Assessing Drug Transfer into Breast Milk

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Assessing Drug Transfer into Breast Milk

• Shinya Ito, MD
• Hospital for Sick Children
• Toronto, Canada

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Four discussion points

• Why do we need data?
• What data do we need?
• Transporters in the mammary gland?
• Graded approach

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1. Why do we need data?

• Uncertainty compromises breastfeeding
• Antibiotics and Propylthiouracil (PTU)
• Identifying a TDM drug
• Lithium
• Identifying a contraindicated drug

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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
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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
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No hard data leads to formula-feeding by default

• Compliance and antibiotics in breastfeeding
• (Ito et al. Ann Pharmacother 19932740-42)
• PTU
• labeling/imprinting
• (Lee et al. Pediatrics 200010627-30)

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Propylthiouracil (PTU) and breastfeeding
Amounts excreted into milk lt0.3 of the
mothers dose on a weight basis
Low et al. Lancet 197921011 Kampman et al.
Lancet 19801736-7 Cooper. N Eng J Med
19843111353-62
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No effect on the thyroid gland of the breastfed
infant Momotani et al. Clin Endocrinol
198931591-5
Eight infants Mothers PTU (50-300 mg/day) Low
T4/high TSH at birth Normalized despite
breastfeeding
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• AAP (1989,1994)
• compatible
• Briggs/Freeman/Yaffe (1994)
• no significant risk
• Bennett/WHO (1988)
• probably safe
• CPS (2001)
• contraindication

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Women on PTU do not start breastfeeding
Lee et al. Pediatrics 2000
Control
PTU
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Women on PTU do not start breastfeeding
Lee et al. Pediatrics 2000
Formula
Adviced by MDs
Breastfeeding
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TDM drug

• TDM to individualize management
• wt-adj maternal dose gt10
• large interindividual variation
• dose-dependent effects
• lithium as an example

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Identifying contraindicated drug

• wt-adj maternal dose gt10
• toxicity (dose-dependent,
• dose-independent)
• TDM unsuitable

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2. What data do we need?

• To estimate infant exposure level
• Infant dose (wt-adj maternal dose)
• Cmilk and maternal dose
• Infant serum C, PD endpoints
• Exposure Index
• To assess effects on milk yield
• To assess transfer mechanisms, PK factors in
  Cmilk variations
• MP ratio (maternal PK-Cmilk)

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Exposure Index
MP ratio
x 10

EI ()
CL (ml/kg/min)
Ito Koren 1994
EIgt10 Phenobarbital 100 Ethosuximide 50
Atenolol 25 Lithium 2-30 Metronidazole
3-18
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3. Carrier-mediated systems

• clinical implications
• interactions
• potential intervention
• net transfer may or may not deviate from a
  diffusion model

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?Organic cation transporters
Maternal plasma
Milk
Cmilk
Cplasma
pH7.4
pH 7.0
Myoepithelia
Epithelia
Diffusion a McNamara lab
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Organic cation transporters
(OCT1, OCT2, OCT3, OCTN1, and OCTN2, etc)
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Human mammary gland
P-glycoprotein ???
hOCT2
hOCT1
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hOCTN1 and N2
hOCTN1
hOCTN2
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P-gp expression in MCF12A
intracellular
surface
MRK16
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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 (n3)
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Carnitine uptake results
4oC
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Saturable carnitine uptake in MCF12A (Kwok et al.
CPT 2001)
Km 1.9 ?M Vmax 158 pmol/106 cells/hr
Mean SD (n3)
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Inhibitor specificity
Mean SD (n3)
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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

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Level 0 Preclinical Study

• various models
• predict in vivo Cmilk, transport systems etc.
• potential effects on prolactin etc.
• provide ethical framework for human
  experimentation

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Level I Clinical Study

• lactating/non-breastfeeding women
• dose-Cmilk (AUC) infant dose, wt-adj maternal
  dose
• MP ratio Exposure Index
• in colostrum, transitional, and mature milk in
  foremilk and hindmilk

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Level II Clinical Study

• breastfeeding dyad
• dose-Cmilk to estimate variations
• Cinfant
• PD endpoints
• infant effects
• milk yield