Comparing two INFs

[EPguy]

This is mostly for science nerds, a comparison of the old PEG-Intron (no longer available) to Pegasys, shedding some light on what the Besremi guys are doing with longer dosing intervals.

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A 2004 report in context of hepatitis therapy:

onlinelibrary.wiley.com/doi...

Clearance rates for three types of INF, longer is better for holding constant INF levels in the body:

2.3hr for conventional (non Pegylated) IFNα-2b

PEG-Intron: The 12kDa PEG-IFNα-2b has a relatively rapid absorption (absorption half-life of 4.6hr)

Pegasys: The 40 kDa PEG-IFNα-2a is absorbed more slowly the absorption half-life is 50hr (~2 days)

For reference, half-life and clearance of BESREMi (Ropeg) is approximately 7 days.

accessdata.fda.gov/drugsatf...

Thus (Peg-Intron) is quickly absorbed, circulates widely and declines to undetectable serum levels within a few days, whereas (Pegasys) is absorbed slowly, is restricted largely to the vasculature and well-perfused organs, such as the liver, (does this mean it gets less into the marrow?) and is still detectable in serum after a week.

Clinical experience with (PEG-Intron) shows that the relatively rapid absorption of the active IFNα leads to the rapid onset of side-effects. Clinicians should expect a rapid fall in neutrophil and platelet counts.

(Pegasys) is absorbed much more slowly and does not reach a steady-state until 4–6 weeks after starting therapy. Patients usually do not develop many side-effects after the first injection but the early side-effects may gradually increase over the first few weeks before starting to abate after the first month of therapy. Clinicians should be aware that the platelet and neutrophil nadirs might not develop until the second month of therapy.

(this aspect of PEG is what Bes claims to have improved further)

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Dose by fixed size or by weight: For Pegasys standard pharmacodynamic principals will apply and thus the drug is used at a fixed dose of 180μg/week. (this is for liver therapy) For Peg-Intron the large volume of distribution of the drug necessitates dosing according to body weight during the induction phase to maintain reasonable drug levels.

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Possible reason we see increasing dosing intervals over time for both Bes and PEG: (Besremi has standard to double to 1/month after a year): A large pharmacokinetic study of several hundred patients receiving (PEG-Intron) showed that the clearance of the drug decreased during therapy and this was associated with an increase in serum bioactivity of IFN. Similar changes were observed with conventional IFNα-2b suggesting that the changes in metabolism are related to alterations in the clearance mechanisms of IFN.

PEG-Intron is processed mostly in the kidneys, so renal risk may be higher. Pegasys is processed in both kidneys and liver so “this dual metabolism means that the drug does not need major dose modifications in patients with renal impairment” (might Bes improve further on this?)

Weight effects, for both IFNs “the response to therapy does vary with body weight and, for both drugs, despite their different regimens (i.e. fixed vs. weight-based), there is a statistically significant reduction in response rates in heavier patients” But the actual effect was less clear.

[Island-Lady]

Thank you for posting that. I found it really helpful since I am planning on switching from hydroxy to Pegasys.

[gvibes]

EPguy,

Your summaries are useful to me. A couple of the facts presented I found interesting:

1) the half lifes of pegasys (50 hours) means that after about a week, there is ~10% of the initial dose remaining and after 2 weeks about 1%. So while it stays in the body with the weekly injections, you still get a serious jump with the next injection and does not get that much higher over time. Now it states that the "clearance rate" decreased during therapy which seems to me to be the same as increasing the half life and having a more constant rate in the body and building up in concentration . This also seems consistent with the idea that pegasys often takes a long time to get to work effectively. 2) the 7 day half life for besremi would result a very different picture although the 2 week interval would mean approximately 25% is remaining when you get the next dose so there is a more constant presence in the body and the concentration builds to some number and then levels.

Now what I dont know (lots of things, I'm sure) is if a constant concentration is desired. Certainly a lower dose is important to prevent side effects but as far as action of the drug. My history showed a temporary higher dose seemed to get thing going (i.e. reduction of hematocrit). I also am on an alternate weekly dose of 90 and 45 (rather than 67) which would seem to result in more peaks and valleys.

I am sure I have oversimplified a very complex interaction....

take care and thanks for sharing your work,