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

High-dose pegylated interferon alpha-2b (peginterferon alpha-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 alpha-2b in patients with high-risk melanoma. For PK analysis, 32 patients received peginterferon alpha-2b 6 mu g/(kg week) subcutaneously for 8 weeks (induction) then 3 mu g/(kg week) for 4 weeks (maintenance). PK profiles were determined at weeks 1, 8, and 12. Exposure-response relationships between peginterferon alpha-2b and absolute neutrophil count (ANC) and alanine aminotransferase (ALT) level were also studied. Peginterferon alpha-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 alpha-2b and ALT could not be established with high precision. Peginterferon alpha-2b was well-absorbed and sustained exposure to peginterferon alpha-2b was achieved with the doses tested. These data confirm and extend previous PK observations of peginterferon alpha-2b in melanoma and solid tumors. Our PK/PD model of exposure and ANC effect provides useful information for prediction of peginterferon alpha-2b-related hematologic toxicity.