An apparent clinical pharmacokinetic drug-drug interaction between bevacizumab and the anti-placental growth factor monoclonal antibody RO5323441 via a target-trapping mechanism.
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).
Roche Innovation Center New York, 430 East 29 Street, New York, NY, 10016, USA. ka.wang@roche.com.
Ka
K
Wang
Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
Franziska Schaedeli
FS
Stark
Roche Innovation Center Munich, Nonnenwald 2, 82377, Penzberg, Germany.
Tilman
T
Schlothauer
Roche Innovation Center Munich, Nonnenwald 2, 82377, Penzberg, Germany.
Angelika
A
Lahr
Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
Valerie
V
Cosson
Roche Innovation Center New York, 430 East 29 Street, New York, NY, 10016, USA.
Jianguo
J
Zhi
Roche Innovation Center Munich, Nonnenwald 2, 82377, Penzberg, Germany.
Kai
K
Habben
Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
Jean
J
Tessier
Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
Eginhard
E
Schick
Roche Innovation Center Munich, Nonnenwald 2, 82377, Penzberg, Germany.
Roland F
RF
Staack
Roche Innovation Center Munich, Nonnenwald 2, 82377, Penzberg, Germany.
Oliver
O
Krieter
D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics*; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics*; D000068258:Bevacizumab / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology*; D015233:Models, Statistical; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D012727:Sex Characteristics
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D008565:Membrane Proteins; C098069:PIGF protein, human; D000068258:Bevacizumab; C569915:TB-403
Bevacizumab; Drug interactions; Pharmacokinetics; Placenta growth factor; RO5323441; Vascular endothelial growth factor receptor