Dosage

Clinical trials of antibodies against endotoxin and tumor necrosis factor-a have generally employed one or two intravenous doses only: HA-1A, single 100-mg infusion; E5, two 2-mg/kg doses 24 h apart; anti-tumor necrosis factor antibodies, single 3- to 15-mg/kg infusion. However, human pharmacokinetic data are limited, and numerous antibody- and host-related factors must be considered when determining the optimum dosing regimen, including preclinical dose-response studies, phase I and II clinical studies, monoclonal antibody class (IgG versus IgM), circulating half-life, immunogenicity, and the effects of critical illness.

The production of neutralizing human anti-mouse antibodies is reduced with more human antibodies and repeated administration is more likely to be associated with immune complex clearance and decreased clinical efficacy. Murine antibodies are eliminated at the greatest rate. For example, the CDR-grafted anti-tumor necrosis factor-a antibody CDP571(Celltech Inc.) has an elimination half-life of 40 to 90 h, which is two to three times longer than its murine counterpart CB0010 (Celltech Inc.).

Critical illness may also alter the serum half-life. Initial phase I pharmacokinetic studies of HA-1A in stable cancer patients demonstrated a half-life of 29.1 ± 11.3 h. In patients with septic shock, multiple factors such as increased catabolism and reticuloendothelial function decrease the half-life to 15.9 ± 8.8 h.

Sleep Apnea

Sleep Apnea

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