Diane R. Mould ¹, Leonard E. Weisman², Barry Bloom³, Fabien Eyal⁴, Mark Polak⁵, Jennifer Fretz⁶, Clara Sei⁶, James J. Mond⁶, John F. Kokai-Kun<sup>6

1</sup>Projections Research Inc., Phoenixville PA; ²Baylor College of Medicine, Houston, TX; ³Wesley Medical Center, Witchita, KS; ⁴USA Women’s and Children’s Hospital, Mobile, AL; ⁵West Virginia University Hospital, Morgantown, WV; ⁶Biosynexus Incorporated, Gaithersburg, MD

BACKGROUND: Pagibaximab, an anti-staphylococcal monoclonal antibody evaluated for prevention of staphylococcal sepsis in very low birth weight (VLBW) infants reported no staphylococcal sepsis when serum levels were >500 µg/ml.

OBJECTIVE: Prior to phase 3 studies, develop dosing scheme to attain pagibaximab serum levels >500 µg/ml for 35 days in VLBW infants.

METHODS: Serum antibody levels from 100 VLBW infants infused with pagibaximab 10 to
90 mg/kg or placebo, for one to three doses were used to develop a pharmacokinetic model and dosing regimen. This regimen was prospectively evaluated in planned and scavenged samples obtained for 35 days from VLBW infants infused with pagibaximab. Observed and predicted pagibaximab levels were compared.

RESULTS: The pharmacokinetics described the concentration time course of pagibaximab as a two compartment model with linear central compartment elimination. Pharmacokinetic parameters from this model were (mean +SE): Cl (ml/h) 0.446, Vl 75, V2 138, C0int 12.3, Ke 0.000836, t1/2 15.4 days. Using this model a dosing scheme of 100mg/kg daily for 3 days and then weekly for 3 weeks was developed to achieve target levels. The observed pharmacokinetic estimates from infants who received this regimen from both scavenged and planned samples were similar and were as predicted by the model. However, inclusion of scavenged samples caused some model instability due to lack of accurate sampling times. In either set of samples, all serum levels were >500 µg/ml.

CONCLUSIONS: We developed a computer model-based dosing regimen for pagibaximab in VLBW infants to maintain serum levels ≥500 µg/ml and prospectively confirmed this regimen. Phase 3 studies can now proceed with the confidence that pagibaximab target levels can be achieved and maintained.