Search

Aims: Ropeginterferon alfa-2b is a novel, long-acting pegylated interferon alfa-2b. We aimed to evaluate its safety, pharmacokinetics (PK) and pharmacodynamics (PD)., Methods: Thirty-six subjects received single subcutaneous injection of ropeginterferon alfa-2b at doses ranging from 24 to 270 μg, and 12 subjects received pegylated IFN alfa-2a subcutaneously at 180 μg. Primary endpoints were safety/PK profiles of ropeginterferon alfa-2b, while secondary endpoints were to compare PK/PD parameters with pegylated IFN alfa-2a., Results: Adverse events in ropeginterferon alfa-2b and pegylated IFN alfa-2a groups were similar, and most of them were mild or moderate. Mean C max increased from 1.78 to 24.84 ng/mL along with the dose escalations in ropeginterferon alfa-2b groups and was 12.95 ng/mL for pegylated IFN alfa-2a. At 180 μg, ropeginterferon alfa-2b showed statistically significant C max geometric mean ratio (1.76; P = .0275). Mean T max ranged from 74.52 to 115.69 h for ropeginterferon alfa-2b groups, and was 84.25 h for pegylated IFN alfa-2a. Mean AUC 0-t increased from 372.3 to 6258 ng•h/mL with the dose escalations in the ropeginterferon alfa-2b groups, while for pegylated IFN alfa-2a it was found to be 2706 ng•h/mL in pegylated IFN alfa-2a. For neopterin and 2',5'-oligoadenylate synthase, mean E max , T max and AUC 0-t of ropeginterferon alfa-2b were similar to those of pegylated IFNα-2a at 180 μg., Conclusion: Ropeginterferon alfa-2b up to 270 μg was safe and well tolerated. The PK/PD parameters of ropeginterferon alfa-2b showed increase in dose-response. Ropeginterferon alfa-2b had higher drug exposures and showed similar safety profile when compared to pegylated IFN alfa-2a at the same dose level., (© 2021 British Pharmacological Society.)

The objective of this study was to mechanistically and quantitatively analyze chenodeoxycholate-enhanced paracellular transport of polar permeants and oligonucleotides in the rat jejunum and ileum. Micellar chenodeoxycholate solutions were used to perturbate the tight junctions. Supporting studies included assessment of the aqueous boundary layer (ABL) with ABL-controlled permeants, measurements of the permeability coefficients and fluxes of the bile acid in dilute and micellar concentrations, and determinations of pore sizes with paracellular probes (urea, mannitol, and raffinose). The paracellular permeability coefficients, P(para), of two model oligonucleotides (ON3 and ON6; 12- and 24-mers with 11 and 23 negative charges, respectively) were determined. The enhanced permeabilities paralleled the increased fluxes of micellar bile salt solutions into mesenteric blood and the opening of the tight junctions as compared to controls. As the pore radius increased from 0.7 nm to a maximum of 2.4 nm in the jejunum and ileum, the absorption of ON3 was enhanced up to sixfold in the jejunum and about 14-fold in the ileum with P(para) values between 0.5 x 10(-6) and 6 x 10(-6) cm/s, whereas ON6 was enhanced up to twofold in the jejunum and fivefold in the ileum with permeabilities between 0.3 x 10(-6) and 2 x 10(-6) cm/s., ((c) 2007 Wiley-Liss, Inc.)