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Assessing Drug Transfer into Breast Milk

Assessing Drug Transfer into Breast Milk. Shinya Ito, MD Hospital for Sick Children Toronto, Canada. Four discussion points. Why do we need data? What data do we need? Transporters in the mammary gland? Graded approach. 1. Why do we need data?. Uncertainty compromises breastfeeding

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Assessing Drug Transfer into Breast Milk

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  1. Assessing Drug Transfer into Breast Milk Shinya Ito, MD Hospital for Sick Children Toronto, Canada

  2. Four discussion points • Why do we need data? • What data do we need? • Transporters in the mammary gland? • Graded approach

  3. 1. Why do we need data? • Uncertainty compromises breastfeeding • Antibiotics and Propylthiouracil (PTU) • Identifying a “TDM” drug • Lithium • Identifying a “contraindicated” drug

  4. Morbidity (Infection) Diarrhea Dewey et al. Pediatrics 1995 Lower respiratory tract infection Wright et al. BMJ 1989 Bacteremia Takala et al. J Pediatr 1989 Otitis media Owen et al. J Pediatr 1993 Bacterial meningitis Cochi et al. J Pediatr 1986 NEC Lucas & Cole. Lancet 1990

  5. Cognitive function IQ 8 pts Silva et al. Aust Ped J 1978 Morley et al. Arch Dis Child 1988 Lucas et al. Lancet 1992 Pollock. Dev Med Child Neurol 1994 Gale & Martyn. Lancet 1996 Horwood & Fergusson Pediatrics 1998

  6. “No hard data” leads to formula-feeding by default • Compliance and antibiotics in breastfeeding (Ito et al. Ann Pharmacother 1993;27:40-42) • PTU • labeling/imprinting (Lee et al. Pediatrics 2000;106:27-30)

  7. <10% Propylthiouracil (PTU) and breastfeeding Amounts excreted into milk <0.3% of the mother’s dose on a weight basis Low et al. Lancet 1979;2:1011 Kampman et al. Lancet 1980;1:736-7 Cooper. N Eng J Med 1984;311:1353-62

  8. No effect on the thyroid gland of the breastfed infant Momotani et al. Clin Endocrinol 1989;31:591-5 Eight infants Mother’s PTU (50-300 mg/day) Low T4/high TSH at birth Normalized despite breastfeeding

  9. AAP (1989,1994): • “compatible” • Briggs/Freeman/Yaffe (1994): • “no significant risk” • Bennett/WHO (1988): • “probably safe” • CPS (2001): • “contraindication”

  10. % 100 50 0 Women on PTU do not start breastfeeding Lee et al. Pediatrics 2000 Control PTU

  11. % 100 50 0 Women on PTU do not start breastfeeding Lee et al. Pediatrics 2000 Formula Adviced by MDs Breastfeeding

  12. “TDM” drug • TDM to individualize management • % wt-adj maternal dose: >10% • large interindividual variation • dose-dependent effects • lithium as an example

  13. Identifying contraindicated drug • % wt-adj maternal dose: >10% • toxicity (dose-dependent, dose-independent) • TDM unsuitable

  14. 2. What data do we need? • To estimate infant exposure level • Infant dose (%wt-adj maternal dose) • [C]milk and maternal dose • Infant serum [C], PD endpoints • Exposure Index • To assess effects on milk yield • To assess transfer mechanisms, PK factors in [C]milk variations • MP ratio (maternal PK-[C]milk)

  15. Exposure Index MP ratio x 10 = EI (%) CL (ml/kg/min) Ito & Koren 1994 EI>10% Phenobarbital 100% Ethosuximide 50% Atenolol 25% Lithium 2-30% Metronidazole 3-18%

  16. 3. Carrier-mediated systems • clinical implications • interactions • potential intervention • net transfer: may or may not deviate from a diffusion model

  17. ?Organic cation transporters Milk Maternal plasma [Cmilk] [Cplasma] pH7.4 pH 7.0 Myoepithelia Epithelia Diffusion + a: McNamara lab

  18. Organic cation transporters • P-glycoprotein • Organic Cation Transporters (OCT1, OCT2, OCT3, OCTN1, and OCTN2, etc)

  19. 12A Human mammary gland P-glycoprotein ??? hOCT2 hOCT1

  20. 785 base pair product 800 base pair product hOCTN1 and N2 hOCTN1 hOCTN2

  21. P-gp expression in MCF12A intracellular surface MRK16

  22. Saturable TEA uptake in the human mammary epithelial cells, MCF12A (Dhillon et al. CPT 2000) Km = 3.4 mM Vmax = 18.5 nmol/mg protein/0.5 hr Mean ± SD (n=3)

  23. Mean ± SD (n=3) with Na+ without Na+ Carnitine uptake results 4oC

  24. Saturable carnitine uptake in MCF12A (Kwok et al. CPT 2001) Km = 1.9 M Vmax = 158 pmol/106 cells/hr Mean ± SD (n=3)

  25. Carnitine Cimetidine inhibition TEA Choline Guanidine Inhibitor specificity Mean ± SD (n=3)

  26. 4. Graded approach • “Level 0”: pre-clinical study • physico-chemical model • in vitro cell model • involvement of transporters • animal model • “Level I”: clinical study • lactating/non-breastfeeding (e.g., weaning) • “Level II”: clinical study • breastfeeding dyad

  27. “Level 0” Preclinical Study • various models • predict in vivo [C]milk, transport systems etc. • potential effects on prolactin etc. • provide ethical framework for human experimentation

  28. “Level I” Clinical Study • lactating/non-breastfeeding women • dose-[C]milk (AUC): infant dose, %wt-adj maternal dose • MP ratio: Exposure Index • in colostrum, transitional, and mature milk; in foremilk and hindmilk

  29. “Level II” Clinical Study • breastfeeding dyad • dose-[C]milk to estimate variations • [C]infant • PD endpoints • infant effects • milk yield

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