The Latest and Greatest
There are two types of new and improved interferon's
- Hoffman-LaRoche - Pegasys
- Schering - Peg Intron
FDA approval for two pegylated versions of interferon alfa * are expected this year. Pegasys (peginterferon alfa-2a) from Hoffman-La Roche and Peg Intron (peginterferon alfa-2b) from Schering are the two formulations that are under FDA review. Widespread availability of these newer formulations will have a great impact upon the treatment of chronic hepatitis C. The differences and similarities of the two formulations were discussed during a satellite meeting at Digestive Disease Week 2000. The title was "Assessment of Novel Hepatitis C Therapies: Pegylated Interferons and Beyond." It was sponsored by Professional Postgraduate Services and supported by an unrestricted educational grant from Hoffman-La Roche. Teresa L. Wright, MD, from the Veterans Administration Medical Center at the University of California at San Francisco reviewed the "pharmacology" (study of drugs) and "pharmacokinetics" (movement and distribution of drugs) of pegylated interferon alfa. Variable anti-HCV effects Dr. Wright first addressed why pegylated interferon alfa would be expected to have better anti-HCV (hepatitis C virus) effects than the non-pegylated versions. When non-pegylated interferon alfa (NPIA) is injected at the standard dose of 3 million international units (MIU) 3-times weekly, the "trough" levels in-between doses are quite low. During the last 12 hours of the 2-day dosing interval, there is no detectable drug. This is due to the short "half-life" (amount of time until half of an original amount is remaining) of NPIA (3-5 hours) that leads to inadequate antiviral activity in-between dosing, with HCV rebound that is observed with monotherapy. These factors likely contribute to the "disappointing sustained response rate" of NPIA monotherapy. It is also possible that those fluctuations could contribute to certain of the drug's side effects. Dr. Wright showed a graph depicting HCV viral load decreases during a 2-week period using different "therapeutic" doses or regimens. When the standard FDA dose of 3 MIU 3-times weekly of NPIA is given for two weeks, the HCV RNA initial decreases by approximately 1.5 log (31-fold) during the first couple days and then returns towards normal. Then there is a slow gradual decline to slightly less than 1 log (10-fold) viral reduction from baseline after two weeks. The second example was daily NPIA or standard dose NPIA plus ribavirin. Each of those options leads to an HCV viral load reduction of approximately 3 log (1,000-fold) reduction by two weeks. The third example was pegylated interferon once weekly: this led to a viral load reduction of approximately 3.5 log (3,100-fold) after two weeks.
Principles of "Pegylation"
Then Dr. Wright discussed the principals of "pegylation." Polyethylene glycol (PEG) is a "non-toxic polymer" (a substance with a high "molecular weight") that is easily excreted in the urine, due to its being soluble in water. The size of the pegylated polymer depends upon the number of repeating units of carbon atoms attached to hydrogen and oxygen. "PEG" also can be linear or branched. It can be attached to the "base" substance (interferon alfa, in this example) by different types of protein linkages. These links or bonds may alter the stability of the PEG-protein and may also affect its activity. The larger or branched PEGs lead to a longer, sustained absorption period. They also have a "reduced clearance" by the kidney. (Clearance is measured as liters or volume per hour per kilogram of body weight.) These larger/branched PEGs are removed from the underlying interferon in the liver. Whereas, smaller and linear PEGs will have a less sustained and shorter absorption period. They have a "greater clearance" by the kidney and are removed from the underlying interferon in the kidney, not the liver. Dr. Wright said that there is a "trade off between increased PEG size and reduced specific activity." The point of significance will only be determined by clinical studies of the two types. Overall, PEG attachment to interferon alfa leads to a longer half-life of the interferon. This occurs due to decreased "clearance" by the kidney and reduced "proteolysis" (slower breakdown of protein). In addition, PEG attachment to interferon leads to lowered "antigenicity" of interferon. This means less probability that the immune system would make antibodies against interferon that can occur among those who use NPIA. PEG attachment also leads to increased chemical and thermal (heat) stability of the "base" substance interferon. Differences between Pegasys and Peg Intron Dr. Wright then reviewed some differences between Pegasys and Peg Intron. Pegasys uses a larger 40 "kilodalton" PEG that is attached to interferon in a branched fashion. Whereas, Peg Intron uses a smaller 12 "kilodalton" PEG that is attached to interferon in a linear fashion. Each formulation has a PEG to interferon ratio of one to one. Distribution of the two formulations is somewhat different. Like NPIA, Peg Intron is distributed widely throughout the body. Whereas, Pegasys is distributed to the blood and organs, including the liver. This means that there may be some compartments within the body that Pegasys does not penetrate. Other differences include the half-lives. Due to it's longer and branched-chain PEG, Pegasys has a half-life ("terminal elimination") of 50-80 hours. Whereas, due to it's shorter and linear-chain PEG, Peg Intron has a half-life of 30-50 hours. (Note that NPIA or non-pegylated interferon alfa has a half-life of only 3-5 hours.) Later, Dr. Wright characterized the half-lives of Pegasys and Peg Intron as "similar." The "clearance" of the formulations from the body is decreased when compared to NPIA. Peg Intron has a 10-fold decreased clearance, while Pegasys has a 100-fold decreased clearance. Each formulation will have increased blood levels with multiple dosing. When using the dose of 1 microgram per kilogram, Peg Intron had a maximal blood serum (no cells) concentration approximately 24 hours after a dose. With multiple weekly doses, the peak level of Peg Intron was approximately 0.8 nanograms per milliliter, with a gradual taper towards zero after the sixth day. Whereas, Pegasys achieves maximal concentration 80 hours after a dose, using its standard dose of 180 micrograms once weekly. With multiple weekly doses, the peak level was approximately 25 nanograms per milliliter, which decreases to approximately 20 nanograms per milliliter at the end of the seventh day (the end of the dosing interval).
Dr. Wright said that Pegasys definitely has some "protection from degradation" and Peg Intron "likely" has the same. Doses used for these calculations for Pegasys was 180 micrograms once weekly, while that for Peg Intron ranged between 0.035 to 2 micrograms per kilogram once weekly.
Molecular differences were also addressed by Dr. Wright. The amino acids involved in PEG attachment to interferon in Peg Intron were lysine and histidine. Whereas, the attachment in Pegasys is predominantly lysine. The clinical relevance of that difference was not discussed. A subtle difference in the attachment to interferon of the linear versus branched PEG forms also was discussed. Even though each form attaches in a "one to one ratio" with interferon, more than one linear PEG theoretically could attach to each interferon in Peg Intron. This "could in theory lead to aggregation or blockage of the active site" [of interferon]. Whereas, the single branched PEG in Pegasys "binds at a specific site, [while the] active site likely remains unhindered." It should be emphasized that these differences are theoretical.
Summing up the differences between Pegasys and Peg Intron, Dr. Wright numerated the following factors. "Clearance" of Pegasys is less than that of Peg Intron. Pegasys "is metabolized by the liver;" Peg Intron "is metabolized by the kidney." The "area-under-the-curve" (total) concentration of Pegasys is "more consistent" than Peg Intron. Dr. Wright said that the "increase in levels [of drug] with time may result in"."either, both or neither" of the following: increased efficacy or side effects of [Pegasys] over [Peg Intron].
Similarities between Pegasys and Peg Intron
The similarities of Pegasys and Peg Intron are as follows. Both can be administered once weekly subcutaneously (under the skin). The half-life of each is significantly longer than NPIA (non-pegylated interferon alfa). Dr. Wright described the half-lives of each as being "similar" to one another. Both have a favorable "pharmacokinetic" or "PK" profile that "supports improved efficacy over standard interferons." In addition, multiple dosing of each leads to increased blood serum levels.
Final Thoughts
Dr. Wright ended her talk by reviewing that changing the "pharmacokinetics" of interferon alfa with pegylation has resulted in once weekly dosing and much reduced differences between peak and trough (lowest) levels of active drug. The optimal dose of either formulation will depend upon the results of clinical trials. Reviewing the differences of Pegasys and Peg Intron, Dr. Wright said that the significance of the various differences between the two formulations would only be determined by clinical studies. Studies to date clearly show that pegylated interferon alfa monotherapy leads to greater levels of sustained HCV virologic responses. The sustained virologic response rates will likely be even greater when combined with ribavirin and/or other anti-HCV agents.
* Note that all four generic versions use the spelling 'alfa' and not 'alpha' interferon.
6/2/00 Reference: Wright TL. Pegylated interferons: pharmacology and pharmacokinetics. Assessment of Novel Hepatitis C Therapies: Pegylated Interferons and Beyond, satellite symposium at Digestive Disease Week 2000; May 21-24, 2000; San Diego, California.