Treatment Options

Pharmacology

Pegylation

Polyethylene glycol (PEG) is an inert, water-soluble, non-toxic polymer used in the modification of molecules. The aim of pegylating biologically-active proteins is to improve the pharmacokinetic and pharmacodynamic properties of the native protein while retaining its intrinsic in-vivo biological activity. Therapeutic benefits of altering proteins with PEG can include an increase in half-life due to reduced renal and cellular clearance, increased protection from proteolysis and a reduction in toxicity. The structure, length and molecular weight of the PEG polymer chain and the modification procedure used, are key factors involved in optimising the pharmacokinetics and pharmacodynamics of a pegylated protein in order to enhance its pharmacological activity and therapeutic efficacy.

Rationale and Advantages of Pegylating Interferon

The efficacy of conventional interferon alfa (IFNα) therapy for the treatment of chronic hepatitis C (CHC) is limited by protein characteristics that include poor stability, a short half-life and high immunogenicity. The terminal elimination half-life of coventional IFNα ranges from 4–16 hours, with peak serum concentrations occurring at 1–8 hours following intramuscular (im) or subcutaneous (sc) administration(Wills, 1990). By 24 hours following intravenous (iv), im or sc administration, little or no detectable IFNα remains in the serum(Barouki et al, 1987; Wills, 1990). These characteristics have several important consequences. Frequent dosing of IFNα is required to achieve effective therapeutic concentrations of drug in the plasma. In the treatment of CHC, conventional IFNα is administered thrice weekly but, due to the unfavourable pharmacokinetic characteristics, large fluctuations in serum concentrations can occur after each dose, resulting in peaks and troughs in the drug concentration. The peaks in drug concentration are linked to the high incidence of adverse events, such as fever, chills, headache, myalgia and dizziness that compromise the tolerability of conventional IFNα(Perry and Jarvis, 2001).

The troughs in drug concentration represent periods of time when IFNα is not in circulation, and so viral suppression is not maintained, which may in turn lead to viral rebound(Lam et al, 1997). Preclinical studies of other pegylated therapeutic proteins demonstrate that PEG polymers can enhance the protein’s in-vivo pharmacological activity in comparison with the native protein (Table 3-2). Most notably, the PEG polymer increases the half-life of the conjugated protein. This increase in half-life is related to reduced renal and intracellular clearance, as well as increased resistance to proteolytic degradation.

Table 3-2: Advantages of pegylation (adapted with permission from Reddy, 2000)

Improved pharmacokinetics
(↑t1/2, ↓ Clearance, ↓Cmax, ↑Cmin)
Less fluctuations in plasma concentrations
Enhanced in-vivo activity
Decreased toxicity associated with decreased Cmax
Once-weekly dosing leading to increased compliance and patients’ quality of life
Decreased immunogenicity and antigenicity
Increased physiological and chemical stability
Improved solubility

Protection from proteolysis

 

Treatment of CHC for 12 months with IFNα monotherapy results in a sustained virological response (SVR) rate of 15–20%(McHutchison et al, 1998; Zeuzem et al, 2001a). With PEGASYS®, the addition of a large, branched, 40 KD PEG polymer to IFNα-2a provides sustained therapeutic concentrations due to a slower absorption and reduced clearance that allows the therapeutic dosing schedule to be lengthened to once a week (qw)(Kozlowski et al, 2001). An increased SVR can be achieved by providing a near constant and adequate exposure of PEGASYS® to the virus(Zeuzem et al, 2001a). In addition, weekly therapeutic dosing improves treatment convenience and the quality of life of the patient(Reddy, 2000).

Read about the Biochemistry of pegylation.

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