An apparent clinical pharmacokinetic drug–drug interaction between bevacizumab and the anti-placental growth factor monoclonal antibody RO5323441 via a target-trapping mechanism
| Autor: | Jianguo Zhi, Franziska Schaedeli Stark, Kai Habben, Angelika Lahr, Jean Tessier, Roland F Staack, Eginhard Schick, Ka Wang, Tilman Schlothauer, Oliver Krieter, Valerie Cosson |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Placental growth factor Sorafenib Cancer Research Bevacizumab Population Angiogenesis Inhibitors Pharmacology Antibodies Monoclonal Humanized Toxicology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Pharmacokinetics Neoplasms Antineoplastic Combined Chemotherapy Protocols medicine Humans Drug Interactions Pharmacology (medical) education Sex Characteristics education.field_of_study Models Statistical Dose-Response Relationship Drug business.industry Antibodies Monoclonal Membrane Proteins Cancer medicine.disease Vascular endothelial growth factor 030104 developmental biology Oncology chemistry 030220 oncology & carcinogenesis Female Ovarian cancer business medicine.drug |
| Zdroj: | Cancer Chemotherapy and Pharmacology. 79:661-671 |
| ISSN: | 1432-0843 0344-5704 |
| DOI: | 10.1007/s00280-017-3242-8 |
| Popis: | RO5323441 is a humanized anti-placental growth factor (PlGF) monoclonal antibody that has shown preclinical activity in several cancer models. The objective of this analysis is to examine the pharmacokinetic (PK) results from four Phase I studies that have been conducted with RO5323441 (n = 61) and to report an apparent drug–drug interaction observed when RO5323441 was administered in combination with bevacizumab. The four Phase I studies were a multiple-ascending dose study in 23 patients with solid tumors (Study 1), an open-label study in seven patients with colorectal/ovarian cancer (Study 2), a sorafenib combination study in nine patients with hepatocellular carcinoma (Study 3), and a bevacizumab combination study in 22 patients with recurrent glioblastoma (Study 4). A two-compartment linear population PK model was developed from these four studies to characterize the PK of RO5323441 in patients with cancer. The PK properties of RO5323441 were similar in the first three studies. However, substantially higher RO5323441 exposures were observed in Study 4 when RO5323441 was administered in combination with bevacizumab. A linear two-compartmental population PK model indicated that the co-administration of bevacizumab would decrease the clearance of RO5323441 by 53%. Clinical data suggested that the decrease in RO5323441 clearance was inversely associated with bevacizumab exposure. The exact reason for the increase in RO5323441 exposure following bevacizumab co-administration is not currently known. One possibility is a drug–drug interaction via a target-trapping mechanism that is mediated by the vascular endothelial growth factor receptor-1 (VEGFR-1). |
| Databáze: | OpenAIRE |
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