Background/Purpose:  Co-administration of methotrexate (MTX) has a significant effect on the pharmacokinetics (PK) of adalimumab (ADAL). MTX may impact the PK of other drugs by multiple mechanisms including immunosuppressant and anti- inflammatory effects.  This pooled analysis was conducted to examine the effect of MTX and other factors on ADAL PK.

Methods:  Individual subjects’ PK and demographics data from 9 ADAL Phase II and III studies in patients with Rheumatoid Arthritis (RA; n=1991) after SC administration of different ADAL dosing regimens were pooled. 642 patients were on 40 mg ADAL every other week dosing regimen. Serum samples were collected prior to dosing and at several time points for up to 1 year for measurement of ADAL and anti-ADAL antibodies (AAA) using ELISA methods. All patients with at least one measurable ADAL were included.  A patient was considered AAA+ if at least one sample had AAA > 20 ng/mL within 30 days after an ADAL dose.  Analyses were conducted utilizing measured ADAL concentrations and population PK (PopPK) modeling.

Results: The median (range) age and weight of patients (77% F, 23%M) were 54 (4-87) yrs and 69.7 (13-186) kg. 48.8% were on a stable dose of concomitant MTX (10 to 30 mg/wk) and 51.2% received ADAL as monotherapy. 91.4% were adults and 8.6% were children (4 to 17 yrs). Patients on a stable dose of MTX at study start had lower baseline C-Reactive Protein (CRP) and Rheumatoid Factor (RF) compared to patients who were not on MTX. Median baseline CRP was 11.0 and 33.5 mg/L with and without MTX. Median baseline RF was 68 and 148 IU/mL with and without MTX. Overall, 8.8% of patients across all 9 studies, with 3.3% of patients on MTX co-medication and 14.7% of patients on ADAL monotherapy, had at least one AAA+ sample. PopPK indicated that MTX had the most significant impact on ADAL apparent clearance (CL) in all patients (AAA+ and AAA-), and even when patients with AAA+ were excluded from the analysis. ADAL clearance (CL) was 10.6 and 20.6 mL/hr with and without MTX in all patients and was 10.1 and 17.5 mL/hr with and without MTX in AAA- patients. Median ADAL CL was similar in patients receiving MTX doses of 10 mg/wk and up to 30 mg/wk.  After accounting for MTX effect, body weight, baseline CRP and baseline RF were also factors that influence the variability in ADAL PK. ADAL CL increased with increase in body weight, and higher baseline levels of CRP or RF.  After accounting for the differences in body weight, ADAL CL, with and without MTX, were similar in males and females, across races, and from 4 to 87 yrs of age.

Conclusion:  Pooled analyses of data from nine ADAL Phase II and III studies in patients with RA after SC administration indicate that MTX has significant effects on ADAL PK in all patients and in AAA- patients.  MTX effects on ADAL PK may potentially be by multiple mechanisms including an anti-inflammatory effect in addition to the immunosuppressant effect by reducing the development of AAA.  After accounting for MTX effect and AAA+ status, body weight, baseline CRP and RF are additional factors that influence the variability in ADAL PK. ADAL PK were similar regardless of patient sex, race and age.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-effect-of-methotrexate-on-adalimumab-pharmacokinetics-pooled-analysis-of-adalimumab-pharmacokinetics-in-patients-with-rheumatoid-arthritis-after-subcutaneous-administration/