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Chapter: Pharmaceutical Biotechnology: Fundamentals and Applications - Monoclonal Antibodies in Cancer

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Panitumumab - Classes of Monoclonal Antibodies: Endothelial Growth Factor Receptor (EGFR) Inhibitors

Pharmacology and Mechanism of Action, Pharmacokinetics/Pharmacodynamics, Indications and Clinical Efficacy, Safety Concerns, Pharmaceutical Considerations: Formulation, Other Routes of Administration, Dosing Regimens,

Panitumumab

 

Pharmacology and Mechanism of Action

Panitumumab (Vectibix ) is the first fully human MAb inhibitor of EGFR in clinical use today. It is an IgG2 kappa MAb that inhibits EGFR by binding to the extracelluar ligand-binding domain of the receptor (Cohenuram and Saif, 2007). As reviewed earlier, inhibition of EGFR is thought to inhibit neoplastic proliferation, metastatic spread, and produce apopto-sis. Although panitumumab shares the same mechan-ism of action as cetuximab, the two monoclonal entities have two main differences. First, panitumu-mab is fully humanized, which theoretically should reduce the risk of immunogenicity. Second, in vitro studies have shown that panitumumab has a stronger affinity and specificity for EGFR compared to cetux-imab (Cohenuram and Saif, 2007).

 

Similar to other EGFR inhibitors, in preclinical mouse models, low-dose panitumumab monotherapy was found to eliminate large tumors (i.e., 1.2 cm3) in one study and completely eradicate up to 65% of inoculated mouse tumors in another study (Yang and Jia, 1999; Cohenuram and Saif, 2007). What many find noteworthy is that up to 9 months after treatment cessation, no tumor regrowth occurred (Yang and Jia, 1999). While elimination of tumors has been shown previously with these agents, the potential for complete eradication for monotherapy panitumumab in these preclinical studies is novel.

 

 

Pharmacokinetics/Pharmacodynamics

 

Preclinical pharmacokinetic studies in Cynomolgus monkeys showed a rapid clearance at nonsaturating doses while a phase I pharmacokinetic study demon-strated low interindividual variability and both liner and saturable EGFR-mediated clearance (Roskos et al., 2002; Cohenuram and Saif, 2007). Phase II clinical trials to date have not shown any drug interactions with any chemotherapeutic agents, in-cluding irinotecan, LV, fluoruracil, paclitaxel, and carboplatin.

 

In terms of pharmacodynamics, one preclinical study demonstrated that the tumor growth inhibition of panitumumab was related to a threshold EGFR level, where xenografts that contained at least 17,000receptors per cell were treatable with panitumumab, while those with less than 11,000 were not treatable (Yang et al., 2001). Similar to other EGFR inhibitors in clinical trials, increasing dose corresponded to an increasing frequency of an acneiform rash. Specifically in the phase I study performed by Rowinsky et al. (2004), patients that received 1, 1.5, 2, and 2.5 mg/kg weekly of panitumumab had 68, 95, 87, and 100% incidence of rash with its apex at 3 to 5 weeks after starting therapy. A post hoc analysis revealed that rash intensity trended toward a relationship with progres-sion free survival in patients.

 

 

Indications and Clinical Efficacy

 

Panitumumab was recently approved by the FDA (September 2006) for the treatment of EGFR expres-sing, metastatic CRC with disease progression on or following fluoropyridine, oxaliplatin, and irinotecan containing chemotherapy regimens (Amgen, 2006). In addition, studies have demonstrated efficacy toward other cancer types such as renal carcinoma and NSCLC.

 

Approval of panitumumab was based solely on the results of a clinical study containing 463 patients randomized to receive best supportive care alone (BSC) or BSC plus panitumumab (6 mg/kg intrave-nously) every 2 weeks (Berlin et al., 2004). All patients met the above mentioned FDA approved indication. The mean progression-free survival was 96 days for the panitumumab group and 60 days for the BSC alone group. Eight percent of patients in the treatment arm exhibited a PR and no observable response was observed in the control arm. There was no difference in overall survival between the two groups, although this may have been confounded by a significant proportion of patients from the BSC group that later crossed over to receive panitumumab.

 

Another study conducted using panitumumab as first-line therapy in combination with irinotecan, 5-fluorouracil, and leucovorin (IFL) showed a 47% response rate with disease stabilization in 32% of patients (Berlin et al., 2004). All individuals who responded developed a skin rash suggesting that the degree of skin toxicity is relative to tumor response to panitumumab therapy. In addition, studies analyzing the utility of panitumumab as monotherapy have shown an 11% response rate in chemorefractory CRC and a 33% disease stabilization (Saif and Cohenuram, 2006).

 

Results are eagerly awaited for the Panitumumab Advanced Colorectal Cancer Evaluation Study (PACCE) that is evaluating first-line therapy in metastastic CRC (Cohenuram and Saif, 2007). The first 800 patients enrolled will receive FOLFOX and bevacizumab with or without panitumumab while the next 200 patients will receive FOLFIRI and bevacizumab with or without panitumumab. The primary endpoint is progression free survival in the FOLFOX arm.

 

Safety Concerns

 

Panitumumab has a black box warning for severe dermatologic toxicities and infusion reactions (Amgen, 2006). Severe skin toxicities (grade 3 or higher) were reported in 12% of patients to include dermatosis acneiform, pruritus, erythema, rash, and skin exfoliation. Severe infusion reactions (occuring in 1% of patients) were also observed and include anaphylactic reactions, bronchospasms, fever, chills, and hypotension. However, the infusion reactions are infrequent (as compared to cetuximab) and no premedication is required (Saif and Cohenuram, 2006). Pulmonary fibrosis has also occurred with panitumumab therapy. The more common adverse reactions include abdominal pain, hypomagnesemia, acneiform eruption (occurring in greater than 70% of patients) and other skin rashes, paronychia, fatigue, nausea, vomiting, and diarrhea (Amgen, 2006).

 

 

Pharmaceutical Considerations: Formulation, Other Routes of Administration, Dosing Regimens

 

Panitumumab does not require a loading dose, unlike cetuximab, or premedications to prevent immuno-genic reactions (Cohenuram and Saif, 2007). Pharmacokinetic studies determined that 2.5 mg/kg is the optimal weekly dose although additional studies suggest that 6 mg/kg every 2 weeks and 9 mg/kg every 3 weeks produce similar trough levels, making alternate dosing regimens a possibility (Rowinsky et al., 2004; Arends and Yang, 2005; Cohenuram and Saif, 2007). The FDA approved regimen is 6 mg/kg every 2 weeks administered IV over 1 hr (Amgen 2006). The drug must be filtered using a 0.22 mm in-line filter or 0.2 mm low protein-binding filter. No other medications should be added to panitumumab.

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