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- Ken Ilett BPharm PhD
- Associate Professor in Pharmacology
- School of Medicine and Pharmacology
- University of Western Australia
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- Oil:water partition coefficient
- Concentration in blood (passive diffusion gradient)
- Fat content of milk (co-solubility for some drugs)
- Ionisation status of drug; acid or base; pKa and pH of milk [7.2 vs 7.4
in plasma]
- Extent of protein binding of drug in plasma and milk
- Molecular weight of drug (only for small molecules; e.g. heparin does
not enter)
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- A measure of equilibrium distribution between milk and plasma
- Examples:
- THC = 8, aspirin 0.08, ethanol 1, diazepam 2.7, venlafaxine 2.9
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- May be used to estimate concentration in milk when only the level in
plasma is known
- Milk concentration = plasma concentration x M:P
- HAS NO DIRECT RELEVANCE TO DRUG SAFETY IN LACTATION
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- Absolute dose
- = Drug concentration in milk x volume of milk ingested
- Drug concentration can be measured (mg/litre)
- Volume of milk can be measured or simply taken as the average value of
0.15 litres/kg/day
- Absolute dose ends up as mg/kg/day
- Interpret by comparing with paediatric doses where the drug has a
legitimate use in infants or children
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- Used where the drug has no usual therapeutic application in infants
- It is simply a comparison with the maternal dose
- Relative infant dose = absolute infant dose (mg/kg/day)
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mother’s dose (mg/kg/day)
- Expressed as a percentage
- We use our knowledge of infant clearance to set a SAFE dose level for
the infant - < 10% is usual
criterion
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- A joint evaluation between mother, father and paediatrician
- For the infant:
- Inherent toxicity of the drug
- Absolute infant dose ideally lower than usual paediatric doses
- Relative infant dose ideally > 10% of maternal dose
- Bonding, antibodies, perhaps less disease
- For the mother
- Adverse consequences untreated disease (e.g. depression)
- Bonding, lowered risk of breast cancer etc
- Always follow-up with regular observation of infant
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- Metformin – an oral antidiabetic drug
- Amphetamine and methamphetamine – used for ADHD and for recreation
purposes respectively
- Nicotine – smoking versus the nicotine skin patch
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- Diabetes - (mostly type II, NIDDM) affects around 6% of the population
and in the last decade there has been a 30% increase in younger
individuals
- Metformin - oral antidiabetic
agent – first line Rx for NIDDM.
Also has beneficial effects in polycystic ovary syndrome
(PCOS). No data on transfer of
metformin into milk.
- Metformin – small highly water soluble
molecule, oral bioavailability 50-60%
half-life 4-5 hours
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- Aims:
To characterise milk/plasma (M/P) ratio and infant dose for
metformin in breastfeeding women, and measure plasma concentrations and
any effects in their infants.
- Hypothesis:
That maternal metformin use is safe for the breastfed infant.
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- Patients:
Seven women taking metformin for treatment of PCOS or NIDDM, and
their infants, were studied.
- Ethics approval:
Research and Ethics Committee of Women’s and Children’s Health
Service, and also by the Texas Tech University Institutional Review
Board.
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- Maternal sample collection:
- Detailed study of milk and plasma metformin concentrations was made
over an 8 h dose interval at steady-state (n=2).
- Metformin concentration in milk (AUC determination) was measured using
samples collected over 3 sequential 8 h dose intervals at steady-state
(n=4).
- Single milk and plasma sample (n=1).
- Infant sample collection and evaluation:
Plasma sample for metformin analysis (n= 4). General health and wellbeing also
evaluated.
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- Analysis of metformin:
Validated high performance liquid chromatographic method for both
milk and plasma with intra- and inter-day precision of <12.1%
- Calculation of M/P ratio:
From plasma- and milk concentration measurements
- Calculation of infant dose:
Absolute and relative doses calculated according to standard
methods
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- Maternal data:
Mean age 34y (range 26-38 y) and
mean body weight 97 kg (range 73-116 kg)
Six women took 500 mg of metformin orally, thrice daily before
meals, while one (#6) took 500 mg of a slow release metformin formulation
once daily
Median daily metformin dose was 14 mg kg-1 day-1
(range 6.9-20 mg kg-1 day-1)
- Five treated for PCOS, and two
for NIDDM
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- Infant data:
4 M and 4 F with a mean age of 14.3 months (range 5-25 months)
and a mean body weight of 10.8 kg
(range 6.5-15 kg)
- All infants progressing well according to mother/paediatrician reports
(no data available for patient #3).
Detailed Denver Development assessments in infants of patients #
1 & 2 were normal
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- Mean M/P of 0.35 is quite low, and in keeping with high water solubility
of metformin
- Mean relative infant dose of 0.28% is well below the 10% level of
concern
- Absence of any adverse effect in
the infants is also reassuring, although our data on this area are
sparse and somewhat subjective
- Women who need to take metformin for control of NIDDM or PCOS should be
encouraged to breastfeed their infants
- T. W. Hale, J. H. Kristensen, L. P. Hackett, R. Kohan, K. F. Ilett:Transfer
of metformin into human milk, Diabetologia, 2002 (in press)
http://link.springer.de/link/service/journals/00125/tocs.htm
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- Dexamphetamine - Widely used for the Rx of ADD or ADHD
- Methamphetamine – popular recreational use
- Concerns about use in breastfeeding
- Limited published data
- Psychoactive drug with potential for insomnia, irritability and
anorexia in infants
- Society generally does not support use
- American Academy of Pediatrics says contraindicated
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- Steiner & Hallberg, 1959
- Dose 15 mg
- Milk concentrations 55-138 mg/l
- Relative infant dose 2.5-6.2%
- No adverse effects
- Ayd, 1973
- Observational study of 103 infants whose mothers took amphetamines
- No neonatal stimulation or insomnia reported
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- 41 year old, 70 kg - ADHD
- 45 mg /day
- M/P = 2.7
- Average 313 mg/l in milk
- Absolute infant dose 10 mg/kg/day
- Relative infant dose 7.3%
- Infant, F aged 5 months
- - no adverse effects
- Dexamphetamine in plasma 18 mg/l
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- 28 year old, 66 kg – ADHD
- 30 mg/day
- M/P not measured
- Average 564 mg/l in milk
- Absolute infant dose
= 85 mg/kg/day
- Relative infant dose 18.6%
- Infant, M aged 2 months
- - no adverse effects
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- Variable relative infant dose a concern
- Limited published data on infant dose
- Plan more studies locally to address need
- Large infant observational study is supportive of use
- Concerns
- ? Effect on infant’s long-term development
- ? Decreased milk production
- Hesitant to recommend breastfeeding – however, the reality is that it
happens – suggest regular assessment of infant’s progress
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- 29 year old, 64 kg
- 1 point
- M/P – not measured
- Average methamphetamine 110 mg/l
& amphetamine 6 mg/l in milk
- Absolute infant dose
=18 mg/kg/day in 24 hours as methamphetamine
- Infant, M aged 4 months
- - no adverse effects
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- 27 year old, 68 kg
- 1 point
- M/P – not measured
- Average methamphetamine 454 mg/l
& no amphetamine in milk
- Absolute infant dose
= 68 mg/kg/day in 24 hours
as methamphetamine
- Infant, F aged 4 months
- - no adverse effects
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- Absolute infant dose is in the same range as therapeutic use of
dexamphetamine
- Only two studies at this stage – limited data
- More studies needed to assess range of doses and infant wellbeing
- Educating mother is most important
- Withholding breastfeeding for 24 hours would protect infant from
exposure
- Suggest express milk day before use and bottle feed to infant
- Someone else around to look after infant during use sessions very
important
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- Background
- In Perth about 12% of lactating women smoke
- Exposure of breastfed infants to environmental tobacco smoke is
undesirable – nicotine, cotinine and carcinogenic pyrolysis products –
in smoke and via milk
- Nicotine can decrease prolactin and hence reduce milk supply
- Hypothesis
- The nicotine patch may assist lactating women to quit
- Exposure to nicotine and cotinine will overall be lower than when
smoking
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- Recruited 25 lactating women who were smokers
- Offered nicotine patch (Nicabate CQÔ, GSK) at equivalent dose, with gradual reduction in
patch strength and cessation over 10 weeks
- 14 women completed the trial;mean 32 y, 73kg, 16.5 cig/day and smoked
for 15.6 y
- Milk samples collected over 24 hours when smoking and at each patch
level
- Measured nicotine and cotinine in milk by high performance liquid
chromatography
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- At equivalent doses the patch and cigarettes deliver the same amount of
nicotine and cotinine into breastmilk
- As the patch strength is decreased, there is a proportionate decrease in
the amount of nicotine and cotinine in milk
- The patch is preferred because:
- The infant dose of nicotine & cotinine is equal to or lower that
that from cigarettes – zero after 10 weeks
- There is no infant exposure to carcinogens in milk or via the
environment
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- Tom Hale
- Department of Pediatrics, Division of Clinical Pharmacology, Texas Tech University School of
Medicine, Amarillo, Texas, USA
- Judy Kristensen and Malcolm Roberts
- Department of Pharmacy, King Edward Memorial & Princess Margaret
Hospitals, Subiaco, Western Australia
- Peter Hackett and Leon Dusci
- Clinical Pharmacology & Toxicology Laboratory, The Western
Australian Centre for Pathology & Medical Research, Nedlands,
Western Australia
- Rolland Kohan
- Department of Neonatal Services, King Edward Memorial Hospital,
Subiaco, Western Australia
- Madhu Page-Sharp
- School of Medicine & Pharmacology, University of Western Australia,
Crawley, Western Australia
- Anne Bartu
- Next Step Drug and Alcohol Services, Mt Lawley, Western Australia
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Notes
