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 µg/ml and 1,000. Maternal regions of the placenta had twice the oligonucleotide concentration compared to fetal regions of the placenta (6 µg/g vs. 3 µg/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 µg/ml and fetal concentrations were