PII-114

W. Wang, J. Leu, H. Zhou; Janssen R&D, Spring House, PA

BACKGROUND: Concomitant dosing of Methotrexatel (MTX) has been shown to significantly decrease the clearance and incidence of immunogenicity of golimumab and other anti-TNFα mAbs in humans. One plausible mechanism for the impact of MTX on the pharmacokinetics (PK) of golimumab is through its pharmacodynamic (PD) effect on immunogenicity. However, there is no definitive evidence for this mechanism, and other hypotheses, e.g., MTX affects the mAb PK by suppressing FcγRI expression, have been proposed.
METHODS: To evaluate the impact of MTX on golimumab PK and immunogenicity, a cynomolgus monkey PK/PD study (n=24) was conducted, and results from a Phase III study of golimumab in patients with psoriatic arthritis (PsA) was further analyzed to support the elucidation of the Therapeutic Protein-Drug Interaction (TPDI) mechanism.
RESULTS: Golimumab elicited high immunogenicity in cynomolgus monkeys. Concomitant dosing of MTX delayed the onset and reduced the magnitude of anti-drug antibody (ADA) formation. The impact of MTX on golimumab PK correlated well with the ADA status of individual animals. Prior to ADA formation, MTX has no effect on golimumab PK. No alteration in FcγRI expression was observed following MTX treatment either. In a Phase III study of golimumab in PsA patients, subjects with no concomitant MTX had ~30% lower steady-state trough golimumab levels compared to those received MTX. However, further analysis showed that the ADA-subjects in both groups actually had comparable trough levels of golimumab.
CONCLUSION: Our results suggest that the mechanism of TPDI between MTX and anti-TNFα mAbs can be attributed to the PD effect of MTX, i.e., the lowering of immunogenicity and immunogenicity-mediated clearance of mAbs. Our conclusion is substantiated by the PK and ADA results of golimumab in PsA patients with and without concomitant MTX.