Aa
pegylated confused
I am confused as to what pegylated means... not that it matters... i am just curious.
I have heard that it makes the interferon particles larger, so it will stay in your system longer..but...
I also saw an animation (not sure where, pegasys site?) That talks about the interferon having pegs or arms attached, and now they are branched pegs , not just one. I was surprised that it also mentioned that these pegs are man made, from silicon or plastic, or something.
It went on to explain that the pegs wave around and protect the interferon from our own enzymes that try to attack it,
and apparently the peg hitting an enzyme is just a matter of chance, thus the branched pegs, more chances.
Does this sound correct.
thanks for your feedback!
bandman
I have heard that it makes the interferon particles larger, so it will stay in your system longer..but...
I also saw an animation (not sure where, pegasys site?) That talks about the interferon having pegs or arms attached, and now they are branched pegs , not just one. I was surprised that it also mentioned that these pegs are man made, from silicon or plastic, or something.
It went on to explain that the pegs wave around and protect the interferon from our own enzymes that try to attack it,
and apparently the peg hitting an enzyme is just a matter of chance, thus the branched pegs, more chances.
Does this sound correct.
thanks for your feedback!
bandman
Ethylene glycol is anti-freeze. Polyethylene glycol is what is attached to the IFN. You can find peg in many foods and lotions, as well.
Mr Liver
Mr Liver
Did you know that one of the treatments for ethylene glycol poisoning consists administering oral or IV ethanol. This treatment is used in conjuction with sodium bicarbonate and hemodialysis to counter the effects. That is probably why we are told to strictly avoid alcohol while on tx.
Trin
Trin
Below is more about the differences between the two drugs but gives good info on the PEG part.
Review article: Pegylated interferons: chemical and clinical differences
Aliment Pharmacol Ther 2004; 20: 825–830.
CHEMISTRY OF THE CURRENTLY AVAILABLE PEG-IFNS
Polyethylene glycols are biologically inert molecules that can be cross-linked to proteins to reduce their degradation while retaining their biological activity.
Proof that pegylated biological proteins could be used therapeutically came in the late-1980s when pegylated bovine adenosine deaminase (ADA) was used to treat children with severe combined immunodeficiency because of ADA deficiency.
Since that time a number of pegylated drugs have been developed and PEG-IFNs are the most recent additions to the family of pegylated pharmaceuticals.
The PEGs consist of monomeric ethylene glycols linked together to form complex chains. There is enormous diversity in the chains that can be produced by linking ethylene glycols together – the chains can differ in length and branching structure and can be linked to proteins in a variety of different ways and at different positions within the IFN molecule. The ultimate aim of pegylating any therapeutic protein is to optimize pharmacokinetics, reduce clearance and, hopefully, improve tolerability, compliance and efficacy. However, the pharmacokinetic profiles of pegylated proteins and their activity are dependent on the structure and characteristics of the PEG, the chemistry used to conjugate the PEG to its target protein, and the number and position of attachment sites.
The two currently available PEG-IFNs use PEG chains of different complexity. The 12 kDa PEG-IFNa-2b consists of IFNa-2b linked to a linear PEG chain, i.e. 12 kDa in size,7 whereas the 40 kDa PEG-IFNa-2a is linked to a branched chain, 40 kDa PEG moiety.8 As the size of the unmodified IFNa is only 19 kDa it is apparent that these different PEG moieties produce major differences with respect to the mass of the IFN – the 40 kDa PEG triples the size of the molecule whereas the 12 kDa PEG-IFN is less than twofold greater in size than standard IFNa. The two PEG-IFNs differ in the way that the PEG
molecule is attached to the IFNa.
The 12 kDa PEGIFNa- 2b is linked to the IFN by a urethane bond in which the PEG molecule is attached primarily to histidine residues. This linkage is susceptible to hydrolysis and, once injected, native, non-PEG-IFNa-2b is released from the PEG and circulates in the body. Thus, 12 kDa PEG-IFNa-2b is probably best regarded as a prodrug that releases the active constituent (IFNa) once it is reconstituted and injected into the subcutaneous tissues.10–12
Once the active IFNa-2b is released from the PEG moiety in the body, it behaves in exactly the same way as conventional IFNa in terms of binding to the receptor, drug metabolism and renal excretion. The cleavable nature of this PEG-IFN bond means that 12 kDa PEG-IFNa-2b is unstable and the lyophilized powder should be reconstituted before use and reconstituted solution should be discarded13 and not stored
for future use.
The attachment chemistry of the 40 kDa PEG-IFNa-2a is different. The branched chain PEG molecule is attached to lysines within the IFNa-2a molecule by a stable, amide bond that is not subject to hydrolysis.
Thus, after injection the entire molecule circulates intact, and it is the PEG-IFNa-2a itself that interacts with the receptor, not the free native IFNa. The stability of the amide bond means that PEG-IFNa-2a is stable in solution and is thus dispensed in this form.14 Table 1 lists the chemical and structural differences between the two PEG-IFNs.
PHARMACOKINETICS OF THE DIFFERENT
PEG-IFNS
The differences in the basic chemistry of the PEG-IFNs are associated with significant differences in the pharmacokinetics and pharmacodynamics of the two drugs.
The 12 kDa PEG-IFNa-2b has a relatively rapid absorption (absorption half-life of 4.6 h, compared with 2.3 h for conventional IFNa-2b), a wide volume of distribution (approximately 0.99 L/kg) a peak-to-trough ratio of >10 (after multiple doses) and reduced clearance (725 mL/h compared with 6000 mL/h for the unmodified IFN).7 The 40 kDa PEG-IFNa-2a is absorbed more slowly (the absorption half-life is 50 h), has a restricted volume of distribution (8 L), a narrow peak-to-trough ratio of 1.5 (after multiple doses) indicating minimal fluctuation in serum concentration, and a markedly reduced rate of clearance (60 mL/h) when compared with non-PEG-IFN.8
Thus, PEG-IFNa-2b is quickly absorbed, circulates widely and declines to undetectable
serum levels within a few days, whereas the 40 kDa PEG-IFNa-2a is absorbed slowly, is restricted largely to the vasculature and well-perfused organs, such as the liver, and is still detectable in serum after a week.
The differences in the absorption and half-lives of the two products lead to differences in the timing of sideeffects.
As with all type I IFNs, the PEG-IFNs are associated with a range of side-effects – chiefly fever and flu-like symptoms, neuropsychiatric effects, including depression, and clinically relevant changes in haematological parameters, in particular neutropenia and
thrombocytopenia. Clinical experience with the 12 kDa PEG-IFNa-2b shows that the relatively rapid absorption of the active IFNa leads to the rapid onset of side-effects (G. R. Foster, unpublished observations) and in clinical practice it is wise to warn patients that they may become febrile a few hours after starting therapy.
In general, patients very quickly become tolerant to the acute adverse effects of IFNa and should be told that these unpleasant acute effects may well abate with time. Clinicians should expect a rapid fall in neutrophil and platelet counts when patients are commenced on 12 kDa PEG-IFNa-2b therapy. Regular monitoring and appropriate dose adjustments may be necessary.
The 40 kDa PEG-IFNa-2a 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 (G. R. Foster, unpublished observations). Clinicians should be aware that the platelet and neutrophil nadirs might not develop until the second month of therapy. Appropriate monitoring is important at this time to ensure that any necessary dose modifications are introduced appropriately.
CS
Review article: Pegylated interferons: chemical and clinical differences
Aliment Pharmacol Ther 2004; 20: 825–830.
CHEMISTRY OF THE CURRENTLY AVAILABLE PEG-IFNS
Polyethylene glycols are biologically inert molecules that can be cross-linked to proteins to reduce their degradation while retaining their biological activity.
Proof that pegylated biological proteins could be used therapeutically came in the late-1980s when pegylated bovine adenosine deaminase (ADA) was used to treat children with severe combined immunodeficiency because of ADA deficiency.
Since that time a number of pegylated drugs have been developed and PEG-IFNs are the most recent additions to the family of pegylated pharmaceuticals.
The PEGs consist of monomeric ethylene glycols linked together to form complex chains. There is enormous diversity in the chains that can be produced by linking ethylene glycols together – the chains can differ in length and branching structure and can be linked to proteins in a variety of different ways and at different positions within the IFN molecule. The ultimate aim of pegylating any therapeutic protein is to optimize pharmacokinetics, reduce clearance and, hopefully, improve tolerability, compliance and efficacy. However, the pharmacokinetic profiles of pegylated proteins and their activity are dependent on the structure and characteristics of the PEG, the chemistry used to conjugate the PEG to its target protein, and the number and position of attachment sites.
The two currently available PEG-IFNs use PEG chains of different complexity. The 12 kDa PEG-IFNa-2b consists of IFNa-2b linked to a linear PEG chain, i.e. 12 kDa in size,7 whereas the 40 kDa PEG-IFNa-2a is linked to a branched chain, 40 kDa PEG moiety.8 As the size of the unmodified IFNa is only 19 kDa it is apparent that these different PEG moieties produce major differences with respect to the mass of the IFN – the 40 kDa PEG triples the size of the molecule whereas the 12 kDa PEG-IFN is less than twofold greater in size than standard IFNa. The two PEG-IFNs differ in the way that the PEG
molecule is attached to the IFNa.
The 12 kDa PEGIFNa- 2b is linked to the IFN by a urethane bond in which the PEG molecule is attached primarily to histidine residues. This linkage is susceptible to hydrolysis and, once injected, native, non-PEG-IFNa-2b is released from the PEG and circulates in the body. Thus, 12 kDa PEG-IFNa-2b is probably best regarded as a prodrug that releases the active constituent (IFNa) once it is reconstituted and injected into the subcutaneous tissues.10–12
Once the active IFNa-2b is released from the PEG moiety in the body, it behaves in exactly the same way as conventional IFNa in terms of binding to the receptor, drug metabolism and renal excretion. The cleavable nature of this PEG-IFN bond means that 12 kDa PEG-IFNa-2b is unstable and the lyophilized powder should be reconstituted before use and reconstituted solution should be discarded13 and not stored
for future use.
The attachment chemistry of the 40 kDa PEG-IFNa-2a is different. The branched chain PEG molecule is attached to lysines within the IFNa-2a molecule by a stable, amide bond that is not subject to hydrolysis.
Thus, after injection the entire molecule circulates intact, and it is the PEG-IFNa-2a itself that interacts with the receptor, not the free native IFNa. The stability of the amide bond means that PEG-IFNa-2a is stable in solution and is thus dispensed in this form.14 Table 1 lists the chemical and structural differences between the two PEG-IFNs.
PHARMACOKINETICS OF THE DIFFERENT
PEG-IFNS
The differences in the basic chemistry of the PEG-IFNs are associated with significant differences in the pharmacokinetics and pharmacodynamics of the two drugs.
The 12 kDa PEG-IFNa-2b has a relatively rapid absorption (absorption half-life of 4.6 h, compared with 2.3 h for conventional IFNa-2b), a wide volume of distribution (approximately 0.99 L/kg) a peak-to-trough ratio of >10 (after multiple doses) and reduced clearance (725 mL/h compared with 6000 mL/h for the unmodified IFN).7 The 40 kDa PEG-IFNa-2a is absorbed more slowly (the absorption half-life is 50 h), has a restricted volume of distribution (8 L), a narrow peak-to-trough ratio of 1.5 (after multiple doses) indicating minimal fluctuation in serum concentration, and a markedly reduced rate of clearance (60 mL/h) when compared with non-PEG-IFN.8
Thus, PEG-IFNa-2b is quickly absorbed, circulates widely and declines to undetectable
serum levels within a few days, whereas the 40 kDa PEG-IFNa-2a is absorbed slowly, is restricted largely to the vasculature and well-perfused organs, such as the liver, and is still detectable in serum after a week.
The differences in the absorption and half-lives of the two products lead to differences in the timing of sideeffects.
As with all type I IFNs, the PEG-IFNs are associated with a range of side-effects – chiefly fever and flu-like symptoms, neuropsychiatric effects, including depression, and clinically relevant changes in haematological parameters, in particular neutropenia and
thrombocytopenia. Clinical experience with the 12 kDa PEG-IFNa-2b shows that the relatively rapid absorption of the active IFNa leads to the rapid onset of side-effects (G. R. Foster, unpublished observations) and in clinical practice it is wise to warn patients that they may become febrile a few hours after starting therapy.
In general, patients very quickly become tolerant to the acute adverse effects of IFNa and should be told that these unpleasant acute effects may well abate with time. Clinicians should expect a rapid fall in neutrophil and platelet counts when patients are commenced on 12 kDa PEG-IFNa-2b therapy. Regular monitoring and appropriate dose adjustments may be necessary.
The 40 kDa PEG-IFNa-2a 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 (G. R. Foster, unpublished observations). Clinicians should be aware that the platelet and neutrophil nadirs might not develop until the second month of therapy. Appropriate monitoring is important at this time to ensure that any necessary dose modifications are introduced appropriately.
CS
I always thought polyethylene glycol is what you got when spilled anti-freeze on a leisure suit.
Not exactly like a pirate with one leg and a wooden stump for another, that would be peg-legged. And, not like the girl made famous in song, that would be Peggy Sue. Pegylation is the process of attaching 1 or more chains of a substance called polyethylene glycol (also known as PEG) to a protein molecule such as interferon. Since the body does not react to PEG, it helps provide a protective barrier around an attached protein so it can survive in the body longer
Ethylene glycol is the ingredient that makes antifreeze tasty. Though colorless and odorless, the syrupy alcohol derivative—which is excellent at lowering the freezing points of vital engine fluids—has a sweet taste that jibes well with soda, juice, and other sugary beverages. As many concerned pet owners and parents are well aware, dogs, cats, and kids are prone to lap up puddles of antifreeze left on garage floors. Every year, 90,000 animals and 4,000 children ingest the toxic liquid; if not treated immediately, the consequences of the poisoning can include renal or cardiovascular failure, brain damage, and death.
All which may explain why tx is the joy that it is. Not sure what Poly has to do with all this, I thought it was ac ute name for a bird.
Ethylene glycol is the ingredient that makes antifreeze tasty. Though colorless and odorless, the syrupy alcohol derivative—which is excellent at lowering the freezing points of vital engine fluids—has a sweet taste that jibes well with soda, juice, and other sugary beverages. As many concerned pet owners and parents are well aware, dogs, cats, and kids are prone to lap up puddles of antifreeze left on garage floors. Every year, 90,000 animals and 4,000 children ingest the toxic liquid; if not treated immediately, the consequences of the poisoning can include renal or cardiovascular failure, brain damage, and death.
All which may explain why tx is the joy that it is. Not sure what Poly has to do with all this, I thought it was ac ute name for a bird.
PEG stands for PolyEthylene Glycol. It's bonded to the interferon to slow it's absorption. Non-peg interferon only has a half-life (the time it takes for half of it to be metabolized) of about 8 hours, I think. So even with three shots a week, the old therapy didn't keep any thing like a steady supply of IFN hitting the virus.
Pegasys uses a branched PEG molecule to bond to its IFN alpha (2a) which keeps it in your system slightly longer than Peg-Intron which uses a non-branched PEG molecule on its IFN alpha (2b). The two pegylated interferons seem to work equaly well
Or something like that.
Pegasys uses a branched PEG molecule to bond to its IFN alpha (2a) which keeps it in your system slightly longer than Peg-Intron which uses a non-branched PEG molecule on its IFN alpha (2b). The two pegylated interferons seem to work equaly well
Or something like that.
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