lf-life (t1/2) of the Fab'. The terminal elimination phase half-life (t1/2) was approximately 14 days for all doses tested. The clearance following IV administration to healthy subjects ranged from 9.21 mL/h to 14.38 mL/h. The clearance following sc dosing was estimated 17 mL/h in the Crohn's disease population PK analysis with an inter-subject variability of 38% (CV) and an inter-occasion variability of 16%. Similarly, the clearance following sc dosing was estimated as 21.0 mL/h in the RA population PK analysis, with an inter-subject variability of 30.8% (%CV) and inter-occasion variability 22.0%. The route of elimination of certolizumab pegol has not been studied in human subjects. Studies in animals indicate that the major route of elimination of the PEG component is via urinary excretion.
Special Populations
Population pharmacokinetic analysis was conducted on data from patients with rheumatoid arthritis and patients with Crohn's disease, to eva luate the effect of age, race, gender, methotrexate use, concomitant medication, creatinine clearance and presence of anti-certolizumab antibodies on pharmacokinetics of certolizumab pegol.
Only bodyweight and presence of anti-certolizumab antibodies significantly affected certolizumab pegol pharmacokinetics. Pharmacokinetic exposure was inversely related to body weight but pharmacodynamic exposure-response analysis showed that no additional therapeutic benefit would be expected from a weight-adjusted dose regimen. The presence of anti-certolizumab antibodies was associated with a 3.6-fold increase in clearance.
Age: Pharmacokinetics of certolizumab pegol was not different in elderly compared to young adults.
Gender: Pharmacokinetics of certolizumab pegol was similar in male and female subjects.
Renal Impairment: Specific clinical studies have not been performed to assess the effect of renal impairment on the pharmacokinetics of CIMZIA. The pharmacokinetics of the PEG (polyethylene glycol) fraction of certolizumab pegol is expected to be dependent on renal function but has not been assessed in renal impairment. There are insufficient data to provide a dosing recommendation in moderate and severe renal impairment.
Race: A specific clinical study showed no difference in pharmacokinetics between Caucasian and Japanese subjects.
Drug Interaction Studies
Methotrexate pharmacokinetics is not altered by concomitant administration with CIMZIA in patients with rheumatoid arthritis. The effect of methotrexate on CIMZIA pharmacokinetics was not studied. However, methotrexate-treated patients have lower incidence of antibodies to CIMZIA. Thus, therapeutic plasma levels are more likely to be sustained when CIMZIA is administered with methotrexate in patients with rheumatoid arthritis.
Formal drug-drug interaction studies have not been conducted with CIMZIA upon concomitant administration with corticosteroids, nonsteroidal anti-inflammatory drugs, analgesics or immunosupressants.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
Long-term animal studies of CIMZIA have not been conducted to assess its carcinogenic potential. Certolizumab pegol was not genotoxic in the Ames test, the human peripheral blood lymphocytes chromosomal aberration assay, or the mouse bone marrow micronucleus assay.
Since certolizumab pegol does not cross-react with mouse or rat TNFα, reproduction |
