P493. Factors affecting adalimumab pharmacokinetics in adult patients with moderate to severe CD
P. Noertersheuser1, D. Eckert1, S. Sharma2, R. Thakkar2, A. Robinson2, W. Sandborn3, S. Hanauer4, J.-F. Colombel5, W. Awni2, 1Abbott Laboratories, Germany, 2Abbott Laboratories, United States, 3University of California, San Diego, United States, 4University of Chicago, United States, 5Centre Hospitalier Universitaire de Lille, Hôpital Claude Huriez, Lille, France
The pharmacokinetics (PK) of adalimumab in adult patients (pts) with Crohn's disease (CD) was evaluated in two studies. CLASSIC I was a 4-week (wk) study of induction of remission in CD pts and CLASSIC II was a 52 wk extension study of CLASSIC I. The serum adalimumab concentrations (conc; Mean±SD) at wk 4 following administration of adalimumab 160/80 mg, 80/40 mg and 40/20 mg at wk 0/2 were 12.6±5.25 µg/mL, 5.65±3.06 µg/mL and 2.79±1.48 µg/mL, respectively. The serum adalimumab conc (Mean±SD) at wk 56 following administration of adalimumab 40 mg eow (double blind, DB), 40 mg weekly (DB) and 40 mg eow, open label (OL) were 10.9±6.57 µg/mL, 15.0±8.72 µg/mL and 7.22±4.58 µg/mL, respectively. The purpose of the present analysis was to identify covariates that influence adalimumab PK.
Serum adalimumab conc data were obtained from CD pts (N = 270) enrolled in CLASSIC I and CLASSIC II studies. Serum adalimumab trough conc were measured at multiple time points. A non-linear mixed effects modeling (NONMEM®) approach was used. The covariates that were evaluated included pt demographics, laboratory measurements, concomitant medications and disease related factors.
Only body weight and plasma albumin were identified as statistically significant covariates; but, they explained only 3.2% and 2.2% of the total variability in adalimumab PK, respectively. Furthermore, a combination of multiple covariates of interest (body weight, albumin, age, sex, C-reactive protein, baseline CDAI and concomitant immunosuppressants (IMM; azathioprine, 6-mercaptopurine and methotrexate) explained <12% of the total variability in adalimumab PK. Adalimumab clearance in males (18.6±7.83 mL/h) was comparable to that in females (19.4±10.2 mL/h). Similarly, adalimumab clearance for pts on concomitant IMM (18.1±8.40 mL/h) was comparable to those without IMM (19.4±9.52 mL/h).
Body weight and plasma albumin were identified as statistically significant baseline covariates for the variability in adalimumab PK, but each explained <5% of the total variability. The PK of adalimumab were variable between pts and even a combination of identifiable baseline covariates explained <12% of the total variability in adalimumab PK and thus were unable to account for the majority in the PK variability.