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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
Otitis mediaOwen et al. J Pediatr 1993
Bacteremia Takala et al. J Pediatr 1989
Bacterial meningitisCochi et al. J Pediatr 1986
NEC Lucas & Cole. Lancet 1990
Silva et al. Aust Ped J 1978Morley et al. Arch Dis Child 1988Lucas et al. Lancet 1992Pollock. Dev Med Child Neurol 1994Gale & Martyn. Lancet 1996Horwood & Fergusson Pediatrics 1998
• Cognitive function
IQ 8 pts
“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)
Propylthiouracil (PTU) and breastfeeding
Amounts excreted into milk<0.3% of the mother’s dose
on a weight basis
Low et al. Lancet 1979;2:1011Kampman et al. Lancet 1980;1:736-7Cooper. N Eng J Med 1984;311:1353-62
<10%
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 infantMomotani et al. Clin Endocrinol 1989;31:591-5
• AAP (1989,1994): “compatible”
• Briggs/Freeman/Yaffe (1994): “no significant risk”
• Bennett/WHO (1988): “probably safe”
• CPS (2001): “contraindication”
Women on PTU do not start breastfeeding
0
50
100% Lee et al. Pediatrics 2000
Adviced by MDs
Breastfeeding
Formula
“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
EI (%) = MP ratio x 10
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
[Cmilk] [Cplasma]
Maternal plasmaMilk
EpitheliaMyoepithelia
pH 7.0 pH7.4
?Organic cation transporters
Diffusion +: McNamara lab
Organic cation transporters
•P-glycoprotein•Organic Cation Transporters(OCT1, OCT2, OCT3, OCTN1, and OCTN2, etc)
Saturable TEA uptake in the human mammary epithelial cells, MCF12A (Dhillon et al. CPT 2000)
Concentration of TEA (mM)0 4 8 12 16 20U
pta
ke (
nm
ol/m
g p
rote
in/0
.5 h
r)
0
20
40
Mean ± SD (n=3)
Km = 3.4 mMVmax = 18.5 nmol/mg protein/0.5 hr
time (min)
0 20 40 60 80 100 120 140 160 180 200
upta
ke (
pm
ol/
106
cells)
0
20
40
60
80
100
120
140
Mean ± SD (n=3)
Carnitine uptake results
with Na+
without Na+
4oC
Saturable carnitine uptake in MCF12A (Kwok et
al. CPT 2001)
[carnitine] mM
0.00 0.01 0.02 0.03 0.04 0.05 0.06 0.07
upta
ke (
pm
ol/106
cells
/hr)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
Mean ± SD (n=3)
Km = 1.9 MVmax = 158 pmol/106 cells/hr
[inhibitors] mM
10-7 10-6 10-5 10-4 10-3 10-2 10-1 100 101 102
perc
enta
ge c
arni
tine
upta
ke
0
20
40
60
80
100
120
140
Inhibitor specificity
CarnitineCimetidineTEACholineGuanidine
Mean ± SD (n=3)
inhibition
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