeling of disposition and drug-drug interactions for atorvastatin and its metabolites. Eur J Pharm Sci 2015; 77: 216-29.
[9]
Duan P, Zhao P, Zhang L. Physiologically based pharmacokinetic (PBPK) modeling of pitavastatin and atorvastatin to predict drug-drug interactions (DDIs). Eur J Drug Metab Pharmacokinet 2016; 14(7): 1-17.
[10]
Jing J, Nelson C, Paik J, Shirasaka Y, Amory JK, Isoherranen N. Physiologically based pharmacokinetic model of all- trans-retinoic acid with application to cancer populations and drug interactions. J Pharmacol Exp Ther 2017; 361(2): 246-58.
[11]
Sager JE, Yu J, Ragueneau-Majlessi I, Isoherranen N. Physiologically based pharmacokinetic (PBPK) modeling and simulation approaches: A systematic review of published models, applications, and model verification. Drug Metab Dispos 2015; 43(11): 1823-37.
[12]
Olafuyi O, Coleman M, Badhan RKS. The application of physiologically based pharmacokinetic modelling to assess the impact of antiretroviral-mediated drug-drug interactions on piperaquine antimalarial therapy during pregnancy. Biopharm Drug Dispos 2017; 38(8): 464-78.
[13]
Templeton I, Ravenstijn P, Sensenhauser C, Snoeys J. A physiologically based pharmacokinetic modeling approach to predict drug-drug interactions between domperidone and inhibitors of CYP3A4. Biopharm Drug Dispos 2016; 37(1): 15-27.
[14]
Umehara K-I, Huth F, Won CS, Heimbach T, He H. Verification of a physiologically based pharmacokinetic model of ritonavir to estimate drug-drug interaction potential of CYP3A4 substrates. Biopharm Drug Dispos 2018; 39(3): 152-63.
[15]
Wang Y-H, Chen D, Hartmann G, Cho CR, Menzel K. PBPK modeling strategy for predicting complex drug interactions of letermovir as a perpetrator in support of product labeling. Clin Pharmacol Ther 2019; 105(2): 515-23.
[16]
Yao Y, Toshimoto K, Kim S-J, Yoshikado T, Sugiyama Y. Quantitative analysis of complex drug-drug interactions between cerivastatin and metabolism/transport inhibitors using physiologically based pharmacokinetic modeling. Drug Metab Dispos 2018; 46(7): 924-33.
[17]
Parrott N, Davies B, Hoffmann G, et al. Development of a physiologically based model for oseltamivir and simulation of pharmacokinetics in neonates and infants. Clin Pharmacokinet 2011; 50(9): 613-23.
[18]
T’jollyn H, Snoeys J, Colin P, et al. Physiology-based IVIVE predictions of tramadol from in vitro metabolism data. Pharm Res 2015; 32(1): 260-74.
[19]
Zane NR, Thakker DR. A physiologically based pharmacokinetic model for voriconazole disposition predicts intestinal first-pass metabolism in children. Clin Pharmacokinet 2014; 53(12): 1171-82.
[20]
Yellepeddi V, Rower J, Liu X, Kumar S, Rashid J, Sherwin CMT. State-of-the-Art Review on Physiologically Based Pharmacokinetic Modeling in Pediatric Drug Development. Clin Pharmacokinet. Springer International Publishing 2018; 97(3): 1-13.
[21]
Templeton IE, Jones NS, Musib L. Pediatric Dose Selection and Utility of PBPK in Determining Dose. AAPS J 2018; 20(2): 31.
[22]
Duan P, Fisher JW, Wang J. Applications of physiologically based pharmacokinetic (PBPK) models for pediatric populations. Fundam Pediat Drug Dos 2016; pp. 109-25.
[23]
Kronenfeld N, Berlin M, Shaniv D, Berkovitch M. Use of psychotropic medications in breastfeeding women. Birth Defects Res 2017; 109(12): 957-97.
[24]
McManaman JL, Neville MC. Mammary physiology and milk secretion. Adv Drug Deliv Rev 2003; 55(5): 629-41.
[25]
Ramsay DT, Kent JC, Hartmann RA, Hartmann PE. Anatomy of the lactating human breast redefined with ultrasound imaging. J Anat 2005; 206(6): 525-34.
[26]
Fleishaker JC. Models and methods for predicting drug transfer into human milk. Adv Drug Deliv Rev 2003; 55(5): 643-52.
[27]
Ito S, Alcorn J. Xenobiotic transporter expression and function in the human mammary gland. Adv Drug Deliv Rev 2003; 55(5): 653-65.
[28]
Mahnke H, Ballent M, Baumann S, et al. The ABCG2 Efflux Transporter in the Mammary Gland Mediates Veterinary Drug Secretion across the Blood-Milk Barrier into Milk of Dairy Cows. Drug Metab Dispos 2016; 44(5): 700-8.
[29]
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.
[30]
Bohets H, Annaert P, Mannens G, et al. Strategies for absorption screening in drug discovery and development. Curr Top Med Chem 2001; 1(5): 367-83.
[31]
Deferme S, Annaert P, Augustijns P. In vitro screening models to assess intestinal drug absorption and metabolismdrug absorption studies 2008. 7: 182-215.
[32]
Artursson P, Palm K, Luthman K. Caco-2 monolayers in experimental and theoretical predictions of drug transport. Adv Drug Deliv Rev 2012; 64: 280-9.
[33]
Hayeshi R, Hilgendorf C, Artursson P, et al. Comparison of drug transporter gene expression and functionality in Caco-2 cells from 10 different laboratories. Eur J Pharm Sci 2008; 35(5): 383-96.
[34]
Kimura S, Morimoto K, Okamoto H, Ueda H, Kobayashi D, Kobayashi J, et al. Development of a human mammary epithelial cell culture model for evaluation of drug transfer into milk. Arch Pharm Res 2006; 29(5): 424-9.
[35]
Srinivasan B, Kolli AR, Esch MB, Abaci HE, Shuler ML, Hickman JJ. TEER measurement techniques for in vitro barrier model systems. J Lab Autom 2015; 20(2): 107-26.
[36]
Jaeger A, Bardehle D, Oster M, et al. Gene expression profiling of porcine mammary epithelial cells after challenge with Escherichia coli and Staphylococcus aureus in vitro. Vet Res (Faisalabad) 2015; 46(1): 50.
[37]
Al-Bataineh MM, Van Der Merwe D, Schultz BD, Gehring R. Molecular and functional identification of organic anion transporter isoforms in cultured bovine mammary epithelial cells (BME-UV). J Vet Pharmacol Ther 2012; 35(3): 209-15.
[38]
Al-Bataineh MM, Van Der Merwe D, Schultz BD, Gehring R. Cultured mammary epithelial monolayers (BME-UV) express functional organic anion and cation transporters. J Vet Pharmacol Ther 2009; 32(5): 422-8.
[39]
Elias JJ. Cultivation of adult mouse mammary gland in hormone-enriched synthetic medium. Science 1957; 126(3278): 842-3.
[40]
Mackenzie DD, Forsyth IA, Brooker BE, Turvey A. Culture of bovine mammary epithelial cells on collagen gels. Tissue Cell 1982; 14(2): 231-41.
[41]
Kietzmann M, Löscher W, Arens D, Maass P, Lubach D. The isolated perfused bovine udder as an in vitro model of percutaneous drug absorption. Skin viability and percutaneous absorption of dexamethasone, benzoyl peroxide, and etofenamate. J Pharmacol Toxicol Methods 1993; 30(2): 75-84.
[42]
Kietzmann M, Niedorf F, Gossellin J. Tissue distribution of cloxacillin after intramammary administration in the isolated perfused bovine udder. BMC Vet Res 2010; 6(1): 46.
[43]
Pinto ISB, Fonseca I, Brandão HM, et al. SHORT-COMMUNICATION Evaluation of perfused bovine udder for gene expression studies in dairy cows. Genet Mol Res 2017; 16(1)
[44]
Sjaastad OV, Hove K, Sand O. Physiology of Domestic Animals. Can Vet J 2013; 54(6): 558.
[45]
Allegri G, Bertazzo A, Biasiolo M, Costa CVL, Ragazzi E. Kynurenine pathway enzymes in different species of animals. Adv Exp Med Biol 2003; 527: 455-63.
[46]
Löscher W. Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs. Seizure 2011; 20(5): 359-68.
[47]
Lorenz J, Glatt HR, Fleischmann R, Ferlinz R, Oesch F. Drug metabolism in man and its relationship to that in three rodent species: monooxygenase, epoxide hydrolase, and glutathione S-transferase activities in subcellular fractions of lung and liver. Biochem Med 1984; 32(1): 43-56.
[48]
Radermacher P, Haouzi P. A mouse is not a rat is not a man: species-specific metabolic responses to sepsis - a nail in the coffin of murine models for critical care research? Intensive Care Med Exp 2013; 1(1): 26.
[49]
Demetrius L. Of mice and men. When it comes to studying ageing and the means to slow it down, mice are not just small humans. EMBO Rep 2005; 6(Spec No): S39-44.
[50]
Cardiff RD. Validity of mouse mammary tumour models for human breast cancer: comparative pathology. Microsc Res Tech 2001; 52(2): 224-30.
[51]
Tero-Vescan A, Dogaru M, Vancea S, Imre S. Olanzapine transfer into Sheep’s milk. An Animal Model. Farmacia 2017; 65(5): 677-82.
[52]
Hurley WL. Comparative mammary anatomy index [Internet]. Lactation Biology website. 2010.[cited 2018 Oct 7]. Available from: . http://ansci.illinois.edu/static/ansc438/Mamstructure/ comparanat_1.html
[53]
Carroll JS, Hickey TE, Tarulli GA, Williams M, Tilley WD. Deciphering the divergent roles of progestogens in breast cancer. Nat Rev Cancer 2017; 17(1): 54-64.
[54]
McNamara PJ, Burgio D, Yoo SD. Pharmacokinetics of cimetidine during lactation: species differences in cimetidine transport into rat and rabbit milk. J Pharmacol Exp Ther 1992; 261(3): 918-23.
[55]
Schrickx JA, Fink-Gremmels J. Implications of ABC transporters on the disposition of typical veterinary medicinal products. Eur J Pharmacol 2008; 585(2-3): 510-9.
[56]
Warren MS, Zerangue N, Woodford K, et al. Comparative gene expression profiles of ABC transporters in brain microvessel endothelial cells and brain in five species including human. Pharmacol Res 2009; 59(6): 404-13.
[57]
Yagdiran Y, Oskarsson A, Knight CH, Tallkvist J. ABC- and SLC-transporters in murine and bovine mammary epithelium--effects of prochloraz. PLoS ONE 2016; 11(3): e0151904.
[58]
Gonzalez LM, Moeser AJ, Blikslager AT. Porcine models of digestive disease: the future of large animal translational research. Transl Res 2015; 166(1): 12-27.
[59]
Bassols A, Costa C, Eckersall PD, Osada J, Sabrià J, Tibau J. The pig as an animal model for human pathologies: A proteomics perspective. BioMed Central 2014; 8(9-10): 715-31.
[60]
Schrickx JA. ABC-transporters in the pig 2006.
[61]
Chavatte-Palmer P, Tarrade A. Placentation in different mammalian species. Ann Endocrinol (Paris) 2016; 77(2): 67-74.
[62]
Ventrella D, Dondi F, Barone F, et al. The biomedical piglet: establishing reference intervals for haematology and clinical chemistry parameters of two age groups with and without iron supplementation. BMC Vet Res 2017; 13(1): 23.
[63]
De Vos M, Huygelen V, Van Raemdonck G, et al. Supplementing formula-fed piglets with a low molecular weight fraction of bovine colostrum whey results in an improved intestinal barrier. J Anim Sci 2014; 92(8): 3491-501.
[64]
Romagnoli N, Ventrella D, Giunti M, et al. Access to cerebrospinal fluid in piglets via the cisterna magna: Optimization and description of the technique. Lab Anim 2014; 48(4): 345-8.
[65]
Lambertini C, Ventrella D, Barone F, et al. Transdermal spinal catheter placement in piglets: Description and validation of the technique. J Neurosci Methods 2015; 255: 17-21.
[66]
Gasthuys E, Schauvliege S, van Bergen T, Millecam J, Cerasoli I, Martens A, et al. Repetitive urine and blood sampling in neonatal and weaned piglets for pharmacokinetic and pharmacodynamic modelling in drug discovery: A pilot study. Lab Anim 7 ed. 2017; 51: pp. (5)498-508.
[67]
Gasthuys E, Vandecasteele T, De Bruyne P, et al. The Potential Use of Piglets as Human Pediatric Surrogate for Preclinical Pharmacokinetic and Pharmacodynamic Drug Testing. Curr Pharm Des 2016; 22(26): 4069-85.
[68]
van der Laan JW, Brightwell J, McAnulty P, Ratky J, Stark C. Regulatory acceptability of the minipig in the development of pharmaceuticals, chemicals and other products. J Pharmacol Toxicol Methods 2010; 62(3): 184-95.
[69]
Forster R, Ancian P, Fredholm M, Simianer H, Whitelaw B. The minipig as a platform for new technologies in toxicology. J Pharmacol Toxicol Methods 2010; 62(3): 227-35.
[70]
Suenderhauf C, Parrott N. A physiologically based pharmacokinetic model of the minipig: data compilation and model implementation. Pharm Res 2013; 30(1): 1-15.
[71]
Swindle MM, Smith AC. Swine in the Laboratory. 3rd ed. 2015; p. 593.
[72]
Peter B, De Rijk EPCT, Zeltner A, Emmen HH. Sexual Maturation in the Female Göttingen Minipig. Toxicol Pathol 2016; 44(3): 482-5.
[73]
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): 704-1.
[74]
Chu X, Bleasby K, Evers R. Species differences in drug transporters and implications for translating preclinical findings to humans. Expert Opin Drug Metab Toxicol 2013; 9(3): 237-52.
[75]
Takeuchi T, Yoshitomi S, Higuchi T, et al. Establishment and characterization of the transformants stably-expressing MDR1 derived from various animal species in LLC-PK1. Pharm Res 2006; 23(7): 1460-72.
[76]
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.
[77]
De Schaepdrijver LM, Annaert P, Chen CL. Ontogeny of ADME processes during postnatal development in man and preclinical species: A comprehensive review Drug Metabolism and Disposition.
[78]
Anderson PO, Valdés V. Variation of milk intake over time: clinical and pharmacokinetic implications Breastfeed Med 2015; 10(3): 142-4. Mary Ann Liebert, Inc. 140 Huguenot Street, 3rd Floor New Rochelle, NY 10801 USA..
[79]
Yates B, Braschi B, Gray KA, Seal RL, Tweedie S, Bruford EA. Genenames.org: the HGNC and VGNC resources in 2017. Nucleic Acids Res 2017; 45(D1): D619-25.
[80]
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.
[81]
Gilchrist SE, Alcorn J. Lactation stage‐dependent expression of transporters in rat whole mammary gland and primary mammary epithelial organoids. Fundam Clin Pharmacol 2010; 24(2): 205-14.
[82]
Groneberg DA, Döring F, Theis S, Nickolaus M, Fischer A, Daniel H. Peptide transport in the mammary gland: expression and distribution of PEPT2 mRNA and protein. Am J Physiol Endocrinol Metab 2002; 282(5): E1172-9.
[83]
Takebe K, Nio-Kobayashi J, Takahashi-Iwanaga H, Yajima T, Iwanaga T. Cellular expression of a monocarboxylate transporter (MCT1) in the mammary gland and sebaceous gland of mice. Histochem Cell Biol 2009; 131(3): 401-9. [Springer-Verlag].
[84]
Ito N, Ito K, Ikebuchi Y, et al. Organic cation transporter/solute carrier family 22a is involved in drug transfer into milk in mice. J Pharm Sci 2014; 103(10): 3342-8.
[85]
Gerk PM, Oo CY, Paxton EW, Moscow JA, McNamara PJ. Interactions between cimetidine, nitrofurantoin, and probenecid active transport into rat milk. J Pharmacol Exp Ther 2001; 296(1): 175-80.
[86]
Lamhonwah A-M, Mai L, Chung C, Lamhonwah D, Ackerley C, Tein I. Upregulation of mammary gland OCTNs maintains carnitine homeostasis in suckling infants. Biochem Biophys Res Commun 2011; 404(4): 1010-5.
[87]
Ling B, Alcorn J. Acute administration of cefepime lowers L-carnitine concentrations in early lactation stage rat milk. J Nutr 2008; 138(7): 1317-22.
[88]
Wu AML, 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.
[89]
Tallkvist J, Yagdiran Y, Danielsson L, Oskarsson A. A model of secreting murine mammary epithelial HC11 cells comprising endogenous Bcrp/Abcg2 expression and function. Cell Biol Toxicol 2015; 31(2): 111-20. [Springer Netherlands].
[90]
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.
[91]
Farke C, Meyer HHD, Bruckmaier RM, Albrecht C. Differential expression of ABC transporters and their regulatory genes during lactation and dry period in bovine mammary tissue. J Dairy Res 2008; 75(04): 406-14.
[92]
Merino G, Alvarez AI, Pulido MM, Molina AJ, Schinkel AH, Prieto JG. Breast cancer resistance protein (BCRP/ABCG2) transports fluoroquinolone antibiotics and affects their oral availability, pharmacokinetics, and milk secretion. Drug Metab Dispos 2006; 34(4): 690-5.
[93]
Merino G, Jonker JW, Wagenaar E, van Herwaarden AE, Schinkel AH. The breast cancer resistance protein (BCRP/ABCG2) affects pharmacokinetics, hepatobiliary excretion, and milk secretion of the antibiotic nitrofurantoin. Mol Pharmacol 2005; 67(5): 1758-64.