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P557 Utility of “trough levels” adalimumab determination in patients with inflammatory bowel disease. Estimation of individual pharmacokinetic parameters through population pharmacokinetic model

Juan G.*1, Alvariño A.2, Mora M.3, Oltra L.3, Maroto N.3, Ferrer I.3, Hinojosa E.3, Hinojosa M.D.3, Hinojosa J.3

1Hospital de Manises, Department of Pharmacy, Manises, Spain 2Hospital de Manises, Department of Labratory, Manises, Spain 3Hospital de Manises, IBD Unit, Manises, Spain

Background

Adalimumab (ADM) is effective in inducing and maintaining remission in patients with Inflammatory Bowel Disease (IBD). However, 10% are primary non-responders and even 15% patients/year lose the response in the follow-up, mainly in relation with inmmunogenicity and their effect on the trough levels of infliximab (TLI). The importance of the plasma clearance of the drug has been pointed out in the individualization of treatment.

Aim: Analyzing trough levels of Adalimumab in a cohort of patients with IBD. Estimating individual pharmacokinetic (PK) parameters through population pharmacokinetic model and bayesian adjustment.

Methods

Prospective, descriptive study of 30 patients with IBD and with ADM therapy (2014–15). Two cohorts were included: A) monitoring during induction phase (week 4); B) monitoring during maintenance phase (in clinic remission at least 12 weeks). Blood samples for TLI analyses were obtained prior to ADM administration. Samples were analyzed by ELISA (Promonitor). Individual PK parameters were estimated using NONMEN VI program and different dosing regimens were simulated.

Results

30 patients (25 CD/ 5 UC);16M/14W; average age 42 years (12–70). 18 patients with Azathioprine. Group A: 12 patients (31 samples); TLI (median) 12.0 μg/ml (RIQ 11.99 μg/ml); >12.2 μg/ml, 80%. Only one patient with undetectable TLI and antibody anti-ADM (+). Group B: 19 patients (31 samples); TLI (mean): 8.5 μg/ml (95% CI: 7.15–9.86). Levels distribution: <4 μg/ml, 16%; 4–8 μg/ml, 29%; 8–12 μg/ml, 19%; >12.2 μg/ml); 36% (high level detected).

The overall pharmacokinetic parameters of Adalimumab are expressed in Table 1. The external validation of the pharmacokinetic model (IMAGE01) has an accuracy of 0.60 mcg/ml (95% CI: −1.8–2.6) and an accuracy of 1.52 mcg/Ml (0.07–2.52). IMAGE02 shows a case of individual predictive model with Bayesian adjustment.

Figure 1. External validation of the population pharmacokinetic model of adalimumab.

Figure 2. Individual predictive model with Bayesian adjustment.

Table 1. Pharmacokinetics parameters of adalimumab

Pharmacokinetics parameters (N=30)Mean (95% CI)
Plasma clearance (L/day)0.26 (0.21–0.31)
Biological half life (t1/2) (day)26.8 (21.4–32.2)
Central distribution volumen (L)8.81 (7.2–10.4)
AUC (mg·d/L)113.3 (100.7–125.8)

Conclusion

Determining TL-ADM along with the estimation of individual PK parameters allows to optimize the treatment in patients with IBD.

References:

[1] Br J Clin Pharmacol, (2014), 79:2;286–97