Assessing Drug Transfer into Breast

Milk

Shinya Ito, MDHospital 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

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%

Control

Lee et al. Pediatrics 2000

PTU

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)

Human mammary gland

P-glycoprotein ???

hOCT1

hOCT212A

hOCTN1 and N2

hOCTN2

800 base pairproduct

hOCTN1

785 base pairproduct

P-gp expression in MCF12A

MRK16

intracellular surface

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

“Level II” Clinical Study

• breastfeeding dyad• dose-[C]milk to estimate

variations• [C]infant • PD endpoints

– infant effects– milk yield