Pharmacokinetic and Pharmacodynamic Perspectives on the Clinical Drug Development of Panitumumab

摘要: Panitumumab is a recombinant, fully human IgG2 monoclonal antibody directed against the epidermal growth factor receptor (EGFR). It indicated for use as monotherapy in treatment of patients with EGFR-expressing metastatic colorectal cancer after disease progression standard chemotherapy. The currently dose 6mg/kg given every 2 weeks. mainly distributed into vascular space and exhibits nonlinear pharmacokinetics that are consistent target-mediated drug disposition, involving saturable binding to EGFR subsequent internalization degradation inside cells. also cleared linear fashion by reticuloendothelial system, similarly other endogenous immunoglobulins. After single-dose administration panitumumab 1-hour intravenous infusion, area under serum concentration-time curve increases greater-than-dose-proportional manner asthe from 0.75 5mg/kg; however, at doses above 2mg/kg, exposure dose-proportional manner. not meaningfully affected tumour type, membrane expression, KRAS mutation, sex, age, race or renal hepatic dysfunction. In addition, irinotecan-containing paclitaxel/carboplatin-containing chemotherapeutic regimens do appear affect pharmacokinetics. results population pharmacokinetic analyses have shown bodyweight most influential covariate on exposure, supporting current bodyweight-adjusted (mg/kg). relationship between weekly skin rash, an on-target pharmacodynamic effect inhibition, reaches plateau 2.5 mg/kg, indicating this optimal dose. Two less-frequent dosing (6 mg/kg weeks 9mg/kg 3 weeks) achieve steady-state trough concentrations similar those achievedby 2.5mg/kg week, ensuring maximal coverage. Anti-panitumumab production uncommon does impact panitumumab.