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* = Presenting author

P411. Pharmacokinetics of adalimumab in pediatric patients with moderate to severe Crohn's disease

D. Eckert1, S. Mensing1, S. Sharma2, R. Thakkar2, A. Robinson2, J. Hyams3, J. Rosh4, F.M. Ruemmele5, W. Awni2, 1Abbott Laboratories, Germany, 2Abbott Laboratories, United States, 3Connecticut Children's Med Ctr, United States, 4NJ Medical School, United States, 5Hôpital Necker-Enfants Malades, France

Background

To characterize the pharmacokinetics (PK) of adalimumab in pediatric patients (pts) with moderate to severe Crohn's disease (CD).

Methods

Trough serum adalimumab and anti-drug antibody (AAA) concentrations (conc) were measured in a 52-week (wk) study (N = 189), which had a 4-wk open-label induction phase (dose was determined by pt weight) followed by a 48-wk double-blind maintenance phase (high and low-dose arms). Pts with inadequate response could increase from eow to ew dosing. A non-linear mixed effects modeling (NONMEM®) approach was used.

Results

At wk 4, the mean±SD adalimumab conc (µg/mL) for pts ≥40 kg, 15.7±6.55 (160/80 mg), was higher (p < 0.001) than for pts <40 kg, 10.6±6.06 (80/40 mg). For the maintenance phase, the mean±SD adalimumab conc (µg/mL) are listed in the table.

Pts receiving ew dosing had higher adalimumab conc at wk 52 (HD: 15.3±11.4, p = 0.065; LD: 6.65±3.49, p = 0.002) compared to those on eow. Anti-TNF naïve pts had slightly higher adalimumab conc than those with prior anti-TNF exposure. Among pts with prior anti-TNF exposure, those with immunogenicity to prior anti-TNF had slightly lower adalimumab levels than those without. Six pts (6/182, 3.3%) were AAA positive during the study; and adalimumab conc were lower in those pts. Pts on concomitant immunosuppressants (azathioprine, 6-mercaptopurine & methotrexate; IMM) had slightly lower (∼18%) adalimumab clearance (12.4±5.74 mL/h) compared to pts without IMM (15.2±7.88 mL/h). Only body weight was identified as a statistically significant covariate; but, it explained only 2.6% of total PK variability. A combination of multiple covariates of interest (body weight, albumin, age, sex, CRP, and concomitant IMM) was able to explain <13% of total PK variability.

Table: Mean±SD adalimumab concentrations in the maintenance phase
 DoseAdalimumab concentration (µg/mL)
 Wk 16*Wk 26*Wk 52*
40/20 mg eow, High-Dose (HD)10.3±4.8010.4±4.269.48±5.61
20/10 mg eow, Low-Dose (LD)3.98±2.383.63±2.503.51±2.21
*Adalimumab conc for HD were higher (p < 0.001) than LD.

Conclusion

Adalimumab trough conc were maintained in pts receiving eow regimen for 52 wks. Dose escalation was associated with an increase in adalimumab conc compared to eow dosing. Pts with prior anti-TNF exposure (especially those with immunogenicity to prior anti-TNF) tended to have lower adalimumab conc compared to anti-TNF naïve pts. Body weight was the only statistically significant baseline covariate affecting adalimumab clearance, but it accounted for <3% of PK variability.