title: Estimating the clinical risk of hypertension from VEGF signal inhibitors by a non-clinical approach using telemetered rats.
abstract: Anti-angiogenic drugs that target Vascular Endothelial Growth Factor (VEGF) signaling pathways caused hypertension as an adverse effect in clinical studies. Since the hypertension may limit the benefit provided for patients, the demand for non-clinical research that predicts the clinical risk of the hypertension has risen greatly. To clarify whether non-clinical research using rats can appropriately estimate the clinical risk of hypertension caused by VEGF signal inhibitors, we investigated the hemodynamic effects and pharmacokinetics (PK) of the VEGF signal inhibitors cediranib (0.1, 3, and 10 mg/kg), sunitinib (5, 10, and 40 mg/kg), and sorafenib (0.1, 1, and 5 mg/kg) in telemetered rats and examined the correlation between the non-clinical and the clinical hypertensive effect. The VEGF signal inhibitors significantly elevated blood pressure (BP) in rats within a few days of the initiation of dosing, and levels recovered after dosing ended. The trend of the hypertension was similar to that in clinical studies. We found that the AUC at which BP significantly increased by approximately 10 mmHg in rats was comparable to the clinical AUC at which moderate to severe hypertension occurred. These results represent correlations between the non-clinical and the clinical hypertensive effect of VEGF signal inhibitors, suggesting that non-clinical research using telemetered rats would be an effective approach to predict the clinical risk of hypertension caused by VEGF signal inhibitors.
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd.
authors.forename: Takehito
authors.initials: T
authors.lastname: Isobe
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Komatsu
authors.forename: Masaki
authors.initials: M
authors.lastname: Honda
authors.forename: Shino
authors.initials: S
authors.lastname: Kuramoto
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Shindoh
authors.forename: Mitsuyasu
authors.initials: M
authors.lastname: Tabo
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced*; D008297:Male; D009536:Niacinamide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D011799:Quinazolines / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012306:Risk; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D000077157:Sorafenib; D013686:Telemetry; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000502:physiology; D007211:Indoles
chemical_list: D020533:Angiogenesis Inhibitors; D009536:Niacinamide; D010671:Phenylurea Compounds; D011799:Quinazolines; D000077157:Sorafenib; D042461:Vascular Endothelial Growth Factor A; C500926:cediranib; D007211:Indoles