Methotrexate influences neither pharmacokinetics nor concentration-effect relationship of infliximab in axial ankylosing spondylitis
D. Ternant(1), F. Lauféron(2), D. Mulleman(2), D. Wendling(3), E. Ducourau(2), C. Vignault(1), J.P. Valat(2), P. Goupille(2), G. Paintaud(1).
(1) Department of pharmacology-toxicology, University Hospital CHRU of Tours, Tours, France; (2) Department of rheumatology, University Hospital CHRU of Tours, Tours, France; (3) Department of rheumatology, University Hospital CHUof Besançon, Besançon, France.
Objectives: The pharmacokinetics of infliximab (IFX), an anti-TNF-α monoclonal antibody, is modified during methotrexate (MTX) coadministration in rheumatoid arthritis[1]. The objective of this study was to assess the influence of MTX on IFX pharmacokinetics and PK-PD in axial ankylosing spondylitis (AAS) patients.
Methods: In this prospective study, 26 AAS patients were randomly assigned to IFX alone (MTX– arm) or to MTX-IFX combination (MTX+ arm) and were treated by 5 mg/kg IFX infusions at weeks 0, 2, 6, 12 and 18. Infliximab concentrations were measured weekly, before and 2 and 4 hours after each infusion. The recommanded clinical endpoint in AAS, BASDAI score, was measured weekly. IFX pharmacokinetics were described using a 2-compartment model with first order transfer constants. The relationship between IFX and BASDAI score was described using an indirect response model. The BASDAI ‘input’ was described by kdis which was inhibited by IFX, and ksub which described nocebo effect; Em was the part of kdis not inhibated by IFX, C50 was IFX concentration leading to 50% of maximum kdis inhibition, and kheal was BASDAI ‘output’. A population approach was used (MONOLIX 3.1 software). The influence of MTX was tested as a covariate on each pharmacokinetic and PK-PD parameter.
Results: Estimated pharmacokinetic parameters (interindividual CV) were: volumes of distribution for central (Vc) = 2.4 L, (10%), and peripheral (Vp) compartment = 1.8 L, (20%), systemic (CL) = 0.21 L/day, (22%), and intercompartment (Q) clearance = 2.3 L/day. Body surface area influenced both Vc and Vp, and antibodies toward IFX increased CL thrice. Estimated pharmacodynamic parameters were: kdis = 0.22 day-1 (85%), ksub = 0.018 day-1 (59%), kheal = 0.034 day-1 (95%) Em = 46%, (59%) and C50 = 6.3 mg/L. Methotrexate influenced neither pharmacokinetic nor PK-PD parameters. The strong negative correlation (–0.97) between ksub and Em interindividual distributions suggests that nocebo effect was higher when IFX efficacy was low. A C50 value lower than most measured IFX concentrations and a value for Em close to 100% in non-responders suggest that the absence of response was not due to under-exposure to IFX, but to IFX inefficacy.
Conclusions: Methotrexate influenced neither pharmacokinetics nor PK-PD of IFX. Therefore its combination with IFX cannot be recommanded to treat AAS. The absence of response to IFX in some patients may be due to a minor role of TNF-α in their disease.
References:
[1] Maini RN, Breedveld FC, Kalden JR, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998;41:1552-63.