EP-015 - EXPLAINING INTERPATIENT VARIABILITY OF ADALIMUMAB RESPONSE IN CHRONIC PLAQUE PSORIASIS BY PHARMACOKINETIC-PHARMACODYNAMIC MODELLING: RESULTS FROM THE OPTIMAP STUDY.

P. Bank^1,2, A. van Huizen¹, P. Spuls¹, R. Mathot¹; ¹University of Amsterdam, Amsterdam, The Netherlands, ²Red Cross Hospital, Beverwijk, Netherlands.

Background: In the OPTIMAP study it has been demonstrated that addition of methotrexate (MTX) to subcutaneous adalimumab (ADL) treatment leads to less development of antidrug antibodies (ADAs), a trend towards higher serum-trough concentrations and a trend to better response in patients with chronic plaque psoriasis (CPP) (1,2). In the current study it was investigated whether MTX affected pharmacokinetics (PK) and/or pharmacodynamics (PD) of ADL.

Methods: In this retrospective analysis ADL serum concentrations, anti-drug antibodies and PASI scores were available from 59 CPP patients receiving ADL over 49 weeks. A population PK-PD model was developed using nonlinear mixed effects modelling.

Results: A total of 251 ADL concentrations and 261 PASI scores were available. 25 patients developed ADAs. Time profiles from ADL serum concentration were adequately described by a one-compartment model with a depot. Volume of distribution was 14.7 L/70 kg and clearance was 0.365 L/day/70 kg; inter-individual variability of Cl was 31.8%. In the univariate (UV) analysis intake of MTX correlated with decreased CL (p < 0.05); the presence of ADAs and use of acitretin were also significant. In the multivariate (MV) analysis, with a more stricter statistical criterium, only ADA was significant (p < 0.001). The relationship between ADL concentrations and PASI was described with a turn-over inhibitory Emax model. Typical IC50 was 1.22 mg/L; IIV was 110.5%. The UV analysis indicated that MTX was correlated with a decreased IC50 (p < 0.10). No significant relationships were found in the MV.

Conclusion: This PK/PD model-based analysis shows a relationship between ADL levels and PASI-scores and high influence of ADA on the clearance of ADL. It further indicates that the addition of MTX may improve the treatment with ADL in CCP patients by influence on both PK and PD.

1. Busard CI, Menting SP, van Bezooijen JS, van den Reek JM, Hutten BA, Prens EP, et al. Optimizing adalimumab treatment in psoriasis with concomitant methotrexate (OPTIMAP): study protocol for a pragmatic, single-blinded, investigator-initiated randomized controlled trial. Trials. 2017;18(1):52.
2. van der Kraaij GE, Busard CI, van den Reek J, Menting SP, Musters AH, Hutten BA, et al. Adalimumab with methotrexate versus adalimumab monotherapy in psoriasis: First-year results of a single-blind randomized controlled trial. J Invest Dermatol. 2022.