Re: Imatinib concentrations in human milk

[Guest guest]

Zavie,

Thanks for sharing this information. This is very interesting and I hope more

studies are done on this subject!

B

Dx 5/2/05

600 mg

Zavie miller <zmiller@...> wrote:

Here is the text of the paper.

A pdf version has been added to the files section of .

Zavie

Correspondence

To the editor:

Imatinib concentrations in human milk

Imatinib substantially changed the course and prognosis of chronic

myeloid leukemia (CML). As a consequence, several female CML

patients decided to become pregnant. In this setting, an unsolved clinical

question regards the potential exposure of the offspring to therapeutic

doses of imatinib through breast feeding. We report here the results

obtained in a 40-year-old CML patient who delivered a healthy male

baby after 38 weeks of gestation. The patient decided to breastfeed her

son. During the fourth week of lactation, plasma and milk samples were

obtained from the patient, after receiving written informed consent, and

collected immediately before and at 1, 2, 3, 4, and 9 hours after the daily

oral administration of 400 mg of the drug. Imatinib and its main active

metabolite N-desmethyl derivative (CGP 74588) were extracted from

milk and plasma using a protein precipitation procedure with acetonitrile1

and quantified by a liquid chromatography coupled to tandem

mass spectrometry method (HPLC/MS/MS). The mass spectrometer

was operated in the multiple-reaction monitoring mode, and following

HPLC separation, the peak areas corresponding to the mass-charge ratio

(m/z) 494_394 reaction for imatinib and m/z 480_394 for CGP 74588

were measured. The limit of quantitation in milk samples was 30 ng/mL

for both analytes, and the recovery rate was greater than 85%.

Figure 1 reports the concentration profiles over time obtained in

plasma and milk. Imatinib and CGP 74588 achieved plasma

steady-state concentrations ranging from 3.0 to 3.2 and 0.8 to 1.1

_g/mL, respectively.

Both the parent drug and the metabolite distributed in human

milk. The milk-plasma ratio reached 0.5 for imatinib and 0.9 for

CGP 74588. Therefore CGP 74588 showed relatively higher

concentrations in milk, reaching a steady-state level of 0.8 _g/mL,

quite close to the concentrations of the parent drug, which ranged

between 1.1 and 1.4 _g/mL. Similar results were obtained in

samples obtained during the second month of breastfeeding.

Milk intake in infants is known2 to average 728 to 777 mL/d

(with a range of 450 to 1165 mL/d). Considering the combined

concentration of imatinib and CGP 74588 and the maximum milk

intake described, it is unlikely that infants will receive more than 3

mg/d. Even when considering infant weight in the first months of

life, this amount is quite far from therapeutic ranges, and the

exposure might correspond to about 10% of a therapeutic dose.

Therefore, these results, although obtained in a single patient and

needing confirmation by larger series, suggest that mothers with CML

could safely breast-feed their children. Given the important biologic and

psychological value of breast-feeding, such information will be useful

for CML patients considering a pregnancy and for the hematologists

caring for them. However, the effects of even low-dose, chronic

exposure of infants to imatinib are not known. Accordingly, in such a

case mothers would want to discuss this option with their pediatrician.

Carlo B. Gambacorti-Passerini, Lucia Tornaghi, Elena Marangon,

Franceschino, Enrico M. Pogliani, Maurizio D'Incalci, and

Massimo Zucchetti

Correspondence: Carlo B. Gambacorti-Passerini, Internal Medicine, University

of Milano Bicocca and San Gerardo Hospital, via Cadore 48, 20052 Monza,

Italy; e-mail: carlo.gambacorti@....

Conflict-of-interest disclosure: The authors declare no competing financial

interests.

References

1. Parise RA, Ramathan RK, MJ, Egorin MJ. Liquid chromatographicmass

spectrometric assay for quantitation of imatinib and its main metabolite

(CGP 74588) in plasma. J Chromatogr B. 2003;791:39-44.

2. Committee on Nutritional Status During Pregnancy and Lactation, Institute

of

Medicine (IOM), National Academy of Sciences (NAS). Nutrition during

lactation.

Washington, DC: The National Academies Press; 1991.

Figure 1. Concentrations of imatinib and CGP 74588 in plasma and milk at

steady state.

1790 BLOOD, 15 FEBRUARY 2007 _ VOLUME 109, NUMBER 4

[Guest guest]

Thanks for sharing that with us Zavie. What great timing for Amy too!

It's too bad they don't mention whether or not this patient continued

to take her Gleevec throughout the pregnancy or if she resumed it only

after delivery but either way, it sure does give hope to women who may

want to get pregnant.

Tracey