ing the administration of 5 mg/kg infliximab.
Population pharmacokinetic analysis showed that in children with juvenile rheumatoidarthritis (JRA) with a body weight of up to 35 kg receiving 6 mg/kg infliximab and childrenwith JRA with body weight greater than 35 kg up to adult body weight receiving 3 mg/kginfliximab, the steady state area under the concentration curve (AUCss) was similar to thatobserved in adults receiving 3 mg/kg of infliximab.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
The significance of the results of nonclinical studies for human risk is unknown. A repeatdose toxicity study was conducted with mice given cV1q anti-mouse TNFα to eva luatetumorigenicity. CV1q is an analogous antibody that inhibits the function of TNFα in mice.
Animals were assigned to 1 of 3 dose groups: control, 10 mg/kg or 40 mg/kg cV1q givenweekly for 6 months. The weekly doses of 10 mg/kg and 40 mg/kg are 2 and 8 times,
respectively, the human dose of 5 mg/kg for Crohn’s disease. Results indicated that cV1q didnot cause tumorigenicity in mice. No clastogenic or mutagenic effects of infliximab wereobserved in the in vivo mouse micronucleus test or the Salmonella-Escherichia coli (Ames)assay, respectively. Chromosomal aberrations were not observed in an assay performed usinghuman lymphocytes. It is not known whether infliximab products can impair fertility inhumans. No impairment of fertility was observed in a fertility and general reproductiontoxicity study with the analogous mouse antibody used in the 6-month chronic toxicity study.
of macrophages in the synovium. In plaque psoriasis, treatment with infliximab products mayreduce the epidermal thickness and infiltration of inflammatory cells. The relationshipbetween these pharmacodynamic activities and the mechanism(s) by which infliximabproducts exert their clinical effects is unknown.
12.3 Pharmacokinetics
In adults, single intravenous (IV) infusions of 3 mg/kg to 20 mg/kg of infliximab showed alinear relationship between the dose administered and the maximum serum concentration.
14 CLINICAL STUDIES
14.1 Crohn’s Disease
Active Crohn’s Disease
The safety and efficacy of single and multiple doses of infliximab were assessed in 2randomized, double-blind, placebo-controlled clinical studies in 653 patients with moderateto severely active Crohn’s disease [Crohn’s Disease Activity Index (CDAI) ≥ 220 and ≤ 400]with an inadequate response to prior conventional therapies. Concomitant stable doses ofaminosalicylates, corticosteroids and/or immunomodulatory agents were permitted and 92%of patients continued to receive at least one of these medications.
In the single-dose trial of 108 patients, 16% (4/25) of placebo patients achieved a clinicalresponse (decrease in CDAI ≥ 70 points) at Week 4 vs. 81% (22/27) of patients receiving 5mg/kg infliximab (p < 0.001, two-sided, Fisher’s Exact test). Additionally, 4% (1/25) ofplacebo patients and 48% (13/27) of patients receiving 5 mg/kg infliximab achieved clinicalremission (CDAI < 150) at Week 4.
In a multidose trial (ACCENT I [Study Crohn’s I]), 545 patients received 5 mg/kg at Week 0and were then randomized to one of three treatment groups; the placebo maintenance groupreceived placebo at Weeks 2 and 6, and then every 8 weeks; the 5 mg/kg maintenance groupreceived 5 mg/kg at Weeks 2 and 6, and then every 8 weeks; and the 10 mg/kg |
