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

  • Author(s): Daud, AI;
  • Xu, C;
  • Hwu, W-J;
  • Urbas, P;
  • Andrews, S;
  • Papadopoulos, NE;
  • Floren, LC;
  • Yver, A;
  • Deconti, RC;
  • Sondak, VK
  • et al.
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.

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