Pharmacokinetic/pharmacodynamic analysis of adjuvant pegylated interferon α-2b in patients with resected high-risk melanoma

Abstract

Purpose: High-dose pegylated interferon α-2b (peginterferon α-2b) significantly decreased disease recurrence in patients with resected stage III melanoma in a clinical study. We investigated the pharmacokinetics (PK) and safety of high-dose peginterferon α-2b in patients with high-risk melanoma.

Methods: For PK analysis, 32 patients received peginterferon α-2b 6 μg/(kg week) subcutaneously for 8 weeks (induction) then 3 μg/(kg week) for 4 weeks (maintenance). PK profiles were determined at weeks 1, 8, and 12. Exposure-response relationships between peginterferon α-2b and absolute neutrophil count (ANC) and alanine aminotransferase (ALT) level were also studied.

Results: Peginterferon α-2b was well-absorbed following SC administration, with a median T (max) of 24 h. Mean half-life estimates ranged from 43 to 51 h. The accumulation factor was 1.69 after induction therapy. PK parameters showed moderate interpatient variability. PK profiles were described by a one-compartmental model with first-order absorption and first-order elimination. Toxicity was profiled and was acceptable; observed side effects were similar to those previously described. Dose reduction produced proportional decreases in exposure and predictable effects on ANC in an Imax model; however, a PK/pharmacodynamic (PK/PD) relationship between peginterferon α-2b and ALT could not be established with high precision.

Conclusions: Peginterferon α-2b was well-absorbed and sustained exposure to peginterferon α-2b was achieved with the doses tested. These data confirm and extend previous PK observations of peginterferon α-2b in melanoma and solid tumors. Our PK/PD model of exposure and ANC effect provides useful information for prediction of peginterferon α-2b-related hematologic toxicity.

Fig. 1

Mean serum concentration–time profiles of peginterferon α-2b following once-weekly subcutaneous dosing in patients who completed 12 weeks of protocol-specified therapy without dose modification and who had complete pharmacokinetic samples for weeks 1, 8, and 12 (n = 20). Experimentally observed values (open circles) as well as the curve-fitted line using a one-compartment pharmacokinetic model are included

Fig. 2

Relationship between peginterferon α-2b area under the concentration–time curve during the dosing interval (AUC_tau) and absolute neutrophil count (ANC) changes as a percentage of baseline in patients with melanoma (n = 32) and solid tumors (n = 34) receiving various doses of peginterferon α-2b (3–12 patients in each dose group)

Fig. 3

Observed and predicted values of percentage changes from baseline in a median absolute neutrophil count (ANC) and b median alanine aminotransferase (ALT) levels. Simulation of percentage changes from baseline in median ANC/ALT with induction dose at 6 μg/(kg week) from weeks 1 to 8, and dose modification of peginterferon α-2b to 3, 2, 1, or 0 μg/(kg week) during weeks 9–12