Assessment of Drug Exposure in the Breastfed Infant

1
Assessment of Drug Exposure in the Breast-fed
Infant

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

2
Outline

• Review of various parameters to assess infant
  exposure
• Infant dose
• wt-adjusted maternal dose
• Therapeutic Dose vs. Exposure Index
• Exposure Index and its determinants
• MP ratio and infant drug clearance
• Overview of infant exposure to CNS-acting drugs
• Challenges (e.g., potential milk-drug interaction)

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Key information for clinical risk assessment

• Likelihood of infant toxicity
• Large epidemiological studies are needed.
• Amount of drug the infant would ingest through
  milk Infant exposure
• Relatively easy to estimate. But, some
  assumptions must be made.

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Parameters of Infant Exposure

• Infant dose through milk Doseinf
• Cmilk x milk intake
• weight-adjusted maternal dose
• (Doseinf per BW /Dosemat per BW ) x 100

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Infant Dose Cmilk x milk intake

• Issues
• Cmilk is time-dependent.
• Within-feeding/-dose variation
• Maximum C, Average C, or AUCmilk
• Foremilk, hind milk, or average
• Lactation phase variation (long range)
• Colostrum, transitional, or mature
• Milk intake must be assumed.
• 150 ml/kg/day is it valid?
• Needs to be compared with a reference dose.

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wt-adjusted maternal dose (Doseinf per BW
/Dosemat per BW ) x 100

• Issues
• Infant dose issues 1 and 2
• Variations in Cmilk and infant dose due to
  differences in maternal doses may not be evident.

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Therapeutic Dose Infant therapeutic dose
(Dosethr) as a reference (Doseinf per BW
/Dosethr per BW ) x 100

• Issue
• Infant therapeutic dose may be unknown.

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Exposure Index (EI)a special form of
Therapeutic Dose, highlighting PK determinants
Milk intake x 100
MP ratio
x 10

EI ()
CL (ml/kg/min)
Ito Koren. Br J Clin Pharmacol 1994
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Milk-to-plasma ratio (MP ratio)

• Parameter of drug excretion into milk
• Partial parameter for infant exposure level

Maternal plasma
Milk
Cmilk or AUC
Cplasma or AUC
Myoepithelia
Epithelia
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Determinants of Exposure IndexSignificance of
infant drug clearance
EI () MP ratio x 10 / CL
Ito. NEJM 2000
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MP ratio does not necessarily reflect infant
exposure level.
MP ratio gt 2 MP ratio Ranitidine 7 Nadolol
6 Sotalol 4 Atenolol 4 Metoprolol 3 Morphine 2
EI gt 10 EI() Phenobarbital 100 Ethosuximide
50 Atenolol 25 Lithium 2-30 Metronidazole
3-18
12
Infant exposure levels Overview- Estimating the
infant dose from published reports -

• Antidepressants
• Antipsychotics
• Anxiolytics
• Antiepileptics
• Medline (1966-2003) drugs and human milk
• 345 papers identified above drug groups
• 94 studies reporting Cmilk
• wt-adjusted maternal dose was analyzed

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Current recommendation on Drug use during
breastfeeding

• American Academy of Pediatrics Committee on
  Drugs. Pediatrics 2001 108776-789
• Cytotoxic drugs
• Drugs of abuse
• Radioactive compounds
• Unknown effects, may be of concern
• Significant effects, give with caution
• Usually compatible
• Food and environmental agents

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AAP Table 4. Unknown effects, may be of concern

• Anti-anxiety e.g., benzos
• Antidepressants e.g., fluoxetine
• Antipsychotic e.g., chlorpromazine
• Others
• Amiodarone
• Chloramphenicol
• Clofazimine
• Lamotrigine
• Metoclopramide
• Metronidazole (and tinidazole)

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SSRIs
wt-adjusted maternal dose
lt1
1 to lt10
10 to lt20
20 to lt50
50 or over
Drugs (n)
Citalopram (11)
Fluoxetine (61)
Fluvoxamine (6)
Mean
Paroxetine (60)
Range
Sertraline (36)
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Other antidepressants
wt-adjusted maternal dose
lt1
1 to lt10
10 to lt20
20 to lt50
50 or over
Drugs (n)
Amitriptyline (6)
Clomipramine (3)
Doxepin (3)
Mean
Imipramine (5)
Range
Lithium (14)
Venlafaxine (9)
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Antipsychotics
wt-adjusted maternal dose
lt1
1 to lt10
10 to lt20
20 to lt50
50 or over
Drugs (n)
Haloperidol (11)
Olanzapine (12)
Clozapine (1)
Mean
Risperidone (1)
Range
18
Anxiolytics
wt-adjusted maternal dose
lt1
1 to lt10
10 to lt20
20 to lt50
50 or over
Drugs (n)
Clonazepam (1)
Diazepam (8)
Oxazepam (1)
Mean
Lorazepam (1)
Range
Temazepam (10)
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Antiepileptics
wt-adjusted maternal dose
lt1
1 to lt10
10 to lt20
20 to lt50
50 or over
Drugs (n)
Carbamazepine (29)
Ethosuximide (6)
Phenobarbital (12)
Mean
Phenytoin (9)
Range
Primidone (5)
Valproic acid (21)
20
Other antiepileptics
wt-adjusted maternal dose
lt1
1 to lt10
10 to lt20
20 to lt50
50 or over
Drugs (n)
Gabapentin (2)
Lamotrigine (11)
Topiramate (3)
Mean
Vigabatrin (2)
Range
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Infant exposure levelsSummary

• The infant dose is mostly lt10 of the adult
  therapeutic dose on a body weight basis.
• Some drugs show wide variations e.g., lithium,
  sertraline, and phenobarbital.
• Some key data are often unreported e.g.,
  mothers body weight
• More data are needed for most drugs.

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How much is too much?gt10 of the adult
therapeutic dose?

• Crucial information
• PK/PD in developing infants
• Ontogeny of drug clearance
• Development of drug responses
• Tissue target site penetration
• Long and short-term effects epidemiological data
• potential milk-drug interaction

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Slow caffeine elimination in infants
Half-life (h)
Postconceptional age (weeks)
Le Guennec and Billon. Pediatrics 198779264-8
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Formulas, but not human milk, induce CYP1A
expression
RT-PCR / HepG2 cells
Western blot / HepG2 cells
CYP1A1 CYP1A2
Fold induction
RT-PCR / fetal mouse liver
HM F1 F2 PBS DBA
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AHR-mediated CYP1A Induction
CYP1A2
L
ARNT
AHR
Toxicity
?
TCDD, PCB
XRE
L
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Formulas activate AhR, but human milk does not.
Plt0.05
M SD n 3-6
10
Fold induction
5
1
0
DBA
PBS
HM
F1
F2
F1P
F2P
F3P
F4P
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Summary

• There is no standardized way to express infant
  exposure levels.
• A guideline is needed for data reporting.
• Therapeutic dose (TD) is a reasonable index
  for infant exposure.
• How to estimate the infant therapeutic dose is a
  challenge.
• Exposure Index( TD) is highly dependent on
  infant drug clearance.

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Summary

• PK/PD in neonates/infants influences the risk
  assessment. But the data are scarce.
• Milk-drug interaction may need attention.
• Acknowledgement
• Canadian Institute of Health Research