Single and Repeat Dose Toxicity Study of 7-Hydroxycoumarin, Ethanol, and Their Mixture in Rats

Abstract Abstract 3381 Baxter is currently developing a recombinant ADAMTS13 (rADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) product for treatment, and routine prophylaxis of acute episodes of thrombotic thrombocytopenic purpura (TTP) in patients with ADAMTS13 deficiency. TTP is a rare, life-threatening microvascular disease characterized by single or recurrent episodes of thrombocytopenia, microangiopathic haemolytic anaemia and widespread microvascular thrombosis, which leads to the ischemic damage of multiple organs. To characterize the safety and the no observed adverse effect level (NOAEL) of Baxter's rADAMTS13, a 1-month repeat dose toxicity study in rats, an escalating dose and pilot 4-week repeat dose toxicity study in cynomolgus monkeys, and a 1-month repeat dose toxicity study including cardiovascular/pulmonary safety pharmacology in cynomolgus monkeys was conducted. Species suitability was shown by demonstrating that human rADAMTS13 can cleave monkey and rat VWF in vitro and in vivo under native conditions to present a worst case scenario for repeat dose toxicity studies. A local tolerance study was conducted in rabbits. Baxter's rADAMTS13 was well tolerated in rats at doses of 80, 400 and 800 FRETS-U/kg administered every third day for one month. Thus, the NOAEL in rats was the highest dose of 800 FRETS-U/kg. In cynomolgus monkeys, no adverse effects were detected at 800 FRETS-U/kg after intravenous treatment with rADAMTS13 once a week for 5 weeks (pilot repeat dose study). The NOAEL for the escalating dose phase of the study was 1790 FRETS-U/kg. Treatment of cynomolgus monkeys with bolus injection of Baxter's rADAMTS13 at doses of 80, 200, and 400 FRETS-U/kg once a week for 29 days did not reveal adverse findings. Thus, the NOAEL for this study was the highest dose of 400 FRETS-U/kg. As expected for a heterologous human protein drug, repeat doses of rADAMTS13 resulted in the formation of anti-drug antibodies specific for human ADAMTS13 and in neutralising human ADAMTS13 activity in animal models. No injection site reactions were observed in animals of either species. rADAMTS13 was well tolerated after intravenous (intended clinical administration route), intraarterial and paravenous administration in rabbits. In conclusion, Baxter's rADAMTS13 was well tolerated in rats, monkeys and rabbits, with no toxicity observed even at the highest dose levels. Disclosures: Piskernik: Baxter Innovations GmbH: Employment. Dietrich:Baxter Innovations GmbH: Employment. Kubik:Baxter Innovations GmbH: Employment. Ruthsatz:Baxter Innovations GmbH: Employment. Scheiflinger:Baxter Innovations GmbH: Employment. Schwarz:Baxter Innovations GmbH: Employment. Muchitsch:Baxter Innovations GmbH: Employment.

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Nonclinical Safety of SHP 826 (BAX 826), a Next Generation Extended Half-Life Recombinant Factor VIII Product

Blood ◽

10.1182/blood.v128.22.4977.4977 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4977-4977 ◽

Cited By ~ 2

Author(s):

Veronika Ehrlich ◽

Peter Leidenmuehler ◽

Barbara Dietrich ◽

Gerald Hoebarth ◽

Tanja Ruthsatz ◽

...

Keyword(s):

Acute Toxicity ◽

Factor Viii ◽

Half Life ◽

Hemophilia A ◽

Toxicity Study ◽

Repeat Dose ◽

Next Generation ◽

Local Tolerance ◽

Repeat Dose Toxicity ◽

Thrombogenic Potential

Abstract Hemophilia A is a rare genetic bleeding disorder caused by missing or defective factor VIII (FVIII), a crucial factor in blood coagulation. Baxalta Innovations / Shire is currently developing SHP 826 (BAX 826), as the next generation EHL rFVIII replacement for the treatment of hemophilia A. SHP 826 is the first EHL rFVIII to utilize novel technology in which polysialic acid (PSA) is conjugated to Baxalta's licensed rFVIII product (Advate) to extend the circulation half-life of FVIII. The potential toxicity of SHP 826 was evaluated in Sprague Dawley rats and cynomolgus monkeys. Acute toxicity was assessed in a dose-escalation study in monkeys that were intravenously administered 350 and 1800 IU rFVIII/kg SHP 826. Repeat dose toxicity was assessed in rats at doses of 80, 350, and 800 IU rFVIII/kg, in monkeys at doses of 800 IU rFVIII/kg every 5 days for 4 weeks, and in monkeys at doses of 80, 350, or 600 IU rFVIII/kg every five days for 31 days. Cardiovascular and respiratory safety was assessed in one of the repeat dose toxicity studies in monkeys. The thrombogenic potential of SHP 826 was evaluated after a single intravenous administration in rabbits (900 rFVIII/kg BW) using a stasis model developed by Wessler et al. (1959). The licensed rFVIII product was used as a comparator in the acute toxicity study and in the Wessler test. Parameters evaluated included local tolerance at the injection site, body weight, clinical pathology, blood gas analysis, analysis of neutralizing and binding antibodies in plasma, organ weight, necropsy observation, and histopathological evaluation. In addition, seminology (epididymal and testicular sperm) was assessed in rats, and urinalysis, ophthalmic and telemetric cardiovascular examination and respiratory rate measurement was performed in monkeys. SHP 826 showed a favorable safety/toxicity profile in both species used, with no abnormalities directly caused by test item administration noted in vivo or during clinical or histopathological examination. The NOAEL was set to the highest dose tested in each study (i.e. 800 IU rFVIII/kg BW in rats and 600 IU rFVIII/ kg BW in monkeys). Toxicokinetic evaluation indicated dose proportional PK. Exposure to FVIII decreased after repeated treatments due to appearance of anti-FVIII antibodies in both species. Development of anti-FVIII antibodies is an expected immune response after repeated application of heterologous proteins, and is not predictive of any potential for triggering development of anti-FVIII antibodies in humans. Safety pharmacology studies with SHP 826 revealed no evidence of thrombogenic potential in rabbits. SHP 826 administered intravenously was well tolerated in conscious telemetered cynomolgous monkeys (part of the repeat dose toxicity study) and did not cause any adverse clinical, cardiovascular, or respiratory effects. The results of these safety studies indicate sufficient safety margins to support the anticipated maximum clinical dose, and therefore entry into clinical development. Disclosures Ehrlich: Shire: Employment. Leidenmuehler:Shire: Employment. Dietrich:Shire: Employment. Hoebarth:Shire: Employment. Ruthsatz:Shire: Employment. Turecek:Shire: Employment. Wolfsegger:Shire: Employment, Equity Ownership. Weber:Shire: Employment. Gritsch:Shire: Employment. Hoellriegl:Shire: Employment. Turecek:Shire: Employment.

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Repeat-Dose Toxicity Study Using the AFPL1-Conjugate Nicotine Vaccine in Male Sprague Dawley Rats

Pharmaceutics ◽

10.3390/pharmaceutics11120626 ◽

2019 ◽

Vol 11 (12) ◽

pp. 626

Author(s):

Reynaldo Oliva ◽

Nya L. Fraleigh ◽

Jordan D. Lewicky ◽

Mildrey Fariñas ◽

Tamara Hernández ◽

...

Keyword(s):

Vaccination Strategy ◽

Blood Chemistry ◽

Toxicity Study ◽

Repeat Dose ◽

Sprague Dawley ◽

Promising Candidate ◽

Promising Alternative ◽

Repeat Dose Toxicity ◽

Sprague Dawley Rats ◽

Vaccination Period

Tobacco smoking is the cause of 20% of Canadian deaths per year. Nicotine vaccines present a promising alternative to traditional smoking cessation products, but to date, no vaccine has been able to move through all phases of clinical trials. We have previously demonstrated that the AFPL1-conjugate nicotine vaccine does not induce systemic or immunotoxicity in a mouse model and that a heterologous vaccination approach is more advantageous than the homologous routes to inducing mucosal and systemic anti-nicotine antibodies. The purpose of this study was to confirm the safety profile of the vaccine in a repeat-dose toxicity study. The heterologous vaccination strategy was again used, and Sprague Dawley rats were administered a dose five times greater than in our previous studies. Physiological conditions, food and water consumption, body temperature, injection site inflammation, relative weights of organs, histopathology, and blood chemistry and hematology were evaluated during the course of the vaccination period to determine the safety of the vaccine. The AFPL1-conjugate nicotine vaccine did not induce clinically relevant changes or induce symptoms that would be associated with toxicity, making it a promising candidate for future investigations.

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