Aa
Aa
A
A
A
Close
Avatar universal

Dosing of IFN

I see that many regulars here have tried different dosing regimens for Peg-IFN.

I am on the alfa-2b product and have been looking at the papers on how its absorbed and metabolized. Lo and behold, a graph in a review (Zeuzem, S et al. Pharmacokinetics of Peginterferons. Seminars Liver Disease 23(1),23-28) shows something interesting.

It's a concentration vs time profile i.e. Give PegIFN at time 0; measure PegIFN concentration in the blood every hour and plot time on the horizontal and concentration on the vertical axis.

The maximum blood levels are reached ~24hrs. They decay rapidly so that by 72 hours you have only about 50% left. By 168 hrs or 1 week, there is no Peg-IFN left in the body!

If you dust off yer pharmacokinetics textbook and find an Excel Worksheet somewhere, and do some simulations you'll find that decreasing the dosing interval to every 96hrs or 4 days predicts a persistent non-zero level of drug.  The level goes to about 40% of the max dose reached with the 168hr or 1 week dosing schedule. Max level on the more frequent dosing goes up slightly.

Time to talk to my hepatologist. On this basis, I should be taking the PEG-IFN every 4 days.

Why would Schering recommend a weekly dosage regimen when it allows drug level to fall to zero? Seems to me to defeat the purpose of pegylation, which is to assure fairly constant drug levels without daily injections of NON-pegylated IFN.

Any pharmacokinetics whiz wanna handle this one?
9 Responses
Sort by: Helpful Oldest Newest
Avatar universal
best of  luck with with your decisions. Here's a couple of things to keep in mind however.  With respect to safety, you might want to read the comments by SJL and JennyPenny in the double dosing thread magnum started 5/28. Tendency to ifn related autoimmune/thyroid/cryo/hematology disorders is more the exception than the rule, but from many posts here is clearly not uncommon. Unfortunately I don't think one can tell until the damage is already done but  caution seems advisable.

Re sample sizes, the Sebastiani study, from their Table 1, was based on 60 patients all 1s whereas the Lodato study only included 26 g 1/4s of whom 9 naive, 12 non-responder,5 relapser.  Among  these 26, they only saw a 46% SVR with double dosing (fig 3) which is about what you'd expect with single dosing among the 9/26 naives - so in the end what they're reporting is an improved SVR rate among 17 non-responders/relapsers, a pretty small group.

Sebastiani had a larger group of 1s to work with, and their results seem very counter intuitive. From the first study you posted and the COMPARE data it's clear ifn2b drops off long before the weekly refill. Why distributing the total dose over two half shots not only doesn't help but seems to make to make things worse isn't at all clear to me.
Helpful - 0
Avatar universal
My doc(family doc, not hepatologist) got in touch with Schering and asked them about the issues of how frequently PEG-IFN alfa2b should be dosed.

They responded by citing three studies:
Lodato et al J Viral Hepatitis 2005; 12:536-542
Lurie et al Clin Gastro Hepatol 2005:3:610-615
Sebastiani et al Aliment Pharmacol Ther 2007;26(7):1077-82

Lurie - monotherapy PEG-IFN alfa2b at various doses and schedules. Control: (unpegylated) Intron. Did not look at SVR as an end point(according to their summary of the paper), fuggedaboudit.

Lodato looked at (mostly)genotype 1 patients, high baseline viral loads, on RBV and either: Group A: SOC(pegetron 1.5mcg/kg/wk) or Group B: Pegetron 1.5mcg/kg Modays and 1.0mcg/kg Fridays.
Small numbers but RVR was higher in the twice-weekly group(23/43 vs 6/22 or 53% vs 27%) - twice as high. Difference persisted to SVR. The SVR in the twice weekly group was 72% vs 25%(the usual!) in the SOC group, with p=0.03. Twice weekly rx HALVED the relapse rate.

Sebastiani looked at giving the total dose of PEG-IFN either once weekly or divided into two doses, ie 1.5mcg/kg/wk vs 0.75mcg/kg twice weekly; both got weight-based RBV.Study numbers were small and the twice weekly IFN had no effect.


Of note safety was NOT an isue with any of the doses noted above.

All in all the second paper clinches it for me. It's clear that there is a trend toward higher dose and more frequent dosing schedule positively affecting RVR and SVR with Genotype 1, even with high viral load. The meta-analyses need to be done, but for me, twice weekly at 1.5 mcg/kg/dose seems right.

(Schering's paper to my FP had the usual caveats about not modifying SOC on the basis of these studies etc. )

Was this a marketing decision? Drugcos usually like to move product and inevitably they end up recommending higher doses and widening indications for their products. I guess they could not very well introduce a competitor to Pegasys which had to be given twice weekly though.

The efficacy against Genotype 1 is clearly superior with the twice-weekly dosing sked; the pharmacokinetics support twice-weekly dosing; and it does not seem to hurt.

Helpful - 0
Avatar universal
interesting point; the relative merits of 2a(roche) vs 2b(schering) come up all the time around here. you might also want to look at the concentration vs time graphs in the COMPARE study
http://www.ncbi.nlm.nih.gov/pubmed/16780997

Overall it looks like the hefty 40 Kda PEG cannonball Roche tags onto its protein keeps the peg-ifn around for much longer than the paltry 12 KDa molecule Schering uses: the COMPARE research found serum availability for 2a to be to around 16 times higher. On the other hand, the same effect that stops proteases from chewing up the Roche's pegIFN,  also seems to interfere with receptor binding: the data showed pretty clearly that 2b yielded higher expression of the mRNA responsible for anti-viral activity and greater viral decline. So it seems Pegasys may hang around much longer but not do as much good whereas  Pegintron decays faster but exerts more anti-viral effect before getting chopped up.

Short of walking around with a slow-drip IV, more frequent dosing of 2b may well give the best results. For  those pursuing a "scorched earth" tx (gauf?) this definitely seems a good strategy. Giving up the "convenience" of once weekly dosing seems a smaller, and safer, path than dose increase.
Helpful - 0
475555 tn?1469304339
The article of E. Formann's certainly supports your analisis. Maybe you should take it along when you go see your doc about this. I've found it highly effective, in lowering the MD/arrogance level, to present them with articles they haven't read. I try to always take along several articles with me when I go see the doctors. (Of course here in Argentina it's a snap, 'cause none of 'em can really read English. :¬]  )

This seems like a pretty important point, so I'm hoping you can clear it up for all of us.

Mike
Helpful - 0
Avatar universal
Study from Vienna, 2003.
REF:  Formann, E et al. Twice-weekly administration of peginterferon alfa-2b improves viral kinetics in patients with chronic hepatitis C genotype 1. J. Viral Hepatitis. 2003;10: 271-276.

Note that dose is lower than current: 1mcg/kg
Also note this is monotherapy, no ribavirin.
Still looking for studies with current dosages of PEG-IFN alfa 2b(1.5mcg/kg/wk) and ribavirin(800-1400mg/day)

Abstract:
The decline in hepatitis C viral load on treatment with peginterferon--2b is not continuous. The aim of this study was to investigate whether twice weekly dosing of peginterferon--2b may improve viral kinetics. Ten interferon-naïve patients with chronic hepatitis C (genotype 1a or b) were randomized to receive either 1.0 g/kg peginterferon--2b once (group A) or twice weekly (group B) for 4 weeks. Viral load and serum concentrations of peginterferon--2b were measured. Peginterferon--2b reached maximal blood concentrations 24 h after the first dose, followed by a linear decline during the subsequent days. On the day before administration of the next dose, peginterferon--2b was undetectable in nine patients in group A (once weekly dosing). The same pattern was observed during the next 3 weeks of therapy. In group B (twice weekly dosing) peginterferon--2b was detectable at any given time point and higher than in group A (P between 0.01 and <0.0001). Viral load decreased in all patients within 2 days after the first dose of peginterferon--2b, but increased again on day 3. In group A, it further increased until day 7. A similar pattern was observed in the second week. In contrast, in group B, viral load decreased again on day 4 and remained lower until the end of the study (P < 0.001). To achieve continuous drug exposure and to improve initial viral clearance, peginterferon--2b has to be given at least two times weekly.


Marcia:
Pegasys has a different concentration vs time curve. Inject it Day 0, measure concentration in the blood hourly, plot concentration vs time, and you get a curve that is broader and flatter than the PegIntron curve, meaning that the drug stays at fairly high levels throughout the week...
Helpful - 0
475555 tn?1469304339
So you agree with FoieGras that a once-a-week dose of Peg-IFN is wrong?

M.
Helpful - 0
476246 tn?1418870914
Can you please explain, why his reasoning is not sound for Pegasys?
How is it different from Pegintron in this regard?

Thanks, Marcia
Helpful - 0
Avatar universal
Your reasoning is sound for PegIntron. But not Pegasys.
PegIntron every 4 days has been studied. in non responders with OK results.

CS
Helpful - 0
475555 tn?1469304339
I can't help out on the pharmacokinetics, but your reasoning is sound: it doesn't make sense to dose so that the drug runs out.

I'd query Schering-Plough as well as your hepatologist, if I were you.

Please give me a heads-up if you solve the riddle.

Mike
Helpful - 0
Have an Answer?

You are reading content posted in the Hepatitis C Community

Top Hepatitis Answerers
317787 tn?1473358451
DC
683231 tn?1467323017
Auburn, WA
Learn About Top Answerers
Didn't find the answer you were looking for?
Ask a question
Answer a few simple questions about your Hep C treatment journey.

Those who qualify may receive up to $100 for their time.
Explore More In Our Hep C Learning Center
image description
Learn about this treatable virus.
image description
Getting tested for this viral infection.
image description
3 key steps to getting on treatment.
image description
4 steps to getting on therapy.
image description
What you need to know about Hep C drugs.
image description
How the drugs might affect you.
image description
These tips may up your chances of a cure.
Popular Resources
A list of national and international resources and hotlines to help connect you to needed health and medical services.
Herpes sores blister, then burst, scab and heal.
Herpes spreads by oral, vaginal and anal sex.
STIs are the most common cause of genital sores.
Condoms are the most effective way to prevent HIV and STDs.
PrEP is used by people with high risk to prevent HIV infection.