scholarly journals Intestinal permeation enhancers for oral peptide delivery

2016 ◽  
Vol 106 ◽  
pp. 277-319 ◽  
Author(s):  
Sam Maher ◽  
Randall J. Mrsny ◽  
David J. Brayden
Keyword(s):  
Peptide Delivery ◽  
Permeation Enhancers ◽  
Oral Peptide Delivery ◽  
Intestinal Permeation ◽  
Intestinal Permeation Enhancers

Abstract 13307: An Oral Antisense Oligonucleotide for PCSK9 Inhibition in Humans

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Peter Gennemark ◽  
Katrin Walter ◽  
Niclas Clemmensen ◽  
Dinko Rekic ◽  
Catarina Nilsson ◽  
...  
Keyword(s):  
Steady State ◽  
Oral Administration ◽  
Antisense Oligonucleotide ◽  
Oral Delivery ◽  
Permeation Enhancers ◽  
Pcsk9 Inhibitors ◽  
Liver Uptake ◽  
Pcsk9 Inhibition ◽  
Intestinal Permeation ◽  
Intestinal Permeation Enhancers

Current PCSK9 inhibitors are administered via subcutaneous (SC) injection. Here, we present a highly potent, chemically modified PCSK9 antisense oligonucleotide (ASO) with potential for oral delivery. Past attempts at oral delivery using earlier ASO chemistries and intestinal permeation enhancers provided encouraging data, suggesting that improving potency of the ASO could make oral delivery a reality. The constrained ethyl chemistry and liver targeting enabled by tri-antennary N -acetyl galactosamine (GalNAc) conjugation make this ASO highly potent. A single SC dose of 90 mg reduces PCSK9 by >90% in humans with elevated LDL-C (A), and a once monthly SC dose of 25 mg ([20, 30], 90% CI) is predicted to reduce PCKS9 by 80% at steady-state. To investigate the feasibility of oral administration, we developed an oral solid tablet wherein the ASO is co-formulated with a transient permeation enhancer. Repeated oral daily dosing of tablets to dogs resulted in a bioavailability of 7% in the liver (target organ), approximately 5-fold greater than the plasma bioavailability (B). Favourable liver uptake following oral administration is supported by similar bioavailability in plasma and kidney. Since the ASO is not active in rodents or dogs, we used a rat-specific GalNAc- Malat-1 ASO with the same chemistry to confirm target engagement. Intrajejunal administration resulted in ≥78% mRNA knockdown in the liver for single doses of 3-40 mg/kg. A monkey tolerability study of the PCSK9 ASO further supports oral feasibility with all tested doses (28-56 mg/day) significantly reducing LDL-C already after 7 days of daily oral dosing. Based on available animal and human data, and an assumption of 5% oral bioavailability in humans, a daily dose of 15 mg ([10, 20], 90% CI) in man is predicted to reduce PCSK9 in plasma by 80% at steady-state. This supports the development of the compound for subcutaneous and oral administration to treat dyslipidemia.

scholarly journals Safety concerns over the use of intestinal permeation enhancers: A mini-review

2016 ◽  
Vol 4 (2) ◽  
pp. e1176822 ◽  
Author(s):  
Fiona McCartney ◽  
John P. Gleeson ◽  
David J. Brayden
Keyword(s):  
Permeation Enhancers ◽  
Safety Concerns ◽  
Intestinal Permeation ◽  
Intestinal Permeation Enhancers
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