Phar-ma-co-ki-net-ics that's the term that encompasses my questions, thank you, thank you thank you!
pharmacokinetics
(the study of the action of drugs within the body. It includes studies of the mechanisms of drug absorption, distribution, metabolism, and excretion; onset of action; duration of effect; biotransformation; and effects and routes of excretion of the metabolites of the drug.)
We members of the Forum are very blessed to have someone with the depth and width of your knowledge and insight on all things HCV. Its like having are own personal doctor on staff. Actually it's better because you are and have lived our life.
We all realize that your thoughts are not to be taken as medical recommendation or a course of treatment but your insight is a cornucopia of knowledge to demystify our concerns.
Many thanks and many more to come.
Matt
-- Edited by Matt Chris on Sunday 17th of March 2013 02:06:19 AM
The pharmacokinetics of interferon and ribavirin are similar in cirrhotics and non-cirrhotics. Indepth studies of Victrelis and Incivek are not available as yet but there should be little difference. Although all HCV antivirals have excellent blood exposure, the decreased liver perfusion is a problem for cirrhotics. As liver fibrosis increases, branches of the hepatic artery, hepatic vein and portal vein are blocked. in particular, the portal vein pressure rises which leads to portal hypertension. The overall effect is that some segments of liver have a very poor blood supply. This reduces the exposure of hepatocytes to the antiviral drugs (this will include the new DAA's). This is why cirrhotics may have rests of virus (in hepatocytes) even though the blood is Undetected. Longer treatment times and higher drug doses (particularly of Ribavirin), are required.
Matt Chris said
Mar 16, 2013
Malcolm
Thanks for that info, it bring a question to mind about how we as cirrhotic HCV Patients assimilate Ribavirin and other Tx Meds .
Are the Tx Meds assimilated with weaker levels in the blood or stronger levels?
Is the transit time faster or slower through our system?
Because we have less percentage of our liver functioning does that effect the Tx Meds effectiveness ?
I sorry about these deep questions but my mind is to inquisitive.
Matt
mallani said
Mar 16, 2013
Hi all,
Ribavirin is an odd drug. It was discovered in 1970 and was found to have antiviral activity. It was sold in Mexico as a cure for the flu. In 1998, it received FDA approval for use in HCV in combination with Interferon. It is useless by itself, but it was found that SVR rates doubled when added to Interferon. The mechanism of action is still uncertain. The main side effect is haemolytic anaemia due to toxic accumulation in red blood cells. It can cause birth defects and may remain in the body for up to 6 months after Rx, so contraception is required.
The dosage of Ribavirin has been the subject of much research. From 1998-2010, Interferon (later Peginterferon) and Ribavirin was the only Rx for HCV. This is the old SOC (Standard of Care). Riba dosage was either fixed (usually 800 mg/day) or weight-based (up to 1,400 mg/day). It was found that Genotype 1 had better results with weight-based dosage, whereas Geno 2 and 3 had similar results with a fixed dose.
At least 40% of patients developed anaemia ( Hb <10 ). It was found that Riba dose reduction could keep the Hb >10. There are a large number of contradictory research papers on this subject. The consensus was that the 80/80 rule should be used i.e. patients should be on 80% of the recommended dose for 80% of the Rx duration. The SVR rate was not affected if this rule was followed. Dose reduction below the 80% level resulted in higher rates of relapse after EOT. Many researchers also throught that dose reduction should not be used in the first 12 weeks of Rx. Others thought that patients with an RVR could safely have dose reductions in this period.
With triple therapy, the rules seem to have changed. Up to 60% of patients will develop anaemia. In the USA this is aggressively managed. Riba dose reductions are often large with patients dropped to a Riba dose of 600mg/day or less. Procrit and other red cell stimulants are often used as well. For most patients, this ensures the Hb stays well above 10. After a Riba dose reduction, many patients do not have the Riba dose adjusted up, irrespective of the Hb level. Recent papers now quote the 60% rule i.e. patients should be on 60% of the recommended dose for 60% of Rx duration. However, cirrhotics are an exception, and should be on the maximum tolerated dose. It's hard to argue against this, as so many Forum members have achieved SVR with massive Riba reductions.
In the UK and Australia, things are quite different. Here, a Hb of 9-10 is considered reasonable and indeed desirable. I admit to being confused about what should be a worldwide standard protocol. This is probably because I was kept on 1,200 mg/day throughout, despite having a Hb of 8-9.5 throughout Rx. My doc kept emphasing the need for cirrhotics to stay on the maximum dose, and showed me reseach confirming this. I have no answers- do what your doc prescribes!
Malcolm you are amazing!
Phar-ma-co-ki-net-ics that's the term that encompasses my questions, thank you, thank you thank you!
pharmacokinetics
(the study of the action of drugs within the body. It includes studies of the mechanisms of drug absorption, distribution, metabolism, and excretion; onset of action; duration of effect; biotransformation; and effects and routes of excretion of the metabolites of the drug.)
We members of the Forum are very blessed to have someone with the depth and width of your knowledge and insight on all things HCV. Its like having are own personal doctor on staff. Actually it's better because you are and have lived our life.
We all realize that your thoughts are not to be taken as medical recommendation or a course of treatment but your insight is a cornucopia of knowledge to demystify our concerns.
Many thanks and many more to come.
Matt
-- Edited by Matt Chris on Sunday 17th of March 2013 02:06:19 AM
Matt,
The pharmacokinetics of interferon and ribavirin are similar in cirrhotics and non-cirrhotics. Indepth studies of Victrelis and Incivek are not available as yet but there should be little difference. Although all HCV antivirals have excellent blood exposure, the decreased liver perfusion is a problem for cirrhotics. As liver fibrosis increases, branches of the hepatic artery, hepatic vein and portal vein are blocked. in particular, the portal vein pressure rises which leads to portal hypertension. The overall effect is that some segments of liver have a very poor blood supply. This reduces the exposure of hepatocytes to the antiviral drugs (this will include the new DAA's). This is why cirrhotics may have rests of virus (in hepatocytes) even though the blood is Undetected. Longer treatment times and higher drug doses (particularly of Ribavirin), are required.
Malcolm
Thanks for that info, it bring a question to mind about how we as cirrhotic HCV Patients assimilate Ribavirin and other Tx Meds .
Are the Tx Meds assimilated with weaker levels in the blood or stronger levels?
Is the transit time faster or slower through our system?
Because we have less percentage of our liver functioning does that effect the Tx Meds effectiveness ?
I sorry about these deep questions but my mind is to inquisitive.
Matt
Hi all,
Ribavirin is an odd drug. It was discovered in 1970 and was found to have antiviral activity. It was sold in Mexico as a cure for the flu. In 1998, it received FDA approval for use in HCV in combination with Interferon. It is useless by itself, but it was found that SVR rates doubled when added to Interferon. The mechanism of action is still uncertain. The main side effect is haemolytic anaemia due to toxic accumulation in red blood cells. It can cause birth defects and may remain in the body for up to 6 months after Rx, so contraception is required.
The dosage of Ribavirin has been the subject of much research. From 1998-2010, Interferon (later Peginterferon) and Ribavirin was the only Rx for HCV. This is the old SOC (Standard of Care). Riba dosage was either fixed (usually 800 mg/day) or weight-based (up to 1,400 mg/day). It was found that Genotype 1 had better results with weight-based dosage, whereas Geno 2 and 3 had similar results with a fixed dose.
At least 40% of patients developed anaemia ( Hb <10 ). It was found that Riba dose reduction could keep the Hb >10. There are a large number of contradictory research papers on this subject. The consensus was that the 80/80 rule should be used i.e. patients should be on 80% of the recommended dose for 80% of the Rx duration. The SVR rate was not affected if this rule was followed. Dose reduction below the 80% level resulted in higher rates of relapse after EOT. Many researchers also throught that dose reduction should not be used in the first 12 weeks of Rx. Others thought that patients with an RVR could safely have dose reductions in this period.
With triple therapy, the rules seem to have changed. Up to 60% of patients will develop anaemia. In the USA this is aggressively managed. Riba dose reductions are often large with patients dropped to a Riba dose of 600mg/day or less. Procrit and other red cell stimulants are often used as well. For most patients, this ensures the Hb stays well above 10. After a Riba dose reduction, many patients do not have the Riba dose adjusted up, irrespective of the Hb level. Recent papers now quote the 60% rule i.e. patients should be on 60% of the recommended dose for 60% of Rx duration. However, cirrhotics are an exception, and should be on the maximum tolerated dose. It's hard to argue against this, as so many Forum members have achieved SVR with massive Riba reductions.
In the UK and Australia, things are quite different. Here, a Hb of 9-10 is considered reasonable and indeed desirable. I admit to being confused about what should be a worldwide standard protocol. This is probably because I was kept on 1,200 mg/day throughout, despite having a Hb of 8-9.5 throughout Rx. My doc kept emphasing the need for cirrhotics to stay on the maximum dose, and showed me reseach confirming this. I have no answers- do what your doc prescribes!