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1557. Population Pharmacokinetics of Suvratoxumab (MEDI4893), an Extended Half-life Staphylococcus aureus Alpha Toxin-Neutralizing Human Monoclonal Antibody, in Healthy Adults and Patients on Mechanical Ventilation in Intensive Care Units

ABSTRACT: Abstract Background Suvratoxumab (suvra), an extended half-life (~80 days), Staphylococcus aureus (SA) alpha toxin-neutralizing IgG monoclonal antibody, is under investigation for prevention of SA pneumonia in patients on mechanical ventilation (MV). We characterized the serum PK of suvra using population pharmacokinetics (popPK) in both healthy volunteers and MV patients and quantified the proportion of patients reaching the serum target of 211 ?g/mL at 30 days post-dose. Methods The popPK analysis included 1,368 serum samples from two early phase studies (NCT02296320; EudraCT 2014-001097-34): (1) Phase 1 study in 26 healthy adults receiving single IV suvra doses ranging from 0.225g to 5g, with PK sampled up to 360 days; and (2) Phase 2 study in MV patients with PCR-confirmed SA colonization of lower respiratory tract receiving one suvra IV dose of 2g (n = 15) or 5g (n = 96), with PK sampled up to 100 days. Results A two-compartment linear model with weight-based scaling of the PK parameters adequately described the serum PK data (Figure 1). MV status, number of days on MV, and age impacted the PK of suvra. A moderate between-subject variability (<45% CV) was estimated for key PK parameters. An estimated two-fold increase in MV patients’ volume of distribution parameters compared with healthy volunteers explained the observed Cmax differences between the two groups (1145±369 ?g/mL vs. 1783±396 ?g/mL) (Figures 2 and 3). Although age, MV status and days on MV post-dose appeared to be associated with higher systemic clearance (CL) in the model, this estimate could be biased due to limited PK data available for only one half-life (~90 days) of the drug in MV patients (Figure 2). More patients achieved suvra levels above the PK target following the 5 g (73.5%; 50/68) vs. 2 g dose (7.6%; 1/13) at 30 days post-dose. Conclusion MV status, post-dose duration on MV, body weight, and age were identified as statistically significant covariates influencing the PK of suvra. Serum PK and popPK analyses support the 5g dose for future studies with suvra in MV patients. Disclosures All authors: No reported disclosures.

SUBMITTER: Pierre V

PROVIDER: S-EPMC6809240 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Project description:Abstract Background Staphylococcus aureus (SA) pneumonia imposes significant morbidity and mortality in mechanically ventilated, intensive care unit (MV ICU) patients despite best clinical care. We assessed efficacy, PK, AT-neutralizing antibodies (AT NAbs), and safety of suvratoxumab (suvra) in MV ICU subjects in the placebo-controlled, randomized Phase 2 SAATELLITE study (NCT02296320; EudraCT 2014-001097-34). Methods Subjects with PCR-confirmed SA colonization of the lower respiratory tract were randomized to either a single intravenous infusion of 5,000 mg suvra (n = 96) or placebo (n = 100) and followed for 190 days post dose. Efficacy endpoints were Endpoint Adjudication Committee-determined relative risk reduction (RRR) of SA pneumonia incidence in suvra vs. placebo recipients within 30 days post dose (primary endpoint, tested at 2-sided ? = 0.1), incidence of all-cause pneumonia, and all-cause pneumonia or death. Serum suvra PK and levels of AT NAbs were measured through 90 days post dose and analyzed for statistical correlation. Treatment-emergent adverse events (TEAEs) and serious AEs (SAEs) were assessed through 190 days post dose. Results Baseline characteristics were similar between groups. Suvra provided 31.9% RRR in incidence of SA pneumonia vs. placebo (17.7% vs. 26%; P = 0.166), 30% RRR (P = 0.146) in incidence of all-cause pneumonia, and 23% RRR (P = 0.164) in incidence of all-cause pneumonia or death. Suvra reduced mean hospital stay and ICU duration by 3.0 and 2.4 days, resp. vs. placebo. Mean serum ± SD suvra level was 296 ± 131 µg/mL at 30 days post dose. Serum AT Nab ± SD levels reached 156.03 ± 72.48 IU/mL at 2 days post dose, declining slowly to 33.74 ± 16.04 IU/mL by 90 days post dose. AT NAbs correlated with PK (r2 = 0.7), thereby confirming functional activity of suvra over time. Proportion of subjects with TEAEs or SAEs was similar between groups: ?1 TEAE (93.8% suvra; 93.0% placebo); ?1 serious; and/or ?grade 3 severity SAE (66.7% suvra; 58.0% placebo). Conclusion A single intravenous dose of suvra produced a trend toward reduced incidence of SA pneumonia, health resource savings, sustained functional exposure in serum, and an acceptable safety profile. These results support continued development of suvra in MV ICU patients. Disclosures All Authors: No reported Disclosures.

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1557. Population Pharmacokinetics of Suvratoxumab (MEDI4893), an Extended Half-life Staphylococcus aureus Alpha Toxin-Neutralizing Human Monoclonal Antibody, in Healthy Adults and Patients on Mechanical Ventilation in Intensive Care Units

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