Novel long-acting ropeginterferon alfa-2b: Pharmacokinetics, pharmacodynamics and safety in a phase I clinical trial.

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 Cmax 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 Cmax geometric mean ratio (1.76; P = .0275). Mean Tmax ranged from 74.52 to 115.69 h for ropeginterferon alfa-2b groups, and was 84.25 h for pegylated IFN alfa-2a. Mean AUC0-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 Emax , Tmax and AUC0-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.

Pharmacokinetics and Pharmacodynamics of Novel Long-Acting Ropeginterferon Alfa-2b in Healthy Chinese Subjects.

INTRODUCTION: Ropeginterferon alfa-2b is a novel mono-pegylated human recombinant interferon (IFN) with the addition of N-terminal proline covalently attached by a 40-kDa polyethylene (peg) moiety. The present study aimed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD) profiles and safety of the product in healthy Chinese. METHODS: Forty subjects were enrolled and treated with a single subcutaneous injection of either 180 mcg peg-IFN alfa-2a or 90, 180, and 270 mcg ropeginterferon alfa-2b. RESULTS: The mean Tmax of ropeginterferon alfa-2b was 92-141 h and the elimination half-life was 78-129 h. Dose-related, non-proportional increase in ropeginterferon alfa-2b exposure was observed, which was higher than for peg-IFN alfa-2a. The PD parameters were similar between each dose level of ropeginterferon alfa-2b. The mean Tmax of ß2-microglobulin ranged from 118 to 132 h after a single dose of ropeginterferon alfa-2b. The average Emax was 3 mcg/ml in all dose levels and the mean AUEC0-t ranged from 1608 to 1775 h/mcg/ml. The TEAEs were comparable among each treatment group and no death nor drug-related SAE was reported. CONCLUSION: Ropeginterferon alfa-2b is safe and well tolerated after a single subcutaneous injection up to 270 mcg in healthy Chinese. CLINICAL TRIAL REGISTRATION: www.chinadrugtrials.org.cn , CTR20190451.

Systematic studies on the paracellular permeation of model permeants and oligonucleotides in the rat small intestine with chenodeoxycholate as enhancer.

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.

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-alpha) 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.