Oral Delivery of Antisense Oligonucleotides in Man

ABSTRACTTreatment of systemic disease with phosphorothioate antisense oligonucleotides (PS ASOs) has been accomplished using local or parenteral routes of administration to date. This report describes, for the first time, the effective oral delivery of a second generation oligonucleotide where significant milligram amounts of intact drug are absorbed in human subjects. In this study, a variety of oral solid dosage formulations were evaluated and it was determined that pulsing the delivery of sodium caprate (C10), a well‐known permeation enhancer, in a novel manner may provide optimal ASO plasma bioavailability. Further, these dosage forms, containing C10 and ASO, were well tolerated in both fasted and fed volunteers. Oral absorption of the 2′‐O‐(2‐methoxyethyl) modified antisense oligonucleotide (2′‐MOE ASO), ISIS 104838, was demonstrated in healthy volunteers with an average 9.5% plasma bioavailability across four formulations tested. The greatest average performance achieved in this study for a single formulation was 12.0% bioavailability within an individual dose and subject range of 1.96–27.5%. The totality of the data suggests that formulations can be devised that allow oral administration of oligonucleotides that maintain systemic concentrations associated with inhibition of targeted human mRNA. © 2007 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:225–236, 2008