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PEG Intron (pegylated interferon-alpha-2b [IFN-α-2b]; Schering-Plough, Kenilworth, NJ) has demonstrated delayed clearance and increased area under the curve compared with native IFN-α-2b. Studies in patients with chronic hepatitis C infection and malignancies have demonstrated both biologic and clinical activity of PEG Intron and have provided empiric data to compare the pharmacokinetics (PK) and pharmacodynamics of PEG Intron and IFN-α-2b.
The authors conducted a review of the available data comparing the PK and pharmacodynamic effects of PEG Intron and IFN-α-2b. Safety and efficacy data from Phase I/II studies of PEG Intron in patients with chronic myelogenous leukemia (CML) and solid tumors were also reviewed.
Data from patients with chronic hepatitis C infection suggest that exposure to IFN at a PEG Intron dose of 0.25 μg/kg per week is similar to that observed after administration of IFN-α-2b at a dose of 3 million International Units, three times per week. PEG Intron at doses up to 6 μg/kg per week was well tolerated and demonstrated clinical activity in patients with CML and solid tumors, including metastatic melanoma and renal cell carcinoma.
Pegylation of therapeutic proteins is a well established method for delaying clearance and reducing protein immunogenicity, and pegylated proteins are safe and effective in humans.1, 2 Pegylation has been used to modify a variety of proteins with clinical applications, including adenosine deaminase, L-asparaginase, interleukin-2, granulocyte-macrophage–colony stimulating factor, tumor necrosis factor-alpha (TNF-α), and human growth hormone (hGH).3–8 These pegylated proteins have improved pharmacologic properties and in some cases are more potent than the native protein (e.g., TNF-α and hGH).7, 8 PEG Intron (pegylated interferon-alpha-2b [IFN-α-2b]; Schering-Plough, Kenilworth, NJ) is a derivative of recombinant IFN-α-2b containing a single straight-chain molecule of polyethylene glycol (PEG) with an average molecular weight (MW) of 12,000 daltons, attached by covalent linkage primarily to histidine-34 on IFN-α-2b.9 Pegylation of IFN-α-2b does not compromise its tertiary structure or spectrum of activity, but significantly decreases clearance, thereby increasing its plasma half-life (t½) 10-fold (from approximately 4 to 40 hours).10 As a result, PEG Intron can be administered once weekly and the increased area under the curve (AUC) compared with standard three times weekly (TIW) dosing with IFN-α-2b results in increased drug exposure without a proportional increase in toxicity.10
Chemical Properties of PEG Intron
The chemical properties of PEG Intron, including the location, MW, linear structure of the PEG chain, and the type of chemical linker used to attach the PEG, have been selected to maximize the specific activity of PEG Intron. Higher-MW PEG species result in a longer t½ but may negatively affect biologic activity.11 The structure of the PEG chain (e.g., straight or branched) can also affect potency, stability, and drug accumulation. Structures that slow absorption into the blood stream can result in extended time to maximum serum concentration. The amino acid to which PEG is linked can also affect the potency of IFN if the PEG molecule interferes with receptor binding or changes the protein structure. Changes in protein structure could also affect antigenicity. Taking all these properties into consideration, the ideal drug must combine a number of characteristics, some of which may be mutually exclusive.
The design of PEG Intron was guided by two important objectives: to develop a molecule that would have delayed clearance and thus a duration of activity compatible with once-weekly dosing and to avoid significantly compromising the potency or altering the biologic activity of PEG Intron compared with IFN-α-2b. Empiric data suggested that there is an inverse relationship between the t½ of pegylated IFNs and their antiviral activity.11 Therefore, it was important to strike a balance between these competing factors. The first attempt to pegylate IFN-α-2b resulted in a multipegylated molecule (approximately four PEG molecules per IFN-α-2b molecule), which had a long t½ but virtually no biologic activity. By applying novel pegylation chemistry, it was possible to generate a monopegylated species with approximately 47% of the PEG molecules linked to the secondary amine of histidine-34 (a site that preserves bioactivity).9 PEG molecules of either 5000 or 12,000 MW were generated and compared. The 12,000-MW species demonstrated a longer t½, consistent with lower clearance relative to the 5,000-MW species. These data are consistent with studies conducted by Jørgensen and Møller,12 who demonstrated the inverse relationship between the MW of flexible polymers (dextran and PEG) and their relative glomerular filtration rates; as the Stokes radius increases, relative clearance decreases (Fig. 1).12 Using this model, one could anticipate that PEG species of MW greater than 12,000 would be poorly cleared. Based on these studies, the 12,000-MW PEG molecule was used for further development of PEG Intron. Analysis of antiviral activity demonstrated that the 12,000-MW PEG Intron species retained approximately 27% of the antiviral activity of native IFN-α-2b. In contrast, when IFN-α is pegylated primarily on lysine residues, it typically retains only a fraction of its native potency. For example, pegylated IFN-α-2a, which is pegylated primarily on lysines, retains only 7% of the native antiviral bioactivity of IFN-α-2a in a cell culture assay.13 As a result of this development process, PEG Intron provides a good balance between high biologic activity and long elimination t½.
Biologic Characteristics of PEG Intron
PEG Intron has demonstrated similar biologic activity compared with IFN-α-2b in a variety of assays. The cytopathic effect assay is the most universally accepted method for defining the biologic activity of IFN-α. In this assay, which is based on the ability of IFN-α to protect cells from virus-induced cytopathogenesis,14 PEG Intron and IFN-α-2b demonstrated similar dose-response curves (Fig. 2; Grace et al., unpublished data). The dose-response curve for PEG Intron is shifted slightly to the left compared with that of IFN-α-2b, which is consistent with its reduced biologic activity in this assay. Interferon-α has also demonstrated antiproliferative effects on many cell lines in vitro.15 In an assay that measured inhibition of cellular proliferation, PEG Intron and IFN-α-2b demonstrated equivalent potency and the degree of inhibition was proportional to the concentration of IFN.16
PEG Intron and IFN-α-2b have similar activity with respect to the up-regulation of major histocompatibility complex class (MHC) I expression and the induction of cell-mediated cytotoxicity.16 The immunologic activities characteristic of IFN-α-2b, namely, stimulation of lymphokine-activated cytotoxic T and natural killer cells, as well as increased MHC expression, all remain intact in PEG Intron.
EXPERIENCE WITH PEG INTRON IN PATIENTS WITH CHRONIC HEPATITIS C INFECTION
Single-Dose Pharmacokinetic Profile
The pharmacokinetic (PK) properties of PEG Intron and IFN-α-2b following administration of a single dose via subcutaneous injection have been studied in patients with chronic hepatitis C infection (Table 1).10 Whereas the absorption kinetics and the volume of distribution of PEG Intron were similar to those of IFN-α-2b, the clearance of PEG Intron was delayed. This resulted in approximately a 10-fold longer terminal elimination t½ compared with IFN-α-2b (approximately 40 hours vs. 4 hours).10 The decreased plasma clearance of PEG Intron relative to IFN-α-2b is illustrated in the plasma concentration-versus-time curves (Fig. 3).10, 17 Following administration of a single 1.0- or 1.5-μg/kg dose, the maximal serum concentration (Cmax) of PEG Intron was observed between 15 and 44 hours postdose and was sustained for 48–72 hours postdose. PEG Intron Cmax and AUC both increased in a dose-related manner. In contrast, IFN-α-2b at a dose of 3 million International Units (MIU) TIW was nearly completely cleared within 24 hours after administration of each dose. A single dose of PEG Intron at a dose of 1.0 μg/kg or higher resulted in the presence of IFN in the circulation at 168 hours (7 days) postdose. Therefore, PEG Intron is available in the circulation for the entire week of treatment, thus dramatically increasing exposure to IFN-α-2b.
Table 1. Summary of Single-Dose Pharmacokinetics of PEG Intron and IFN-α-2b
PEG Intron: pegylated interferon-alpha-2b; IFN: interferon; t½: half-life; Cmax: maximal concentration; Vd/F: volume of distribution; CL/F: total body clearance.
Multidose PK and Pharmacodynamic Profiles of PEG Intron and IFN-α-2b
The PK and pharmacodynamic profiles of PEG Intron and IFN-α-2b have been further compared in a multidose, dose-ranging study in patients with chronic hepatitis C infection.18, 19 In this study, PEG Intron was administered at doses ranging from 0.035–2.0 μg/kg per week subcutaneously for 24 weeks and IFN-α-2b was administered at the standard dose for chronic hepatitis C infection (3 MIU subcutaneously TIW). PK and pharmacodynamic parameters were assessed at Weeks 1 and 4. Exposure to PEG Intron increased in a dose-related manner across the dose range studied. Based on the observed AUC at Week 4, it was estimated that PEG Intron at a dose of 0.25 μg/kg per week yielded equivalent exposure compared with IFN-α-2b at a dose of 9 MIU per week (Table 2).18, 19 Both PEG Intron and IFN-α-2b showed a small increase in bioavailability following multiple doses compared with a single dose. However, the relationship between dose and AUC remained fairly linear between PEG Intron doses of 0.25 and 1.5 μg/kg per week.
Table 2. Pharmacokinetic Comparability of PEG Intron and IFN-α-2b Doses Based on the Observed AUC in a Multidose, Dose-Ranging Study in Patients with Chronic Hepatitis C Infection
PEG Intron dose (μg/kg/week)
IFN-α-2b dose (MIU/week)
PEG Intron: pegylated interferon-alpha-2b; IFN: interferon; AUC: area under the curve; MIU: Million International Units.
The pharmacodynamic effects of PEG Intron were qualitatively similar to those of IFN-α-2b after single and multiple doses.10 In healthy volunteers and in patients with chronic hepatitis C infection, both agents increased body temperature. They also decreased neutrophil, white blood cell (WBC), and platelet counts and increased serum concentrations of effector proteins such as neopterin and 2′5′-oligoadenylate synthetase (both of which are associated with the antiviral and immunomodulatory effects of IFN-α).10 Quantitative analysis of the biologic effects of PEG Intron versus IFN-α-2b on these parameters demonstrated dose-related effects of PEG Intron and suggested that PEG Intron at a dose of 1.0 μg/kg per week had approximately equivalent pharmacodynamic activity as 3 MIU TIW (9 MIU per week) IFN-α-2b. As shown in Figure 4, the effects of PEG Intron on neutrophil and WBC counts at doses ranging from 0.5 to 2.0 μg/kg per week were similar to the effects associated with 9 MIU per week IFN-α-2b (boxed areas on Fig. 4).10 At 1 μg/kg per week, PEG Intron decreased WBC and neutrophil counts to approximately 70% and 50% of baseline, respectively, compared with 68% and 54% of baseline in patients treated with 9 MIU per week IFN-α-2b. However, despite the similar pharmacodynamic activity, PEG Intron at a dose of 1.0 μg/kg per week produced superior antiviral effects compared with IFN-α-2b (3 MIU TIW).19
The randomized Phase III pivotal trial of PEG Intron versus IFN-α-2b in patients with chronic hepatitis C infection has demonstrated that the increased exposure achieved with PEG Intron yields improved antiviral efficacy.19 In this trial, the antiviral activity of PEG Intron (0.5, 1.0, and 1.5 μg/kg) administered weekly for 48 weeks was directly compared with the approved dose of IFN-α-2b (3 MIU TIW). The results demonstrated that weekly administration of PEG Intron significantly improved sustained virologic response rates at doses of 0.5 (P = 0.04), 1.0 (P < 0.001), and 1.5 μg/kg (P < 0.001) compared with IFN-α-2b (3 MIU TIW).19
SAFETY AND PHARMACOLOGY OF PEG INTRON IN PATIENTS WITH CML
PEG Intron has been investigated recently in patients with chronic myelogenous leukemia (CML). Prolonged treatment of CML patients with daily subcutaneous injection of IFN-α is both inconvenient and poorly tolerated. Dose-limiting toxicity occurs in 30–50% of patients at the typical doses used (i.e., 3–5 MIU/m2 per day).20 In a Phase I dose-escalation trial, 27 chronic-phase CML patients, all of whom had failed previous IFN-α therapy, were treated with PEG Intron at doses ranging from 0.75–9.0 μg/kg per week for 4 weeks.21 Nine patients had developed hematologic resistance to IFN-α, 12 had developed cytogenetic resistance; and 6 were unable to tolerate IFN-α. A similar dose-ranging study has also been conducted in patients with solid tumors.
Similar to what was observed in patients with hepatitis C infection, the AUC of PEG Intron demonstrated a linear correlation with the administered dose after a single dose of up to 3.0 μg/kg and there was evidence of accumulation after multiple doses at Week 4 (Fig. 5).21 Regardless of the dose, the PEG Intron accumulated by a factor of approximately 1.5 after multiple doses. Based on the Week 4 AUC at a PEG Intron dose of 6 μg/kg per week, exposure was estimated to be approximately 80 times that observed after 9 MIU per week IFN-α-2b.
No dose-limiting toxicity occurred during the initial 4 weeks of therapy and the maximum tolerated dose was not reached. However, with longer duration of therapy on an extension protocol, dose-limiting toxicities including severe fatigue, neurotoxicity, liver function abnormalities, and myelosuppression were observed at weekly doses of 7.5 μg/kg or higher.21 The safety profile of PEG Intron in this study was qualitatively similar to that of IFN-α-2b, as expected from the experience in patients with hepatitis infection. The most common adverse events were constitutional symptoms consistent with the flulike syndrome, including fever (85%), headache (85%), fatigue (74%), rigors (74%), and myalgia (63%).21 Ten patients reported 19 severe adverse events that included rigors (four events), myalgia and fatigue (three events each), fever and headache (two events each), and arthralgia, bone pain, leg cramps, influenzalike symptoms, and pain (one event each). Hematologic toxicity, including decreased neutrophil and platelet counts, was uncommon and primarily Grade 1 in severity at doses of 6 μg/kg and higher per week. Increases in the frequency and severity of hematologic toxicity were observed at higher doses. The majority of adverse events were mild to moderate in severity and none was treatment limiting, but there appeared to be a dose-related increase in the frequency of mild to moderate adverse events.
Based on the safety and tolerability profile of PEG Intron in this study, the dose of 6 μg/kg per week was selected for further study in Phase II and III trials. Although the number of CML patients treated at each dose level was small, 6 μg/kg per week of PEG Intron was associated with a safety profile that appears comparable with that associated with 3–5 MIU/m2 per day IFN-α.20 Moreover, no dose-limiting toxicity occurred in patients treated with 6 μg/kg per week for longer durations. Weekly administration of PEG Intron was also associated with a shorter duration of acute flulike symptoms compared with daily IFN-α. The majority of patients experienced acute symptoms only on the day of administration of PEG Intron (i.e., 1 day each week). In contrast, patients receiving daily IFN-α subcutaneously frequently have acute symptoms throughout the week and as a result may discontinue therapy.
This Phase I trial has further demonstrated the antileukemic activity of PEG Intron in CML patients (Table 3).21 Of 27 patients, 13 (48%) who had failed IFN-α-2b therapy had either a complete hematologic or improved cytogenetic response. Among 18 patients with active disease, 1 patient achieved a complete cytogenetic response, 6 achieved a complete hematologic response, and 3 had a partial hematologic response. Among nine patients treated in complete hematologic response, eight (90%) patients improved to either a complete cytogenetic response (five patients) or partial cytogenetic response (three patients). Moreover, all six patients who were intolerant to IFN-α-2b tolerated PEG Intron and four of these patients had an improvement in cytogenetic response. These results demonstrate not only that PEG Intron is better tolerated than standard doses of IFN-α-2b, but that the increased exposure achieved with PEG Intron may translate into meaningful hematologic and cytogenetic responses even in CML patients who have previously failed IFN-α therapy. These promising early results have demonstrated that weekly subcutaneous dosing with PEG Intron is convenient, well tolerated, and may be more effective than IFN-α-2b in the initial treatment of CML patients.
Table 3. Response to PEG Intron in Patients with Chronic Myelogenous Leukemia Who Had Failed or Were Intolerant to IFN-α Therapy
A Phase I study was conducted to investigate the safety and tolerability of PEG Intron in combination with cytarabine (ara-C) in 41 previously treated patients. The addition of low-dose ara-C (10 mg per day or 20 mg/m2 × 10 days each month) to standard doses of IFN-α-2b (5 MIU/m2 per day) improved the cytogenetic response rate and may improve the survival rate compared with single-agent IFN-α-2b.22, 23 Similar to the single-agent Phase I trial, this study tested weekly doses of PEG Intron ranging from 0.75–9 μg/kg for 4 weeks combined with ara-C (either 10 mg per day or 20 mg/m2 × 10 days). The most frequently reported adverse events were fever, fatigue, chills, headache, sweats, dizziness, nausea, anorexia, diarrhea, vomiting, and insomnia.24 These were predominantly mild to moderate in severity and there were no major differences between treatment groups with respect to toxicity. The majority (approximately 80%) of patients demonstrated hematologic improvement during the 4-week treatment period and continued to receive treatment on an extension protocol. At completion of the extension protocol, 19 of 41 (46%) patients had achieved a complete hematologic response and 9 (22%) had a major cytogenetic response to PEG Intron plus ara-C.24 The results of this study demonstrate that full doses of PEG Intron can be administered in combination with ara-C and that the maximum tolerated dose of PEG Intron is not affected. Moreover, response rates were consistent with those achieved with IFN-α-2b plus ara-C in previously treated patients.
Increased Exposure to IFN-α-2b May Improve Efficacy in CML Patients
A comparative analysis of IFN-α trials has provided evidence of a dose-response relationship for IFN-α in patients with CML.20, 25 Most studies suggest that IFN-α doses of 4–5 MIU/m2 per day (50–60 MIU per week) are more likely to induce cytogenetic remission than lower doses and achieving a major cytogenetic response is associated with prolonged survival.22 Studies with IFN-α-2b also suggest that increased AUC may be more critical for the antileukemic effect than peak plasma levels.20 These data suggest that treatment with PEG Intron may improve cytogenetic response rates and the quality of responses by increasing exposure to IFN-α, which could translate into a survival benefit. The Phase I study of PEG Intron in CML patients who failed IFN-α therapy has demonstrated that weekly administration of PEG Intron at 6 μg/kg can increase dramatically exposure to IFN-α compared with standard doses of IFN-α and that PEG Intron has antileukemic activity in patients who are resistant to IFN-α.21 Therefore, 6 μg/kg PEG Intron has been further evaluated in a randomized trial comparing it with standard doses of IFN-α-2b.
PEG INTRON FOR SOLID TUMORS
A Phase I dose-escalation study, similar to the CML study, has been conducted in patients with solid tumors.26 Patients with measurable disease were treated for 12 weeks with PEG Intron at doses ranging from 0.75–7.5 μg/kg per week, with the option to extend treatment beyond 12 weeks for patients achieving partial response or disease stabilization. All patients enrolled in this trial had been previously treated and had progressive metastatic disease. The majority had either melanoma (n = 6) or renal cell carcinoma (RCC; n = 22). Among 31 patients evaluable for response, 6 (19%) patients had a partial response and 4 (13%) had stable disease (Table 4).26 The majority of objective tumor responses occurred in patients treated at the higher dose levels (i.e., ≥6 μg/kg per week) and responses were observed at visceral and nonvisceral sites of disease (Table 5).26 Responses generally occurred within 2 months of the initiation of treatment with PEG Intron and several durable responses are ongoing beyond 1 year.
Table 4. Clinical Outcome among 31 Patients with Metastatic Solid Tumors
Based on the antitumor activity demonstrated in the Phase I trial, a Phase Ib protocol was initiated in patients with metastatic RCC. Patients enrolled in this study had received no previous systemic therapy and had good performance status. A total of 41 patients were treated; 22 patients received 6 μg/kg per week and 19 patients received 7.5 μg/kg per week (including 6 patients treated with 7.5 μg/kg per week in the Phase I protocol). Among 19 patients who qualified for extended treatment beyond 3 months, the median duration of treatment was 7 months. Among 35 patients evaluable for response (i.e., patients who received at least 8 weeks of PEG Intron therapy), 5 (14%) had a partial response and 14 (40%) had stable disease. Responses were observed with slightly higher frequency at the dose level of 7.5 μg/kg per week (20% partial response rate).
These early studies in patients with metastatic melanoma and RCC have demonstrated the antitumor activity of PEG Intron at doses of 4.5–7.5 μg/kg per week, which were well tolerated. In the Phase Ib trial, six patients discontinued therapy due to adverse events (one patient at the 6 μg/kg dose and five patients at the 7.5 μg/kg dose). Chronic fatigue was the major dose-limiting toxicity with long-term treatment.
Pegylation of IFN-α-2b delays renal clearance and significantly increases exposure to drug with less frequent dosing. PK data from patients with chronic hepatitis C infection have demonstrated that 0.25 μg/kg per week PEG Intron results in similar exposure to IFN compared with subcutaneous administration of 9 MIU per week IFN-α-2b (3 MIU TIW) and that higher doses of PEG Intron administered to CML patients appear to increase exposure by as much as 80 times that observed after 9 MIU per week IFN-α-2b. This suggests that IFN-α dose intensification can be achieved safely in the treatment of patients with CML and solid tumors using PEG Intron and may potentially improve efficacy. Moreover, the greater convenience of the weekly subcutaneous dosing with PEG Intron may improve compliance. In patients with solid tumors, the good tolerability of PEG Intron could diminish the toxicity associated with long-term adjuvant IFN-α-2b therapy for high-risk patients with melanoma and could facilitate combination therapy with other agents in patients with advanced disease.
The initial trials with PEG Intron have confirmed that the agent possesses potent antitumor activity. Studies are currently ongoing to determine the optimal dose in various oncologic indications. The goal should not be to achieve equivalent exposure, but rather to capitalize on the greater tolerability of PEG Intron to achieve dose intensification and perhaps improve efficacy. The initial studies described here also provide a sound rationale for further investigation of PEG Intron in combination with other agents for treating patients with CML and solid tumors. The combination of PEG Intron and ara-C already has been investigated preliminarily in patients with CML and has been shown to be feasible, with no reduction in the PK or tolerability of PEG Intron. In addition, studies investigating the combination of PEG Intron and the tyrosine kinase inhibitor STI 571 are planned in CML patients. In patients with metastatic RCC, studies are ongoing to investigate the safety and efficacy of PEG Intron in combination with low-dose subcutaneous interleukin-2 or with thalidomide to enhance antiangiogenesis. These and other studies will help to define the future role of PEG Intron in the treatment of cancer.