The conjugation of PEG reagent (bis-monomethoxypolyethylene glycol) to interferon alfa-2a forms a pegylated interferon alfa-2a. Peginterferon alpha-2a possesses the in vitro antiviral and antiproliferative activities that are characteristic of interferon alfa-2a.
Interferon alfa-2a is conjugated with bis-[monomethoxy polyethylene glycol] at a degree of substitution of one mole of polymer/mole of protein. The average molecular mass is approximately 60,000 of which the protein moiety constitutes approximately 20,000.
HCV RNA levels decline in a biphasic manner in responding patients with hepatitis C who have received treatment with 180 micrograms peginterferon alfa-2a. The first phase of decline occurs 24 to 36 hours after the first dose of peginterferon alfa-2a and is followed by the second phase of decline which continues over the next 4 to 16 weeks in patients who achieve a sustained response. Ribavirin had no significant effect on the initial viral kinetics over the first 4 to 6 weeks in patients treated with the combination of ribavirin and pegylated interferon alfa-2a or interferon alfa.
Following a single subcutaneous injection of peginterferon alpha-2a 180 micrograms in healthy subjects, serum concentrations of peginterferon alfa-2a are measurable within 3 to 6 hours. Within 24 hours, about 80% of the peak serum concentration is reached. The absorption of peginterferon alpha-2a is sustained with peak serum concentrations reached 72 to 96 hours after dosing. The absolute bioavailability of peginterferon alpha-2a is 84% and is similar to that seen with interferon alfa-2a.
Peginterferon alfa-2a is found predominantly in the bloodstream and extracellular fluid as seen by the volume of distribution at steady-state (Vd) of 6 to 14 litres in humans after intravenous administration. From mass balance, tissue distribution and whole body autoradioluminography studies performed in rats, peginterferon alfa-2a is distributed to the liver, kidney and bone marrow in addition to being highly concentrated in the blood.
The metabolism of peginterferon alpha-2a is not fully characterised; however studies in rats indicate that the kidney is a major organ for excretion of radiolabelled material.
In humans, the systemic clearance of peginterferon alfa-2a is about 100-fold lower than that of the native interferon alfa-2a. After intravenous administration, the terminal half-life of peginterferon alfa2a in healthy subjects is approximately 60 to 80 hours compared to values of 3-4 hours for standard interferon. The terminal half-life after subcutaneous administration in patients is longer with a mean value of 160 hours (84 to 353 hours). The terminal half-life may not only reflect the elimination phase of the compound, but may also reflect the sustained absorption of peginterferon alpha-2a.
Dose-proportional increases in exposure of peginterferon alpha-2a are seen in healthy subjects and in patients with chronic hepatitis B or C after once-weekly dosing.
In CHB or CHC patients, peginterferon alfa-2a serum concentrations accumulate 2 to 3 fold after 6 to 8 weeks of once weekly dosing compared to single dose values. There is no further accumulation after 8 weeks of once weekly dosing. The peak to trough ratio after 48 weeks of treatment is about 1.5 to 2. Peginterferon alfa-2a serum concentrations are sustained throughout one full week (168 hours).
A clinical trial evaluated 50 CHC patients with either moderate (creatinine clearance 30 to 50 mL/min) or severe (creatinine clearance less than 30 mL/min) renal impairment, or with end stage renal disease (ESRD) requiring chronic hemodialysis (HD). Patients with moderate renal impairment receiving peginterferon alpha-2a 180 mcg once weekly exhibited similar peginterferon alfa-2a plasma exposures compared to patients with normal renal function. Patients with severe renal impairment receiving peginterferon alpha-2a 180 mcg once weekly showed a 60% higher peginterferon alfa-2a exposure than patients with normal renal function, therefore a reduced dose of peginterferon alpha-2a 135 mcg once weekly is recommended in patients with severe renal impairment. In 13 patients with ESRD requiring chronic HD, administration of peginterferon alpha-2a 135 mcg once weekly resulted in 34% lower peginterferon alfa-2a exposure than in patients with normal renal function. However, several independent studies have demonstrated the 135mcg dose to be safe, efficacious and well tolerated, in patients with ESRD.
The pharmacokinetics of peginterferon alpha-2a after single subcutaneous injections was comparable between male and female healthy subjects.
Peginterferon, alpha-2a pharmacokinetics have been characterized in paediatric patients with CHB (YV25718), as well as in paediatric patients with CHC (NR16141), using population pharmacokinetics. In both studies, peginterferon alpha-2a apparent clearance and apparent volume of distribution were related linearly to body size ie. either BSA (NR16141) or body weight (YV25718).
From the YV25718 study, 31 paediatric patients 3 to 17 years of age with CHB participated in the PK sub-study and received peginterferon alpha-2a according to a BSA category dosing regimen. Based on the population pharmacokinetic model, the mean exposure (AUC) during the dosing interval for each BSA category was comparable with that observed in adults receiving 180 mcg fixed dosing.
From the NR16141study, 14 children 2 to 8 years of age with CHC received peginterferon alpha-2a monotherapy at a dose of: 180 mcg x BSA of the child/1.73 m². The PK model developed from this study shows a linear influence of BSA on the apparent clearance of the drug over the age range studied. Thus, the lower the BSA of the child, the lower the clearance of the drug and the higher the resultant exposure. The mean exposure (AUC) during the dosing interval is predicted to be 25% to 70% higher than that observed in adults receiving 180 mcg fixed dosing.
In subjects older than 62 years, the absorption of peginterferon alpha-2a after a single subcutaneous injection of 180 micrograms was delayed but still sustained compared to young healthy subjects (tmax of 115 hours vs. 82 hours, older than 62 years vs. younger, respectively). The AUC was slightly increased (1663 vs. 1295 ng·h/ml) but peak concentrations (9.1 vs. 10.3 ng/ml) were similar in subjects older than 62 years. Based on drug exposure, pharmacodynamic response and tolerability, a lower dose of peginterferon alpha-2a is not needed in the geriatric patient.
The pharmacokinetics of peginterferon alpha-2a were similar between healthy subjects and patients with hepatitis B or C. Comparable exposure and pharmacokinetic profiles were seen in cirrhotic (Child-Pugh Grade A) and non-cirrhotic patients.
Subcutaneous administration of peginterferon alpha-2a should be limited to the abdomen and thigh, as the extent of absorption based on AUC was about 20% to 30% higher upon injection in the abdomen and thigh. Exposure to peginterferon alpha-2a was decreased in studies following administration of peginterferon alpha-2a in the arm compared to administration in the abdomen and thigh.
The non-clinical toxicity studies conducted with peginterferon alfa-2a were limited due to species specificity of interferons. Acute and chronic toxicity studies have been carried out in cynomolgus monkeys, and the findings observed in peginterferon dosed animals were similar in nature to those produced by interferon alfa-2a.
Reproductive toxicity studies have not been performed with peginterferon alfa-2a. As with other alfa interferons, prolongation of the menstrual cycle was observed following administration of peginterferon alfa-2a to female monkeys. Treatment with interferon alfa-2a resulted in a statistically significant increase in abortifacient activity in rhesus monkeys. Although no teratogenic effects were seen in the offspring delivered at term, adverse effects in humans cannot be excluded.
When used in combination with ribavirin, peginterferon alfa-2a did not cause any effects in monkeys not previously seen with either active substance alone. The major treatment-related change was reversible mild to moderate anaemia, the severity of which was greater than that produced by either active substance alone.
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