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Population Pharmacokinetics and Exposure-Response Relationship of Intravenous and Subcutaneous Abatacept in Patients With Rheumatoid Arthritis.

ABSTRACT: Abatacept population pharmacokinetics (PK) and exposure-response (E-R) models for selective efficacy end points were developed using phase 2 and 3 study data in patients with rheumatoid arthritis treated with abatacept (intravenous [IV] or subcutaneous [SC]), followed by simulations. Two efficacy end points were assessed in the E-R analyses: Disease Activity Score in 28 joints (DAS28) and American College of Rheumatology response criteria for 20/50/70% improvement (ACR20/50/70). The analyses were performed with data from 11 clinical studies for the population PK analysis and from 3 clinical studies for the E-R analyses (DAS28 and ACR20/50/70). The PK of abatacept were time invariant and can be described by a linear 2-compartment model with first-order elimination and with zero-order IV infusion or first-order absorption for SC abatacept. Baseline body weight was the only clinically meaningful covariate; that is, abatacept clearance and volume of central compartment increased with increasing baseline body weight. Steady-state trough concentration (C_minss ) of abatacept was identified as the best exposure predictor of DAS28 response compared with other exposure measures. In addition, the E-R relationship was the same for IV and SC abatacept. Similar results were confirmed in the ACR20/50/70 E-R analyses. Efficacy responses increased with increasing C_minss and a near-maximal response was associated with C_minss ≥10 μg/mL. The model-based analyses confirmed that the weight-tiered ∼10 mg/kg IV and fixed 125 mg SC abatacept dosing regimens are comparable and achieved plateau responses, by delivering C_minss ≥10 μg/mL in RA patients across all body weights.

SUBMITTER: Li X

PROVIDER: S-EPMC6585965 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveTo compare the efficacy and safety of subcutaneous (SC) and intravenous (IV) abatacept.MethodsIn this phase IIIb double-blind, double-dummy, 6-month study, patients with rheumatoid arthritis (RA) and inadequate responses to methotrexate were randomized to receive 125 mg SC abatacept on days 1 and 8 and weekly thereafter (plus an IV loading dose [∼10 mg/kg] on day 1) or IV abatacept (∼10 mg/kg) on days 1, 15, and 29 and every 4 weeks thereafter. The primary end point for determining the noninferiority of SC abatacept to IV abatacept was the proportion of patients in each group meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at month 6. Other efficacy end points, immunogenicity, and safety were also assessed.ResultsOf 1,457 patients, 693 of 736 (94.2%) treated with SC abatacept and 676 of 721 (93.8%) treated with IV abatacept completed 6 months. At month 6, 76.0% (95% confidence interval 72.9, 79.2) of SC abatacept-treated patients versus 75.8% (95% confidence interval 72.6, 79.0) of IV abatacept-treated patients achieved an ACR20 response (estimated difference between groups 0.3% [95% confidence interval -4.2, 4.8]), confirming noninferiority of SC abatacept to IV abatacept. Onset and magnitude of ACR responses and disease activity and physical function improvements were comparable between the SC and IV abatacept-treated groups. The proportions of adverse events (AEs) and serious AEs over 6 months were 67.0% and 4.2%, respectively, in the SC abatacept-treated group and 65.2% and 4.9%, respectively, in the IV abatacept-treated group, with comparable frequencies of serious infections, malignancies, and autoimmune events between groups. SC injection site reactions (mostly mild) occurred in 19 SC abatacept (IV placebo)-treated patients (2.6%) and 18 IV abatacept (SC placebo)-treated patients (2.5%). Abatacept-induced antibodies occurred in 1.1% of SC abatacept-treated patients and 2.3% of IV abatacept-treated patients.ConclusionSC abatacept provides efficacy and safety comparable with that of IV abatacept, with low immunogenicity and high retention rates, consistent with the established IV abatacept profile. Rates of injection site reactions were low. SC abatacept will provide additional treatment options, such as an alternative route of administration, for patients with RA.

Project description:IntroductionThe purpose of the present study was to determine whether the abatacept autoinjector can be used by the intended population without patterns of preventable use errors, and is acceptable when assessed against key user needs.MethodsTwo independently conducted simulated-use studies, with no active drug administered, quantified use errors and evaluated the abatacept autoinjector and competitor devices on key attributes (comfort, control, ease of use, confidence of dose) and overall acceptability. Autoinjector preference was also assessed. Participants were patients with rheumatoid arthritis, caregivers, and healthcare professionals (HCPs). Participants were informed that a new rheumatoid arthritis autoinjector was being tested but were blinded to the intended drug and sponsor identity.ResultsIn the formative (pre-validation) study (n = 54), two high-priority use errors occurred, both of which resulted from protocol non-compliance rather than mental confusion or physical limitations. In the summative (validation) study (n = 99), one high-priority use error occurred; this was deemed a simulated-use study artifact as participant behavior was guided by actual experience associated with the feel of drug delivery into the skin rather than by protocol, so no mitigation steps were considered necessary. Across user groups, average scores were consistently high for the pre-defined key attributes. Overall acceptability scores (7-point scale) were significantly higher for the abatacept versus competitor autoinjectors-formative study: patients 6.7 vs 5.2 (P = 0.0001), caregivers 7.0 vs 4.6 (P = 0.0093), HCPs 6.8 vs 5.1 (P = 0.0020); summative study: patients 6.5 vs 5.9 (P = 0.0404), caregivers 6.8 vs 5.8 (P = 0.0047), HCPs 6.8 vs 5.1 (P = 0.0002). The abatacept autoinjector was preferred to competitor devices: patients 85.7% vs 14.3% (P = 0.00002), caregivers 84.2% vs 15.8% (P = 0.00443), HCPs 95.0% vs 5.0% (P = 0.00004). Positive experiences with the abatacept autoinjector were attributed to the rubberized grip, device size, visualization of dose progression, button ergonomics, and ease of use.ConclusionThe abatacept autoinjector demonstrated usability without patterns of preventable use errors, and with high acceptability ratings across all key attributes assessed. Preference over competitor autoinjectors was due to device ergonomics, visualization of dose progression, confidence of dose delivery, and overall ease of use.FundingBristol-Myers Squibb.

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Population Pharmacokinetics and Exposure-Response Relationship of Intravenous and Subcutaneous Abatacept in Patients With Rheumatoid Arthritis.

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