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Pharmacokinetics and pharmacodynamics of a human anti‐TNF‐alpha monoclonal antibody in patients with rheumatoid arthritis
Author(s) -
Jang H.,
Marini J. C.,
Pendley C.,
Jiao Q.,
Marciniak S. J.,
Cohen S.,
Fleischmann R.,
Everitt D. E.,
Davis H. M.,
Graham M. A.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2003.11.200
Subject(s) - cmax , pharmacokinetics , rheumatoid arthritis , medicine , placebo , pharmacodynamics , monoclonal antibody , pharmacology , arthritis , gastroenterology , antibody , immunology , pathology , alternative medicine
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