Peginterferon α-2b is assuming a role in melanoma therapy based on the recent pivotal EORTC 18991 trial showing its efficacy in resected stage III melanoma [15
]. The dose used in the EORTC 18991 trial, 6 μg/(kg week) for 8 weeks followed by 3 μg/(kg week) for up to 5 years, is much higher than that used for hepatitis C [1.5 μg/(kg week)]. Prior to the current study being initiated, there were only limited data on systemic exposure to high-dose peginterferon α-2b, and no data were available for melanoma patients receiving adjuvant therapy.
We show that peginterferon α-2b was well-absorbed following SC administration. Some accumulation occurred following 8 weeks of treatment at 6 μg/(kg week). The AUCtau
for the 6 μg/(kg week) dose in this study was comparable with that observed in a small phase I/II trial [2
] in patients with advanced solid tumors, although the AUCtau
for 3 μg/(kg week) was lower in our study [2
]. As expected, the CL/F of peginterferon α-2b was greatly reduced compared with the clearance of native interferon α-2b (231 mL/h kg) [23
]. Therefore, peginterferon α-2b has an approximately 10-fold longer t1/2
as compared with native interferon α-2b (43–51 vs. 4 h, respectively). The CL/F and t1/2
in patients with melanoma were similar to those reported in patients with hepatitis C (22 mL/h kg and 27–39 h, respectively). The Cmax
observed here was 3,980–5,070 pg/mL at the 6 μg/(kg week) dose and 2,620 pg/mL at the 3 μg/(kg week) dose (measured at 24 h). In a hepatitis C study, Cmax
varied between 15 and 44 h postdose [23
]. Hence, the Cmax
in the current study could be potentially underestimated for some patients since we collected the first postdose PK sample at 24 h. The Cavg
observed in the current study for the 3 μg/(kg week) dose (1,400 pg/mL) was comparable to the mean serum concentration observed in the limited PK analysis of the 18991 study (1,434 pg/mL). There is a difference in mean trough estimate at the 3 μg/(kg week) dose level between the 18991 PK study (1,069 pg/mL) and the present study (626 pg/mL). This may be because the timing of sampling to assess trough levels in the 18991 PK study was not as rigorous as in our study, and the 18991 analysis may have included post-dose samples, potentially leading to an overestimation of mean trough concentration [16
]. In addition, PK sampling took place over a much longer time period for the 18991 PK analysis compared with the present study (up to 5 years vs. 12 weeks, respectively).
The comparison of pegylated and native interferon α-2b doses used in clinical trials is complicated by the differing measurement methods and units, schedules, and the specific activities. Data in patients with hepatitis C show that 0.25 μg/(kg week) peginterferon α-2b results in a similar anti-viral effect as 9 MIU/week (3 MIU three times weekly) native interferon α-2b. Extrapolating from this data, 6.0 μg/(kg week) may achieve exposure comparable with that of interferon α-2b at 20 MIU/m2
/day intravenous infusion five times weekly (180 MIU/week). The observed AUCtau
in patients with melanoma confirmed the extrapolation. We observed that SC dosing of 6 μg/(kg week) for 8 weeks followed by 3 μg/(kg week) was well tolerated with toxicity similar to that observed in the EORTC 18991 trial; based on our experience with high-dose native interferon α-2b in patients with melanoma, it appeared to us that our patients had lower incidence of fever and chills, but more skin rashes and hypertriglyceridemia. The data suggest that high-dose peginterferon α-2b has a better overall tolerability profile compared with high-dose native interferon α-2b. In phase I/II studies, peginterferon α-2b has also been shown to be well tolerated and clinically active in chronic myelogenous leukemia and renal cell cancer [13
We developed PK/PD models and performed simulations in order to visualize the effect of peginterferon α-2b exposure on ANC and ALT levels, as these are clinically relevant interferon toxicities. We modeled the relationship between peginterferon α-2b AUCtau
and the observed reduction in ANC using data from our study as well as data from a prior study in patients with advanced solid tumors [2
]. This analysis shows a steep dose response followed by a plateau around AUC 400,000 pg h/mL. The PK/PD model predicts that the ANC nadir is reached approximately 2 weeks after treatment initiation. The trough peginterferon α-2b concentration (Cmin
) closely mirrors the ANC nadir (Fig. a). A similar relationship between peginterferon α-2b dose and ANC changes after 4 weeks of dosing was reported in patients with hepatitis C [23
]. Future studies with more intensive PD and PK sampling will assist in confirming that the wave-like fluctuation in ANC levels shown in Fig. a occur in clinical practice, as predicted by the PK/PD model.
Since clinicians may be interested in peginterferon α-2b dose reductions for excessive neutropenia, we also simulated the effect of dose reduction on the ANC. If peginterferon α-2b dose is reduced from 6 μg/(kg week) to 0, the ANC trends upward rapidly. While stepwise dose reductions (3–2–1 μg/kg) were prescribed in the EORTC 18991 trial, the Imax model used here suggests that treatment should be interrupted and resumed at a much lower dose (50 or 33% of starting dose) upon resolution of neutropenia, if grade 3 or 4 neutropenia is observed. Clearly, future trials should examine this clinically relevant issue.
Progressive transaminase elevations (reversible upon discontinuation of the drug) are a major factor in the ability of patients with melanoma to tolerate the full prescribed dose of peginterferon α-2b; ALT elevation is an important PD surrogate of high-dose interferon effect on the liver [3
]. Although the number of patients with grade 3 ALT elevations in the current study is low (four patients; 13%), the frequency is consistent with the EORTC 18991 trial data (10% grade 3 liver function test AEs) [15
]. There were no grade 4 ALT elevations in our study. We explored this relationship using a fully integrated PK/PD model. Our model predictions for ALT did not appear to fit our observed data as well as for ANC, so further evaluation of this aspect of peginterferon administration is also clearly warranted.
In this study, the PK profile of high-dose peginterferon α-2b in patients with resected high-risk melanoma is described. The tolerability and safety of this dose and schedule appears to be broadly similar to that seen in previous studies. The PK/PD model of the effects of peginterferon α-2b exposure on ANC provides a useful framework. In contrast to high-dose interferon α-2b, hematologic and/or hepatic toxicity was less common and primarily grade 1 or 2 in severity with peginterferon α-2b 6 μg/(kg week) (induction) and 3 μg/(kg week) (maintenance). Based on the safety profile and PK data, combined with greater dosing convenience, peginterferon α-2b may potentially improve compliance and efficacy of adjuvant therapy for patients with high-risk melanoma.