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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

Assessing Drug Transfer into Breast Milk

Shinya Ito, MD

Hospital for Sick Children

Toronto, Canada

four discussion points
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
1. Why do we need data?
  • Uncertainty compromises breastfeeding
    • Antibiotics and Propylthiouracil (PTU)
  • Identifying a “TDM” drug
    • Lithium
  • Identifying a “contraindicated” drug
slide4

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

slide5

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
“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)

slide7

<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

slide8

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

slide9

AAP (1989,1994):

  • “compatible”
  • Briggs/Freeman/Yaffe (1994):
  • “no significant risk”
  • Bennett/WHO (1988):
  • “probably safe”
  • CPS (2001):
  • “contraindication”
slide10

%

100

50

0

Women on PTU

do not start breastfeeding

Lee et al. Pediatrics 2000

Control

PTU

slide11

%

100

50

0

Women on PTU

do not start breastfeeding

Lee et al. Pediatrics 2000

Formula

Adviced by MDs

Breastfeeding

tdm drug
“TDM” drug
  • TDM to individualize management
  • % wt-adj maternal dose: >10%
  • large interindividual variation
  • dose-dependent effects
  • lithium as an example
identifying contraindicated drug
Identifying contraindicated drug
  • % wt-adj maternal dose: >10%
  • toxicity (dose-dependent,

dose-independent)

  • TDM unsuitable
2 what data do we need
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
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
3. Carrier-mediated systems
  • clinical implications
    • interactions
    • potential intervention
  • net transfer: may or may not deviate from a diffusion model
slide17

?Organic cation transporters

Milk

Maternal plasma

[Cmilk]

[Cplasma]

pH7.4

pH 7.0

Myoepithelia

Epithelia

Diffusion + a: McNamara lab

organic cation transporters
Organic cation transporters
  • P-glycoprotein
  • Organic Cation Transporters

(OCT1, OCT2, OCT3, OCTN1, and OCTN2, etc)

slide19

12A

Human mammary gland

P-glycoprotein ???

hOCT2

hOCT1

slide20

785 base pair

product

800 base pair

product

hOCTN1 and N2

hOCTN1

hOCTN2

slide21

P-gp expression in MCF12A

intracellular

surface

MRK16

slide22

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)

slide23

Mean ± SD (n=3)

with Na+

without Na+

Carnitine uptake results

4oC

slide24

Saturable carnitine uptake in MCF12A (Kwok et al. CPT 2001)

Km = 1.9 M

Vmax = 158 pmol/106 cells/hr

Mean ± SD (n=3)

slide25

Carnitine

Cimetidine

inhibition

TEA

Choline

Guanidine

Inhibitor specificity

Mean ± SD (n=3)

4 graded approach
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
“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
“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
“Level II” Clinical Study
  • breastfeeding dyad
  • dose-[C]milk to estimate variations
  • [C]infant
  • PD endpoints
    • infant effects
    • milk yield