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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 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 • Antibiotics and Propylthiouracil (PTU) • Identifying a “TDM” drug • Lithium • Identifying a “contraindicated” drug
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
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
“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)
<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
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
AAP (1989,1994): • “compatible” • Briggs/Freeman/Yaffe (1994): • “no significant risk” • Bennett/WHO (1988): • “probably safe” • CPS (2001): • “contraindication”
% 100 50 0 Women on PTU do not start breastfeeding Lee et al. Pediatrics 2000 Control PTU
% 100 50 0 Women on PTU do not start breastfeeding Lee et al. Pediatrics 2000 Formula Adviced by MDs Breastfeeding
“TDM” drug • TDM to individualize management • % wt-adj maternal dose: >10% • large interindividual variation • dose-dependent effects • lithium as an example
Identifying contraindicated drug • % wt-adj maternal dose: >10% • toxicity (dose-dependent, dose-independent) • TDM unsuitable
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)
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%
3. Carrier-mediated systems • clinical implications • interactions • potential intervention • net transfer: may or may not deviate from a diffusion model
?Organic cation transporters Milk Maternal plasma [Cmilk] [Cplasma] pH7.4 pH 7.0 Myoepithelia Epithelia Diffusion + a: McNamara lab
Organic cation transporters • P-glycoprotein • Organic Cation Transporters (OCT1, OCT2, OCT3, OCTN1, and OCTN2, etc)
12A Human mammary gland P-glycoprotein ??? hOCT2 hOCT1
785 base pair product 800 base pair product hOCTN1 and N2 hOCTN1 hOCTN2
P-gp expression in MCF12A intracellular surface MRK16
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)
Mean ± SD (n=3) with Na+ without Na+ Carnitine uptake results 4oC
Saturable carnitine uptake in MCF12A (Kwok et al. CPT 2001) Km = 1.9 M Vmax = 158 pmol/106 cells/hr Mean ± SD (n=3)
Carnitine Cimetidine inhibition TEA Choline Guanidine Inhibitor specificity Mean ± SD (n=3)
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
“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
“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
“Level II” Clinical Study • breastfeeding dyad • dose-[C]milk to estimate variations • [C]infant • PD endpoints • infant effects • milk yield