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Estimating the Clinical Risk of Hypertension from VEGF Signal The Journal of Toxicological Sciences (J. Toxicol. Sci.) 237 Vol.39, No.2, 237-242, 2014 Letter Estimating the clinical risk of hypertension from VEGF signal inhibitors by a non-clinical approach using telemetered rats Takehito Isobe, Ryuichi Komatsu, Masaki Honda, Shino Kuramoto, Hidetoshi Shindoh and Mitsuyasu Tabo Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan (Received November 1, 2013; Accepted January 20, 2014) 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 esti- mate the clinical risk of hypertension caused by VEGF signal inhibitors, we investigated the hemody- namic 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 lev- els 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 compara- ble to the clinical AUC at which moderate to severe hypertension occurred. These results represent corre- lations 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. Key words: VEGF signal inhibitor, Hypertension, Telemetered rats INTRODUCTION predicting the clinical risk of the hypertension is eagerly awaited. Several non-clinical studies showed that VEGF Angiogenesis, the formation of new blood vessels from signal inhibitors increased blood pressure (BP) in rats existing ones, is required for tumor growth and metas- (Curwen et al., 2008; Franklin et al., 2009; Kappers et al., tases (Kerbel et al., 2008). Since vascular endothelial 2010); however, it has not been investigated whether non- growth factor (VEGF) was proved to play a pivotal role clinical research using rats can appropriately estimate the in angiogenesis (Ferrara et al., 2003 and 2004), anti-an- clinical risk of hypertension by VEGF signal inhibitors. giogenic drugs targeting VEGF signaling pathways have In this study, therefore, to clarify the usefulness of a been developed as a chemical therapy for cancer patients. non-clinical rat study for predicting the clinical risk of Although many VEGF signal inhibitors have shown effi- hypertension, we investigated the hemodynamic effects cacy against different kinds of tumors, hypertension has and pharmacokinetics (PK) of VEGF signal inhibitors appeared as a common adverse effect (Chen and Cleck, in rats and examined the correlation between the non- 2009). clinical hypertensive effect and the clinical hyperten- Hypertension is clinically observed at the therapeutic sive effect. We used cediranib, sunitinib, and sorafenib, dose of VEGF signal inhibitors, and requires intense man- which are potent VEGF-receptor tyrosine kinase inhibi- agement using anti-hypertensive agents in clinical prac- tors (Mendel et al., 2003; Wilhelm et al., 2004; Wedge tice (Bair et al., 2013). Since the hypertension may limit et al., 2005) that clinically elicit hypertension as a major the benefit provided for patients, non-clinical research on adverse event (Drevs et al., 2007; Le Tourneau et al., Correspondence: Takehito Isobe (E-mail: [email protected]) Vol. 39 No. 2 238 T. Isobe et al. 2007; Wu et al., 2008). Germany)/42.5% propylene glycol (Nacalai Tesque, Inc.)/42.5% polyethylene glycol 400 (w/v) (Wako Pure MATERIALS AND METHODS Chemical Industries, Ltd., Osaka Japan) with sorafenib. The low dose of each VEGF signal inhibitor was set to Chemicals obtain a dose that has no effect on BP, and the middle Cediranib, sunitinib, and sorafenib were synthesized at and high doses were set to investigate a dose-dependent Chugai Pharmaceutical Co., Ltd. (Tokyo, Japan). effect on BP. The administration time was approximate- ly 10:00 AM on the days of treatment. The BP signal was Animals gathered through Data Exchange Matrix (Data Sciences Male Wistar rats obtained from Japan Slc Inc. International, St. Paul, MN, USA) to data-acquisition (Shizuoka, Japan) and weighing from 280 to 470 g were software (Data quest ART silver ver. 4.0; Data Sciences used in this study. The animals had free access to food International, St. Paul, MN, USA). Systolic blood pres- and water, and were housed in an environmentally con- sure (SBP), diastolic blood pressure (DBP), mean blood trolled room with a temperature maintained at 23°C ± pressure (MBP), and heart rate (HR) were automatical- 3°C, humidity at 55% ± 20%, and a 12-hr light/dark cycle ly analyzed and continuously recorded at 5-min intervals. (lights on 07:00-19:00). Care of the animals and the pro- Recording started 24 hr before the first administration and tocol used complied with the “General Considerations for continued through 4 days of administration (administra- Animal Experiments” promulgated in Chugai Pharma- tion period) and for 3 days after the end of administration ceutical Co., Ltd. and were approved by the Institution- (recovery period). Entry into the telemetry room was not al Animal Care and Use Committee, which is accredited allowed except to administer drugs or clean the room. The by the Association for Assessment and Accreditation of times staff entered into and out of the room were logged Laboratory Animal Care (AAALAC). and were not included in analysis. Since the VEGF signal inhibitors would increase Surgical implantation of telemetry-transmitters BP through their effect on the peripheral blood ves- For the surgical implantation of a transmitter, atropine sels (Facemire et al., 2009), we analyzed DBP to detect sulfate hydrate (Mitsubishi Tanabe Pharma Corporation, increased vascular resistance. Baseline DBP was deter- Osaka, Japan) at 0.05 mg/kg was intramuscularly injected mined by the 24-hr mean of DBP before administration, to rats followed by an inhalational anesthesia with isoflu- and a change after administration in each 24-hr mean of rane (Mylan Pharmaceutical Co., Ltd., Tokyo, Japan). A DBP from baseline (∆DBP) was represented as a mean ± catheter of the telemetry transmitter (TA11PA-C40; Data S.D. Although only the figures for DBP are shown in this Sciences International, St. Paul, MN, USA) was insert- paper, SBP and MBP showed similar trends to DBP (data ed into the abdominal aorta. The transmitter was sutured not shown). to the inside wall of the abdominal cavity to secure it in place. At the end of surgery, an antibiotic (cefazolin sodi- Measurement of plasma concentrations of um hydrate; Astellas Pharma Inc., Tokyo, Japan) and an cediranib, sunitinib and sorafenib analgesic (flunixin meglumine; DS Pharma Animal Health PK of the VEGF signal inhibitors in rats was investi- Co., Ltd., Osaka, Japan) were intraperitoneally injected. gated in a separate study. Doses and the dosing schedule Rats were allowed a 2-week postsurgical recovery period of the VEGF signal inhibitors in the PK study were the before treatment with the test compounds. same as those in the telemetry study. Blood samples were collected at 1, 2, 4, 8 and 24 hr after the first administra- Measurement of blood pressure in telemetered tion, and at 4 and 24 hr after the second, third and fourth rats administrations. Blood samples were centrifuged at 4°C Telemetered rats were dosed with vehicle or drugs by with 2,600 × g for 5 min to obtain plasma. The plasma oral gavage once a day for 4 consecutive days. Cediranib samples were stored at -80°C until analysis. (0, 0.1, 3, and 10 mg/kg), sunitinib (0, 5, 10, and 40 mg/kg), Samples from PK studies were analyzed by the LC- and sorafenib (0, 0.1, 1, and 5 mg/kg) were administered. MS/MS after protein precipitation with acetonitrile. Vehicles were 1% polyoxyethylenesorbitan monooleate The plasma concentrations of cediranib and sunitinib (w/v) (Nacalai Tesque, Inc., Kyoto, Japan) with cediranib, were determined by column switching method and API 0.5% sodium carboxymethylcellulose (w/v) (Maruishi 3000 triple quadrupole mass spectrometer (AB Sciex, Pharmaceutical Co., Ltd., Osaka, Japan) with Framingham, MA, USA) was used. The extraction col- sunitinib, and 15% pluronic F-68 (AppliChem GmbH, umn was Oasis HLB, 20 × 2.1 mm, 25 μm particle size Vol. 39 No. 2 239 Estimating the risk of hypertension from VEGF inhibitors (Waters, Milford, MA, USA) and the analytical column period, each vehicle control elicited no effect on ∆DBP. was Imtakt Unison UK-18, 30 × 2.0 mm, 3 μm particle Cediranib, sunitinib, and sorafenib produced no increase size (Imtakt, Kyoto, Japan). The plasma concentrations in ∆DBP at the low dose, but dose-dependently increased of sorafenib were determined by single column method ∆DBP at the middle and the high dose of each drug. Sig- and QTRAP 5500 triple quadrupole mass spectrometer nificant elevation of BP was observed within the four (AB Sciex, Framingham, MA, USA) was used. The days of treatment in this study. DBP recovered to near analytical column was same as that of cediranib and baseline during the recovery period, except that DBP sunitinib. PK parameters were calculated by non-compart- was slightly elevated from baseline with the highest dose mental method using Watson version 7.1 (Thermo Fisher of cediranib. Clinical studies of VEGF signal inhibitors Scientific, Waltham, MA, USA).
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