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 Otitis media Owen et al. J Pediatr 1993 Bacteremia Takala et al. J Pediatr 1989 Bacterial meningitis Cochi et al. J Pediatr 1986 NEC Lucas & Cole. Lancet 1990

5. 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 & FergussonPediatrics 1998 Cognitive function IQ 8 pts

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. 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 <10%

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

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

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

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

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 EI (%) = MP ratiox 10 CL (ml/kg/min) Ito & Koren 1994 EI>10% Phenobarbital100% Ethosuximide50% Atenolol25% Lithium2-30% Metronidazole3-18%

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

17. [C milk ][C plasma ] Maternal plasmaMilk Epithelia Myoepithelia pH 7.0 pH7.4 ?Organic cation transporters Diffusion +  : McNamara lab

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

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

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

21. P-gp expression in MCF12A MRK16 intracellularsurface

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

23. Mean ± SD (n=3) Carnitine uptake results with Na + without Na + 4oC4oC

24. Saturable carnitine uptake in MCF12A (Kwok et al. CPT 2001) Mean ± SD (n=3) K m = 1.9  M V max = 158 pmol/10 6 cells/hr

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

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