Population pharmacokinetics of infliximab in patients with ankylosing spondylitis.
The population pharmacokinetics of infliximab were characterized in patients with active ankylosing spondylitis (n = 274). Serum infliximab concentration data, from a 2-year period, were analyzed using NONMEM. A 2-compartment linear pharmacokinetic model was chosen to describe the pharmacokinetic characteristics of infliximab in serum. Population estimates (typical value +/- standard error) were obtained from the final covariate model: clearance (CL: 0.273 +/- 0.007 L/day), volume of distribution in the central compartment (V(1): 3.06 +/- 0.057 L), intercompartment clearance (Q: 1.72 +/- 0.48 L/day), and volume of distribution in the peripheral compartment (V(2): 2.94 +/- 0.17 L). Interindividual variability for CL and V(1) was 34.1% and 17.5%, respectively. White blood cell count at baseline and the antibody-to-infliximab status were significant covariates to CL; body surface area and sex were significant covariates to V(1). The CL for patients with a positive antibody-to-infliximab status was estimated to be 41.9% to 76.7% higher than for the remaining patients. Other covariates (baseline disease activity and the concomitant medication use of prednisolone, omeprazole, nonsteroidal anti-inflammatory drugs, or analgesics) did not affect infliximab pharmacokinetics. The development of antibodies to infliximab was associated with accelerated infliximab clearance and may represent a potential underlying mechanism for an inadequate response, or loss of response, to infliximab treatment.
Xu
Zhenhua
Z
Pharmacokinetics, Modeling & Simulation, Clinical Pharmacology Sciences, Centocor Research and Development, Inc., 200 Great Valley Parkway, Malvern, PA 19355, USA.
Seitz
Kathleen
K
Fasanmade
Adedigbo
A
Ford
Joyce
J
Williamson
Paul
P
Xu
Weichun
W
Davis
Hugh M
HM
Zhou
Honghui
H
D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D000917:Antibody Formation; D018501:Antirheumatic Agents / Q000493:pharmacokinetics*; D001830:Body Surface Area; D004347:Drug Interactions; D005260:Female; D006801:Humans; D000069285:Infliximab; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D012737:Sex Factors; D013167:Spondylitis, Ankylosing / Q000188:drug therapy*; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D000069285:Infliximab