Pharmacokinetic and Pharmacodynamic Perspectives on the Clinical Drug Development of Panitumumab

Abstract

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 6 mg/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 as the dose increases from 0.75 to 5 mg/kg; however, at doses above 2 mg/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 9 mg/kg given every 3 weeks) achieve steady-state serum trough concentrations similar to those achieved by 2.5 mg/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.

ABT-414, an Antibody–Drug Conjugate Targeting a Tumor-Selective EGFR Epitope

“…Further evidence of low normal tissue uptake of ABT-806 in patients is provided by its long halflife and dose-proportional pharmacokinetics. Other EGFR-targeting antibodies, including cetuximab and panitumumab, do not display dose-proportional pharmacokinetics and are characterized by significant target-mediated clearance (13)(14)(15)(16). ABT-806, therefore, represents an attractive candidate for use as an ADC to deliver a potent cytotoxic payload to tumor cells expressing wildtype or mutant EGFR with limited toxicity to normal tissues.…”

Panitumumab in the management of patients with KRAS wild-type metastatic colorectal cancer

“…Gain of function mutations in KRAS result in a constitutively active protein, regardless of EGFR activation, resulting in increased proliferation, tumor angiogenesis, metastasis, and inhibition of apoptosis, which support continued cancer cell survival [Peeters et al 2009a]. This provides the biological rationale for the finding that KRAS mutations predict for resistance to anti-EGFR antibody therapy [Yang et al 2010].…”

Pharmacogenetics and Pharmacogenomics of Colorectal Cancer: Moving Towards Personalized Medicine

“…Although similar strategies are now developed with other small molecules such as pazopanib (Suttle et al, 2010), no such trend is currently proposed with monoclonal antibodies, despite the fact that dose/exposure/efficacy and dose/exposure/toxicities relationships have been described (Lu et al, 2009, Keiser et al, 2010. Both non-clinical and clinical studies suggest that 90% of target inhibition should be continuously achieved to ensure a maximum efficacy, thus stressing the usefulness to monitor residual concentrations of monoclonal antibodies such as panitumumab, as for other target therapies (Yang et al, 2010). For instance, plasma residual concentrations of 10-30 ug/ml are considered necessary with bevacizumab for an optimal efficacy (Data on File Genentech Inc).…”