Background/Purpose:

For anti-TNFα agents, infections and malignancies are key safety concerns.  It is unknown whether safety events are driven by peak (C_max), trough (C_min), average (C_avg) concentrations or by total systemic exposure (AUC). This PK/safety analysis was performed by pooling data from Phase 3 IV/SC golimumab (GLM) studies to investigate if there is any relationship between PK exposure and the occurrence of infections, serious infections, SAEs and malignancies after treatment with  IV or SC GLM in pts with RA, PsA, or AS.

Methods:

Seven Phase 3 GLM rheumatology studies (2 IV/ 5 SC) were included to leverage data from a large number of pts over a wide range of dosing regimens. Dosing regimens ranged from 2 mg/kg q8w to 4 mg/kg every q12w (IV studies) and 50 mg q4w to 100 mg q4w (SC studies) and included GLM as monotherapy and in combination with MTX/other nonbiologic DMARDs.  Established population PK models of SC & IV GLM were used to generate empirical Bayesian estimates of steady-state GLM PK exposure metrics (C_max, C_avg, C_min and Cumulative AUC) for individual pts using actual dosing records.  Infections, serious infections and SAEs were evaluated through ~1yr after initial GLM exposure.  Malignancies were evaluated through the latest data cut for the IV program (Aug 15, 2012) and through wk 160 in the SC studies to leverage as much data available as possible due to lower incidence of malignancies compared to infections and SAEs. A total of 2486 pts were included in the PK/safety dataset.  For infections, serious infections and SAEs, 2 analyses were performed: (1) a quartile analysis where the proportion of pts with these events were assessed by 4 PK quartile subgroups and (2) the distribution of PK exposure vs.  number of occurrences. For malignancies, the distribution of PK exposure vs. the occurrence of malignancies was plotted.

Results:

From the quartile analyses of the pooled SC & IV data, as systemic exposures to GLM increased there was no trend of increasing infections, serious infections or SAEs regardless of the distribution of the number of safety events for all PK exposure metrics. When comparing SC to IV data for serious infections, there was also no trend of increasing serious infections with higher exposures.  From the distribution plots of the combined IV & SC data, it was observed that for C_avg, C_max, and AUC, the ranges of exposures across categories of having 0, 1, or >1 infections were similar, while for SAEs and serious infections, higher rates of infections trended to occur in pts having lower exposures.  A trend toward the observation of higher systemic exposure to GLM correlating with more safety events was not observed, contrary to what might be expected.  From the distribution plots for malignancies, no difference was observed in the PK exposure for pts who had no malignancies vs. pts who had malignancies.

Conclusion:

No correlation of the occurrence of infections, serious infections, and SAEs with GLM C_max, C_avg, C_min and Cumulative AUC was observed over 1yr of treatment with SC or IV GLM. There was also no correlation of PK GLM exposure with malignancy occurrences up to 3yrs of treatment. The data suggest that the GLM IV and SC dosing regimens evaluated in these studies have similar safety profiles.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/lack-of-correlation-between-golimumab-exposure-and-selected-safety-events-following-intravenous-or-subcutaneous-administration-in-an-integrated-analysis-of-phase-3-data-of-patients-with-rheumatoid-art/