https://pubmed.ncbi.nlm.nih.gov/35860862/
Salerno, S. N., Deng, R., & Kakkar, T. Physiologically-based pharmacokinetic modeling of immunoglobulin and antibody coadministration in patients with primary human immunodeficiency. CPT: Pharmacometrics & Systems Pharmacology. 2022. doi: 10.1002/psp4.12847.
Abstract
Intravenous immunoglobulin (IVIG) (2000 mg/kg) increased the clearance of the mouse monoclonal antibody 7E3, directed against platelet integrin IIb/IIIa (αIIbβ3, CD41/CD61) in rodents. We wanted to investigate the effect of IVIG on clearance of monoclonal antibodies in humans as there is extremely limited data regarding this interaction in literature. Using the anti CD117 (c-Kit) humanized monoclonal antibody (JSP191) as a case study, we used physiologically-based pharmacokinetic (PBPK) modeling to evaluate the pharmacokinetic (PK) interaction between monoclonal antibodies and IVIG at doses (300-600 mg/kg) administered to patients with primary human immunodeficiency (PI). We first characterized the interaction between monoclonal antibodies and IVIG in PK-Sim/MoBi® using published literature data including: IVIG plus 7E3 in mice and rats and IVIG plus the human anti-C5 monoclonal antibody tesidolumab in adults with end-stage renal disease. We next developed a PBPK model using digitized data for JSPI91 alone in older adults with myelodysplastic syndrome and acute myeloid leukemia (AML) and in pediatric patients with severe combined immunodeficiency (SCID). Finally, we simulated the impact of IVIG (300-2000 mg/kg) co-administration with JSP191 on the area under the curve (AUC) of JSP191 in SCID patients. Model predictions were within 1.5-fold of observed values for 7E3 plus IVIG and tesidolumab plus IVIG as well as for JSP191 administered alone. Based on our simulations, IVIG doses ≥ 500 mg exceeded the 80-125 percent no-effect boundaries. IVIG treatment with monoclonal antibodies in patients with PI may result in a clinically significant interaction, depending on the IVIG dose administered and the exposure response relationship for the specific monoclonal antibody.
https://pubmed.ncbi.nlm.nih.gov/35860862/ Salerno, S. N., Deng, R., & Kakkar, T. Physiologically-based pharmacokinetic modeling of immunoglobulin and antibody coadministration in patients with primary human immunodeficiency. CPT: Pharmacometrics & Systems Pharmacology. 2022. doi: 10.1002/psp4.12847.
Abstract Intravenous immunoglobulin (IVIG) (2000 mg/kg) increased the clearance of the mouse monoclonal antibody 7E3, directed against platelet integrin IIb/IIIa (αIIbβ3, CD41/CD61) in rodents. We wanted to investigate the effect of IVIG on clearance of monoclonal antibodies in humans as there is extremely limited data regarding this interaction in literature. Using the anti CD117 (c-Kit) humanized monoclonal antibody (JSP191) as a case study, we used physiologically-based pharmacokinetic (PBPK) modeling to evaluate the pharmacokinetic (PK) interaction between monoclonal antibodies and IVIG at doses (300-600 mg/kg) administered to patients with primary human immunodeficiency (PI). We first characterized the interaction between monoclonal antibodies and IVIG in PK-Sim/MoBi® using published literature data including: IVIG plus 7E3 in mice and rats and IVIG plus the human anti-C5 monoclonal antibody tesidolumab in adults with end-stage renal disease. We next developed a PBPK model using digitized data for JSPI91 alone in older adults with myelodysplastic syndrome and acute myeloid leukemia (AML) and in pediatric patients with severe combined immunodeficiency (SCID). Finally, we simulated the impact of IVIG (300-2000 mg/kg) co-administration with JSP191 on the area under the curve (AUC) of JSP191 in SCID patients. Model predictions were within 1.5-fold of observed values for 7E3 plus IVIG and tesidolumab plus IVIG as well as for JSP191 administered alone. Based on our simulations, IVIG doses ≥ 500 mg exceeded the 80-125 percent no-effect boundaries. IVIG treatment with monoclonal antibodies in patients with PI may result in a clinically significant interaction, depending on the IVIG dose administered and the exposure response relationship for the specific monoclonal antibody.