# Presentation: 375940

## 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**
**Antibiotics and Propylthiouracil (PTU) **
**Identifying a “TDM” drug**
**Lithium **
**Identifying a “contraindicated” drug**

## Diarrhea 	Dewey et al. Pediatrics 1995

**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***

## Silva et al. 			Aust Ped J 1978

**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

**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;2:1011*
*Kampman et al. Lancet 1980;1:736-7*
*Cooper. N Eng J Med 1984;311:1353-62*

## No effect on the thyroid 

**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*

##  AAP (1989,1994): 

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

## Women on PTU 

**Women on PTU **
**	****	****do not start breastfeeding**

**Control**

***Lee et al. Pediatrics 2000***

**PTU**

## Women on PTU 

**Women on PTU **
**	****	****do not start breastfeeding**

***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**

## ?Organic cation transporters

- <date/time>

**[C****milk****]**

**[C****plasma****]**

**Maternal plasma**

**Milk**

***Epithelia***

***Myoepithelia***

**pH 7.0**

**pH7.4**

**?Organic cation transporters**

**Diffusion +********: *****McNamara lab***

## Organic cation transporters

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

## Human mammary gland

**P-glycoprotein ???**

**hOCT1**

**hOCT2**

## hOCTN1 and N2

**hOCTN2**

**hOCTN1**

## P-gp expression in MCF12A

**P-gp expression in MCF12A**

**MRK16**

**intracellular**

**surface**

## 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**

## Carnitine uptake results

**Carnitine uptake results**

**4****o****C**

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

- Mean ± SD (n=3)

- Km = 1.9 M
- Vmax = 158 pmol/106 cells/hr

## Inhibitor specificity

**Inhibitor specificity**

- Mean ± SD (n=3)

## 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**