Efalizumab dosing

J.G. Krueger, C. Leonardi, B. Miller, and A. Joshi. 2005. Pharmacokinetics and pharmacodynamics of multiple weekly subcutaneous efalizumab doses in patients with plaque psoriasis./. Clin. Pharmacol. 45 286—298. 

Due to their high molecular mass (and other reasons), the vast majority of mAbs that have been approved or are currently in clinical development are administered by intravenous (IV) infusion. This route allows the total dose to be available in the circulation, as F (the systemically available fraction of the dose) is, by definition, 1. In consequence, maximum concentrations in serum are rapidly observed, and are higher compared to those achieved by other routes. Therefore, adverse reactions after IV administration occur more often but are generally reversible. In addition, IV infusions represent the most inconvenient (they often require hospitalization) as well as time- and cost-consuming means of administration. Consequently, ex-travascular routes have been chosen as alternatives, including subcutaneous administration (SC e. g., adalimumab, efalizumab) and intramuscular administration (IM e.g., palivizumab) (Table 3.4). 

The population PK/PD of efalizumab were recently evaluated in patients with moderate to severe plaque psoriasis following SC administration of 1.0 and 2.0 mg/kg for 12 weeks [81-83]. Steady-state serum concentrations were achieved by four to eight weeks following administration of 1 and 2 mg/kg doses, respectively. At both doses, CDlla expression on T lymphocytes was reported to be maximally down-modulated. In addition, at doses of 1 and 2 mg/kg, >95 % of CDlla binding-sites were reported to be saturated at steady-state serum trough concentrations of 9 and 24 pg/mL, respectively. The improvement in PAS I scores was observed quickly, and efalizumab administration was reported to result in 60-70% improvement in PASI scores when compared to baseline after 12 weeks of treatment. The current recommended dose for efalizumab is a single 0.7 mg SC conditioning dose which is followed by weekly SC doses of 1 mg/kg. 

Sun,Y.N., J.F. Lu, A. Joshi, P. Compton, P. Kwon, and R.A. Bruno. 2005. Population pharmacokinetics of efalizumab (humanized monoclonal anti-CDll a antibody) following long-term subcutaneous weekly dosing in psoriasis subjects./. Clin. Pharmacol. 45 468—476. 

Wu B, Joshi A, Ren S, Ng C.The application of mechanism-based PK/PD modeling in pharmacodynamic-based dose selection of muM17 a surrogate monoclonal antibody for Efalizumab. / Pharmaceut Sci 2006 95 1258-68. 

Clinical studies with efalizumab have shown efficacy with few adverse effects. In an open-label, multicenter, dose-escalating study of repeated intravenous infusions of efalizumab over 7 weeks in 39 subjects with moderate to severe psoriasis, the individuals who were exposed to the optimum dose (1 mg/kg weekly) showed a mean decrease in PASI of 47%. A subcutaneous formulation is under investigation. 

Gottlieb AB, Krueger JG, Wittkowski K, et al. Psoriasis as a model for T-cell-mediated disease immunobiologic and clinical effects of treatment with multiple doses of efalizumab, an anti-CD 1 la antibody. Arch Dermatol 2002 138 591-600. 

Autacoids Recurrent angioedema has been reported in a 63-year-old man with severe plaque psoriasis after efalizumab treatment for 15 weeks [233 ]. There was swelling of the periorbital area, cheek, tongue, and Ups, and after the next dose he developed the same sjmiptoms as weU as acute abdominal pain. Efalizumab was withdrawn and the sweUing and abdominal pain resolved within 3 weeks. 

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