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Overview of Pharmacokinetic Properties of Pegasys
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This article reviews Pegasys and its distribution in the body, metabolism, elimination, in the elderly/cirrhotics/renal impairment. In the end what matters most is the clinical effect of a drug. In other words, in this case, does it reduce your viral load to undetectable and sustain it, and well does the drug do this in large numbers of patients; and is it safe. The FDA (Food and Drug Adminstration) is reviewing the application for approval for this drug now. The effectiveness and safety of Pegasys has been reported in a number of studies presented at conferences. The public reporting of this data by the FDA should take place at the end of its review simultaneous to approval. Data so far presented at conferences can be read on the NATAP website.
Excerpted from full report from Adis Intl., written by Caroline Perry and Blair Javis; www.adis.com; report supported by grant from Roche, manufacturer of Pegasys.
Peginterferon-a -2a (40kD) (Pegasys) is well absorbed after single subcutaneous doses in healthy volunteers or multiple subcutaneous doses in patients with chronic hep-atitis C. Three to 8 hours after a single 180 ug dose of the drug, 'substantial' concentrations (values not reported) of peginterferon-a -2a (40kD) were detected in the serum of 10 healthy volunteers. Peginterferon-a -2a (40kD) was delivered to the systemic circulation at a sustained rate; the mean maximum serum concentration (Cmax) of peginterferon-a -2a (40kD) was 14.2 µg/L and was reached in mean time (tmax) of 78 hours. After single 180 ug doses of peginterferonao -2a (40kD), serum peginterferon-a -2a (40kD) concentrations were sustained for longer than concentrations of interferon-a -2a in healthy volunteers. In 16 patients with chronic hepatitis C who received multiple doses of peginterferon-a -2a (40kD) 180 µg/week, the peginterferon-a -2a Cmax was 25.6 µg/L and the tmax was 45 hours. After single 180ug doses (n = 14), Cmax and tmax values were 15.4 µg/L and 80 hours, respectively; steady-state concentrations of the drug were attained 5 to 8 weeks after initiation of the once-weekly regimen in these patients.
Peginterferon-a -2a (40kD) is cleared by both the liver and kidney and the liver
plays an important role in the metabolism of the drug. Because of its large size
and branched nature, peginterferon-a -2a (40kD) undergoes reduced renal clearance compared with that of standard interferon-a , thus prolonging hepatic exposure to the pegylated interferon. Pegylation resulted in a >100-fold reduction in the renal clearance of interferon-a -2a in 10 volunteers who received a single 180 ug dose of peginterferon-a -2a (40kD). Metabolic products of peginterferon-a-2a (40kD) are eliminated via the kidneys. However, clearance via the kidneys does not appear to be extensive as the pharmacokinetics of the drug in patients with chronic renal impairment (creatinine clearance values >20 ml/min; >1.2 L/h) are not appreciably different from those in patients with normal renal function.
In patients with chronic hepatitis C and cirrhosis, the terminal half-life of
peginterferon-a -2a (40kD) was 70 to 90 hours. Peginterferon-a -2a (40kD) showed no significant effects on drug metabolism mediated by CYP2C9, 2C19, 2D6 and 3A4 isoenzymes in healthy nonsmoking male volunteers. However, as documented with interferon-a, the clearance of theophylline (metabolised by CYP1A2) was significantly reduced (compared with baseline) in volunteers receiving multiple doses of peginterferon-a -2a (40kD).
Editorial note: in patients with HIV who take HIV antiretrovirals, there is some potential for interaction of ribavirin with NRTI medications. Ribavirin is an NRTI without HIV or HCV antiviral effect. In vitro studies show interaction between ribavirin and 3TC, AZT, d4T, and ddI. Ribivarin reduced exposure to all of these but increased ddI exposure. In human clinical studies there has not been evidence that these potential interactions are of clinical significance, but studies are ongoing. HIV viral load does not appear to increase when IFN/RBV is administered along with an HIV regimen. Its been suggested this could be due to the effect of interferon in reducing HIV viral load, or perhaps there is no clinical effect.
Elderly Volunteers
The absorption of peginterferon-a -2a (40kD) after a single 180 ug dose is slower in healthy elderly men aged >60 years (n = 12; tmax 116 hours)
than in healthy young men aged 18 to 25 years (n = 12; tmax 81 hours). [25] Peginterferon-a -2a (40kD) Cmax values were similar in elderly and
young men (9.1 and 10.3 µg/L), but the elderly group had greater systemic exposure to the drug (area under the serum concentration-time curve
values were 1663 and 1295 µg h/L, respectively) suggesting that the drug should be used with caution in elderly patients with chronic hepatitis C.
However, this was not considered by the investigators to result in an increase in the biological activity of the drug.
Distribution
Peginterferon-a -2a (40kD) displays restricted biodistribution in patients with chronic hepatitis C [31] and in animals, [29] with highest concentrations occurring in the liver where the drug can be most effective. [29] The drug was recovered from injection site tissue, blood, liver, kidneys and spleen in rats after a single intravenous or subcutaneous dose of radiolabelled peginterferon-a -2a (40kD). Amounts of radioactive peginterferon-a -2a (40kD) were highest in the liver and kidney (6.9 and 1.4%, respectively) 14 days after the single intravenous dose; similar results were obtained after a single subcutaneous dose of the drug. [29] Con centrations of peginterferon-a -2a (40kD) were <1% in all other organs examined.
Metabolism and Elimination
Peginterferon-a -2a (40kD) is cleared by both the liver and the kidney and the liver plays an important role in the metabolism of the drug. [29] Because of its large size and branched nature, peginterferon-a -2a (40kD) undergoes reduced
renal clearance compared with that of standard interferon-a , thus prolonging hepatic exposure to the pegylated interferon. Pegylation resulted in a >100-fold reduction in the renal clearance of interferon-a -2ain 10 vol-unteers
who received a single 180 ug dose of peginterferon-a -2a (40kD); clearance values for peginterferon-a -2a (40kD) and standard interferon-a were 0.08 and 11.8 L/h (data from previous investigations), respectively. [30] Peginterferon-a -2a (40kD) had a mean clearance of 0.060 L/h in 16 patients with chronic hepatitis C who received peginterferon-a -2a (40kD) 180 µg/week for 48
weeks. [31]
Peginterferon-a -2a (40kD) was shown to be cleared mainly by hepatic metabolism in rats [after an initial period of >24 hours when 14 C-labelled
peginterferon-a -2a (40kD) remained unmetabolised in the liver]. [29] The liver : blood ratio of radio-labelled peginterferon-a -2a (4kD) concentrations
was greater than that of interferon-a , suggesting that peginterferon-a -2a (40kD) provides the liver with greater exposure to interferon-a than standard
interferon-a. [30] Metabolic products of peginterferon-a -2a (40kD)
are eliminated via the kidneys. However, clearance via the kidneys does not appear to be extensive as the pharmacokinetics of the drug in patients with
varying degrees of chronic renal impairment (CLCR values >20 ml/min; >1.2 L/h) are not appreciably different from those in patients with normal renal
function. [32] Elimination occurred at a consistent rate during the 14-day period after administration of a single intravenous or subcutaneous dose in
rats. [29] During this time, proportions of the total radioactive dose eliminated in the urine and faeces were 51 and 9.6%, respectively. In patients with chronic hepatitis C and cirrhosis, the terminal half-life (t 1 Ž2 ) of peginterferon-a
-2a (40kD) [70 to 90 hours] was similar to that in healthy volunteers (77 hours). [34] The t 1 Ž2 of peginterferon-a -2a (40kD) was longer in elderly than in young men (110 vs 61 hours). [25]
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