Pharmacokinetics and pharmacodynamics of a human anti‐TNF‐alpha monoclonal antibody in patients with rheumatoid arthritis

Purpose To evaluate the PK of a human anti‐TNFα monoclonal antibody (mAb), and the PK‐PD relationship between serum concentration and CRP in patients with rheumatoid arthritis (RA) following single ascending IV infusions. Methods: A randomized, double‐blind, placebo‐controlled study in which subjects with active RA received a single IV infusion (placebo or 0.1, 0.3, 1, 3, 6, or 10 mg/kg). Serum mAb concentrations were determined using a validated ELISA method. PK modeling and simulations were employed using WinNonlin and Trial Simulator software. Results : The median t1/2 ranged from 7 to 19 days. The mean Cmax and the AUC increased in a dose proportional manner. The mean CL, Vd and MRT after IV administration of mAb ranged from 5 to 7 mL/day/kg, 58 to 126 mL/kg and 10 to 24 days, respectively. The majority of subjects receiving this human anti‐TNF α mAb demonstrated a greater reduction in serum CRP level by day 7 compared to those receiving placebo and maximum responses generally occurred between weeks 2 and 8. The higher dose cohorts demonstrated responses of greater magnitude and duration than the lower dose cohorts. Conclusions: The human anti‐TNFα monoclonal antibody had long serum half‐life after a single IV infusion. Drug exposure (Cmax and AUC) appeared to increase in a dose proportional manner over the 0.1–10 mg/kg range. This human anti‐TNFα mAb resulted in a marked reduction in CRP concentration at 2 weeks in a dose and Cmax dependent manner. Clinical Pharmacology & Therapeutics (2004) 75 , P53–P53; doi: 10.1016/j.clpt.2003.11.200