Pharmacokinetic and Pharmacodynamic Perspectives on the Clinical Drug Development of Panitumumab
- Bing-Bing YangAffiliated withAmgen Inc. Email author
- , Peggy LumAffiliated withAmgen Inc.
- , Alin ChenAffiliated withAmgen Inc.
- , Rosalin ArendsAffiliated withAmgen Inc.
- , Lorin RoskosAffiliated withAmgen Inc.
- , Brian SmithAffiliated withAmgen Inc.
- , Juan José Pérez RuixoAffiliated withAmgen Inc.
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Panitumumab is a recombinant, fully human IgG2 monoclonal antibody directed against the epidermal growth factor receptor (EGFR). It is indicated for use as monotherapy in the treatment of patients with EGFR-expressing metastatic colorectal cancer after disease progression with standard chemotherapy. The currently indicated dose is 6mg/kg given every 2 weeks.
Panitumumab is mainly distributed into the vascular space and exhibits nonlinear pharmacokinetics that are consistent with target-mediated drug disposition, involving saturable binding to EGFR and subsequent internalization and degradation inside the cells. Panitumumab is also cleared in a linear fashion by the reticuloendothelial system, similarly to other endogenous immunoglobulins. After single-dose administration of panitumumab as a 1-hour intravenous infusion, the area under the serum concentration-time curve increases in a greater-than-dose-proportional manner asthe dose increases from 0.75 to 5mg/kg; however, at doses above 2mg/kg, the exposure to panitumumab increases in a dose-proportional manner. Panitumumab pharmacokinetics are not meaningfully affected by the tumour type, EGFR membrane expression, tumour KRAS mutation, sex, age, race or renal or hepatic dysfunction. In addition, irinotecan-containing and paclitaxel/carboplatin-containing chemotherapeutic regimens do not appear to affect panitumumab pharmacokinetics. The results of population pharmacokinetic analyses have shown that bodyweight is the most influential covariate on panitumumab exposure, supporting the current use of bodyweight-adjusted doses (mg/kg). The relationship between the weekly dose of panitumumab and skin rash, an on-target pharmacodynamic effect of EGFR inhibition, reaches a plateau at 2.5 mg/kg, indicating that this is the optimal weekly dose. Two less-frequent dosing regimens (6 mg/kg given every 2 weeks and 9mg/kg given every 3 weeks) achieve steady-state serum trough concentrations similar to those achievedby 2.5mg/kg given every week, ensuring maximal EGFR coverage. Anti-panitumumab antibody production is uncommon and does not appear to have an impact on the pharmacokinetics of panitumumab.
- Pharmacokinetic and Pharmacodynamic Perspectives on the Clinical Drug Development of Panitumumab
Volume 49, Issue 11 , pp 729-740
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