Maternal and fetal distribution of a phosphorothioate oligonucleotide in rats after intravenous infusion.
BACKGROUND
Fetal uptake of an antisense oligonucleotide was evaluated after intravenous (i.v.) dosing of ISIS 2105, a 20-base phosphorothioate oligonucleotide, in timed-pregnant Sprague-Dawley rats.


METHODS
To maximize the potential for fetal exposure, ISIS 2105 was administered as a 3-hr infusion at 6.6 mg/kg/hr with a total dose of 20 mg/kg, or as a continuous 7-day infusion at 0.35 mg/kg/hr with a total dose of 59 mg/kg. This dosing regime is higher than a patient would be expected to receive in the clinical use of oligonucleotides. Infusions were delivered through a jugular vein cannula by syringe pump on gestation day (GD) 19 (3-hr exposure) or by osmotic pumps implanted subcutaneously (s.c.) starting on GD 12 (7-day exposures).


RESULTS
After a 3-hr infusion, maternal and fetal plasma concentrations of ISIS 2105 were >100 microg/ml and <0.07 microg/ml, respectively with a maternal fetal ratio of >1,000. Maternal regions of the placenta had twice the oligonucleotide concentration compared to fetal regions of the placenta (6 microg/g vs. 3 microg/g). After this acute exposure the concentrations in fetal kidney and liver were approximately 140- and 500-fold less than the maternal kidney and liver respectively. After 7-day infusion maternal plasma concentrations were 0.82 microg/ml and fetal concentrations were <0.22 microg/ml. By capillary gel electrophoresis (CGE) only the fetal liver consistently had quantifiable oligonucleotide concentrations (range=1.01-4.95 microg/g) compared to a mean concentration of 50.11+/-1.71 microg/g in the maternal liver a maternal to fetal ratio of approximately 10:50 after 7 days of infusion.


CONCLUSIONS
There was a low level of transfer from dam to fetus, consistent with a slow equilibrium but the permeability of placenta to this 6 kDa polyanionic compound seemed to be limited even at supraclinical doses.
Soucy
Nicole V
NV
Graduate School of Public Health, San Diego State University, San Diego, California, USA. nsoucy@ciit.org
Riley
Jason P
JP
Templin
Michael V
MV
Geary
Richard
R
de Peyster
Ann
A
Levin
Arthur A
AA
D000818:Animals; D005260:Female; D007262:Infusions, Intravenous; D008431:Maternal-Fetal Exchange / Q000502:physiology*; D009841:Oligonucleotides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013873:Thionucleotides / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D009841:Oligonucleotides; D013873:Thionucleotides; C084960:afovirsen sodium