Oral bioavailability and multiple dose tolerability of an antisense oligonucleotide tablet formulated with sodium caprate

In vivo study was performed to determine the tolerability and pharmacokinetics of ISIS 104838, a phosphorothioate antisense oligonucleotide targetting human tumour necrosis factor alpha (TNF‐α) mRNA, following multi‐dose administration via intravenous and oral routes. Oral tablet formulations of ISIS 104838 were pre‐formulated with the permeation enhancer, sodium caprate, in an enteric‐coated solid dosage form. The average plasma bioavailability of ISIS 104838 was 1.4% relative to IV. The tissue distribution profile was similar following both routes of administration, with highest concentrations observed in the kidney followed by the liver, lymph nodes and spleen. Plasma bioavailability underestimated the tissue accumulation of ISIS 104838 observed 1 day after the last dose. Mean systemic tissue bioavailability ranged from 2.0 to 4.3%, relative to IV tissues, and was dependent on tissue type. No marked differences were noted in the pharmacokinetic parameters following multi‐dosing either via intravenous or oral routes. All formulations administered were well tolerated. This paper reports the first evaluation of solid oral dosage forms comprising sodium caprate and an antisense oligonucleotide. Furthermore, this study demonstrates the oral delivery of ISIS 104838 from solid oral dose formulations, with the achievement of comparable tissue concentrations of the oligonucleotide to that of the intravenous treatment. © 2004 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 93: 1431–1439, 2004