NATAP at AASLD: Clearance of Pegylated (40KDA) Interferon Alfa-2a (Pegasys) Is Primarily Hepatic

[Guest guest]

NATAP

www.natap.org

-----------------

AASLD Conference

October 27-31 2000, Dallas

Reported by Jules Levin

Below is the abstract reported by Modi of

Roche saying that

Pegasys

is cleared through the liver rather than the kidney.

During her oral

talk she

said injections in the stomach were likely to produce

the best pk.

CLEARANCE OF PEGYLATED (40KDA) INTERFERON ALFA-2A

(PEGASYS™) IS

PRIMARILY

HEPATIC

W Modi, Jeffery S Fulton, D.K Buckmann,

Hoffmann-La Roche,

Nutley,

NJ; L , Univ of San Francisco, San

Francisco, CA; J

,

Hoffmann-La Roche, Nutley, NJ

Background: Pegylation of interferon alfa-2a (IFN

a-2a) with a branched

40

kDa polyethylene glycol (PEG) moiety results in a new

molecular entity

with

pharmacokinetic characteristics that are unique from

the native

protein, IFN.

PEG (40kDa) IFN a-2a exhibits sustained absorption and

has a smaller

volume

of distribution and an overall clearance that is

100-fold lower than

that of

IFN. The kidney is the main site of catabolism for

standard IFN. In

contrast,

the size and branching of the PEG (40kDa) IFN a-2a

molecule suggest

that the

kidney will not be the major site of metabolism of

this new molecular

entity.

Objective: To characterize the tissue distribution,

clearance, and

major

routes of excretion of PEG (40kDa) IFN a-2a and

related radiolabeled

material.

Methods: Mass balance and autoradioluminography

studies in male Spr

ague-Dawley rats were conducted at 0.5 hours, 24

hours, and 14 days

after a

single iv or sc dose of 14C lysyl-labeled PEG (40kDa)

IFN a-2a.

Characterization of radiolabeled material was by SDS

PAGE, TCA

precipitation,

Western blot analysis, and immunoprecipitation.

Results: The highest radioactivity was found in the

blood of highly

perfused

organs 0.5 hours after an iv dose of 14C-PEG (40kDa)

IFN a-2a. Tissue

concentrations were lower than those in the blood.

Immunoprecipitation

of

liver homogenates showed that the radioactivity

migrated with the

standard

intact 14C-PEG (40kDa) IFN a-2a. Western blot analysis

confirmed the

presence

of intact 14C-PEG (40kDa) IFN a-2a in the liver. No

depegylated IFN was

detected in these liver samples or in the blood 0.5

hours after an iv

dose.

No intact 14C-PEG (40kDa) IFN a-2a was found in the

brain. The kidney

and sc

injection site were the only tissues with

radioactivity greater than

the

blood 24 hours after a single sc dose. IFN antibody

immunostaining of

tissue

samples (blood, liver, kidney, and spleen) indicated

that IFN was still

attached to the PEG moiety 24 hours after dosing. The

highest levels of

radioactivity were found in the sc injection site

tissue, blood, liver,

kidney, and spleen. Intact 14C-PEG (40kDa) IFN a-2a

was primarily

cleared via

hepatic metabolism. The kidney eliminated the

metabolic products of

intact

14C-PEG (40kDa) IFN a-2a, with 51% and 9.6% of the

total radioactive

dose

appearing in the urine and feces, respectively, within

14 days of an iv

dose.

The remaining activity was found in the blood,

tissues, and carcass.

The

greatest amount of radioactivity was detected in the

liver (6.9%) and

kidney

(1.4%). No other organ had more than 1% of the

radioactive dose.

Similar

results were seen after the sc dose. The radiolabeled

material excreted

in

the urine was mainly fragments of IFN attached to

parts of the PEG

moiety as

characterized by TCA precipitation and SDS PAGE. The

metabolic

processing of

intact 14C-PEG (40kDa) IFN a-2a did not change over

the first 12 days,

with a

consistent amount of radioactivity appearing in the

urine.

Conclusions: PEG (40kDa) IFN a-2a is cleared mainly

via hepatic (liver)

metabolism. PEG (40kDa) IFN a-2a remains intact in the

blood and in the

liver

for at least 24 hours after dosing. The kidney

excretes the metabolic

products of PEG (40kDa) IFN a-2a. The metabolic

processing of PEG

(40kDa) IFN

a-2a is consistent over the first 14 days after dosing

in the rat.

Further,

the liver-to-blood ratio of radio-labeled PEG (40kDa)

IFN a-2a is

greater

than that seen with IFN, suggesting more effective

antiviral activity

in the

liver with PEG (40kDa) IFN a-2a. 1Algranati NE, Sy S,

Modi M, et al. A

branched methoxy 40 kDa polyethylene glycol (PEG)

moiety optimizes the

pharmacokinetics (PK) of peginterferon alpha-2a

(PEG-IFN) and may

explain its

enhanced efficacy in chronic hepatitis C. Hepatology.

1999;30(suppl):190A.

2Bocci. J Interferon Res. 1982;4:309-14.

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