An apparent clinical pharmacokinetic drug-drug interaction between bevacizumab and the anti-placental growth factor monoclonal antibody RO5323441 via a target-trapping mechanism.

Autor:	Wang, Ka, Stark, Franziska, Schlothauer, Tilman, Lahr, Angelika, Cosson, Valerie, Zhi, Jianguo, Habben, Kai, Tessier, Jean, Schick, Eginhard, Staack, Roland, Krieter, Oliver, Stark, Franziska Schaedeli, Staack, Roland F
Předmět:	DRUG interactions PLACENTAL growth factor MONOCLONAL antibodies ANIMAL models of cancer BEVACIZUMAB VASCULAR endothelial growth factor receptors ANTINEOPLASTIC agents CLINICAL trials COMPARATIVE studies DOSE-effect relationship in pharmacology HUMAN reproduction RESEARCH methodology MEDICAL cooperation MEMBRANE proteins NEOVASCULARIZATION inhibitors RESEARCH TUMORS EVALUATION research STATISTICAL models CHEMICAL inhibitors
Zdroj:	Cancer Chemotherapy & Pharmacology; Apr2017, Vol. 79 Issue 4, p661-671, 11p
Abstrakt:	Purpose: 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.Methods: 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.Results: 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.Conclusions: 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). [ABSTRACT FROM AUTHOR]
Databáze:	Complementary Index
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