CiToxLAB France

Évreux, France

CiToxLAB France

Évreux, France
SEARCH FILTERS
Time filter
Source Type

Dagher R.,Genzyme | Dagher R.,Catabasis Pharmaceuticals, Inc. | Watzinger M.,CiToxLAB France | Watzinger M.,Galapagos | And 4 more authors.
Regulatory Toxicology and Pharmacology | Year: 2015

Eliglustat is a novel glucosylceramide synthase inhibitor for long-term oral treatment of type 1 Gaucher disease (GD1), an inherited metabolic disorder. The carcinogenic potential of this drug has been evaluated in lifetime carcinogenicity bioassays in mice and rats. Administration of eliglustat to Swiss CD-1 mice at 0, 10, 25 or 75 mg/kg/day for 104 weeks by dietary admixture did not influence survival or bodyweight evolution, or produce any clinical indication of poor condition. At histopathology, no increases in tumor incidence for any tumor type were attributed to treatment with eliglustat. Systemic exposure to eliglustat was confirmed by a reduction in circulating levels of glucosylceramide. Administration of eliglustat to Sprague-Dawley rats by oral gavage for 105 weeks at 0, 10, 25 or 75 mg/kg/day (males) or 103 weeks at 0, 5, 15 or 50 mg/kg/day (females) did not affect survival rates, but resulted in reduced bodyweight evolution in male rats (-18% at high dose), indicating that the MTD had been achieved. At histopathology, no increases in tumor incidence were attributed to treatment with eliglustat. Systemic exposure was confirmed by toxicokinetic analyses. In conclusion, eliglustat was not carcinogenic to mice or rats in standard lifetime bioassays. © 2015 Elsevier Inc.


PubMed | TNO, CiToxLAB France and GSK Vaccines
Type: Journal Article | Journal: Journal of applied toxicology : JAT | Year: 2016

Combination of tumor antigens with immunostimulants is a promising approach in cancer immunotherapy. We assessed animal model toxicity of AS15 combined with various tumor antigens: WT1 (rabbits), or p501, dHER2 and recPRAME (cynomolgus monkeys), administered in seven or 20 dose regimens versus a saline control. Clinical and ophthalmological examinations, followed by extensive post-mortem pathological examinations, were performed on all animals. Blood hematology and biochemistry parameters were also assessed. Antigen-specific antibody titers were determined by enzyme-linked immunosorbent assay. Additional assessments in monkeys included electrocardiography and immunohistochemical evaluations of the p501 expression pattern. Transient increases in body temperature were observed 4 h or 24 h after injections of recPRAME+AS15 and dHER2+AS15. Edema and erythema were observed up to 1 week after most injections of recPRAME+AS15 and all injections of dHER2+AS15. No treatment-related effects were observed for electrocardiography parameters. Mean fibrinogen levels were significantly higher in all treated groups compared to controls, but no differences could be observed at the end of the treatment-free period. Transient but significant differences in biochemistry parameters were observed post-injection: lower albumin/globulin ratios (p501+AS15), and higher bilirubin, urea and creatinine (dHER2+AS15). Pathology examinations revealed significant increases in axillary lymph node mean weights (recPRAME+AS15) compared to controls. A 100% seroconversion rate was observed in all treated groups, but not in controls. p501 protein expression was observed in prostates of all monkeys from studies assessing p501+AS15. These results suggest a favorable safety profile of the AS15-containing candidate vaccines, supporting the use of AS15 for clinical development of potential anticancer vaccines.


PubMed | Genzyme and CiToxLAB France
Type: Journal Article | Journal: Regulatory toxicology and pharmacology : RTP | Year: 2015

Eliglustat is a novel glucosylceramide synthase inhibitor for long-term oral treatment of type 1 Gaucher disease (GD1), an inherited metabolic disorder. The carcinogenic potential of this drug has been evaluated in lifetime carcinogenicity bioassays in mice and rats. Administration of eliglustat to Swiss CD-1 mice at 0, 10, 25 or 75 mg/kg/day for 104 weeks by dietary admixture did not influence survival or bodyweight evolution, or produce any clinical indication of poor condition. At histopathology, no increases in tumor incidence for any tumor type were attributed to treatment with eliglustat. Systemic exposure to eliglustat was confirmed by a reduction in circulating levels of glucosylceramide. Administration of eliglustat to Sprague-Dawley rats by oral gavage for 105 weeks at 0, 10, 25 or 75 mg/kg/day (males) or 103 weeks at 0, 5, 15 or 50 mg/kg/day (females) did not affect survival rates, but resulted in reduced bodyweight evolution in male rats (-18% at high dose), indicating that the MTD had been achieved. At histopathology, no increases in tumor incidence were attributed to treatment with eliglustat. Systemic exposure was confirmed by toxicokinetic analyses. In conclusion, eliglustat was not carcinogenic to mice or rats in standard lifetime bioassays.


Forster R.,CiToxLAB France | Bourtourault M.,Armor Proteines | Chung Y.J.,Nestlé | Silvano J.,CiToxLAB France | And 5 more authors.
Regulatory Toxicology and Pharmacology | Year: 2014

TM0601p is a whey protein isolate derived from cow milk, containing a concentrated amount of transforming growth factor β2 (TGF-β2), and is intended for nutritional use in infants and adults. In vivo and in vitro studies have been performed to evaluate the safety of this product. In a 13-week toxicity study, treatment of adult Sprague-Dawley rats by gavage at up to 2000. mg/kg/day did not result in any significant findings other than minor non-adverse changes in urinary parameters in females. The no-observed-adverse-effect level (NOAEL) was established as 2000. mg/kg/day. In a juvenile toxicity study, rat pups received 600. mg/kg/day by gavage from postnatal day (PND) 7 to PND 49. Transient lower bodyweight gain in the pre-weaning period was attributed to gastrointestinal effects of the viscous test material; following weaning, bodyweight gain was comparable to the vehicle controls. Reduced eosinophil counts and changes in urinary parameters (females) were recorded in treated pups at PND 49, and higher thymus weights were recorded in males only at the end of the recovery period (Day 77). None of the findings were considered adverse. There were no other significant findings and the NOAEL was established as 600. mg/kg/day. No evidence of genotoxicity was seen in the bacterial reverse mutation test or the in vitro micronucleus test. Overall the results obtained present a reassuring safety profile for TM0601p. © 2014 Elsevier Inc.


Fonsi M.,CiToxLAB France
Drug Metabolism Letters | Year: 2014

As the liver is generally considered the organ most involved in metabolic transformations, metabolism in other organs is often overlooked and in vitro screening systems largely adopted in drug discovery are generally based on liver tissue fractions. First pharmacokinetics of new chemical entities (NCEs) are initially based on preclinical species; rat is used in the majority of the cases to assess early in vitro-in vivo correlation (IVIVC). It is important, in this perspective, to address as early as possible the relevant differences between rat and human and the limits using pharmacokinetic studies in this species as a model for the human PK. In this paper the author reports at least three clear examples in drug discovery where the use of hepatic in-vitro systems resulted in a very poor IVIVC due to relevant extrahepatic metabolism in rats. © 2014 Bentham Science Publishers.


PubMed | CiToxLAB France
Type: Journal Article | Journal: Journal of immunotoxicology | Year: 2013

Limited non-clinical immunotoxicity data are available in the dog, although this is a major non-rodent species in regulatory safety studies. The present study aimed to test whether widely accepted immunotoxicity endpoints including lymphocyte subset immunophenotyping, the anti-KLH TDAR assay, and histological examination of the main lymphoid organs were reliable to detect immunosuppression induced by cyclosporine and cyclophosphamide in dogs and could, therefore, be used for non-clinical immunotoxicity evaluation in this species. Male and female Beagle dogs were treated orally from Day 1 for 4 weeks with 25mg/kg cyclosporine daily, or with 2mg/kg cyclophosphamide on 4 consecutive days each week, or the same volume of drinking water daily. Blood samples were withdrawn pre-test and on Days 11, 18, and 23 to measure standard hematology parameters and analyze lymphocyte subsets. All animals received an intramuscular injection of 5mg KLH on Day 11. Sandwich ELISA assays were used to quantify anti-KLH IgM and anti-KLH IgG levels in blood samples taken pre-test, on Days 18 and 23, and pre-test, on Days 23 and 28, respectively. At the end of the treatment period, all animals were submitted to histological examination of lymphoid organs, liver, and kidneys. No signs of marked toxicity were observed. No changes in lymphocyte subsets, but markedly decreased primary anti-KLH IgM and IgG responses, and a slightly-to-markedly increased cortex/medulla ratio in the thymus were observed in cyclosporine-treated dogs. Lower total WBC counts correlating with lower total and B-lymphocyte subset and decreased germinal center development in mesenteric lymph nodes, but no changes in primary anti-KLH IgM and IgG responses were observed in cyclophosphamide-treated dogs. These results demonstrate that widely accepted immunotoxicity endpoints can adequately detect the effects of known immunosuppressive drugs in the dog and support the conclusion that it is a relevant animal species for immunotoxicity evaluation.


PubMed | CiToxLAB France
Type: Journal Article | Journal: Journal of pharmacological and toxicological methods | Year: 2012

During the development of a new vaccine, the purpose of nonclinical studies is to provide safety information to support the clinical development and licensure of the product. In this article the study designs currently accepted for the nonclinical safety testing of new vaccines are described for single dose, local tolerance, repeat dose toxicity and safety pharmacology studies; these studies together form the basis of a typical nonclinical safety evaluation dossier. The detailed design of the preclinical package must take account of the intended clinical use, patient population, route of administration, formulation, dose level and immunisation schedule. The test item that is used for these studies must be adequately representative of the intended clinical formulation. The animal model used for these studies must be selected on criteria of relevance. Single dose toxicity studies provide information on acute actions or the potential effect of accidental overdose, but this information is often available from the repeat dose toxicity study, obviating the need for the acute study. Local tolerance studies provide information on tissue reactions at the site of administration. Evaluation of the findings must distinguish between normal tissue responses to injected material and findings indicative of undesirable pathological changes. The repeated dose toxicity studies are the principal studies that support the safety profile of the vaccines. The design of these studies must take full account of the features of the vaccine in the choice of treatment regime, dose levels, pharmacodynamic monitoring and timing of investigations and sacrifice. Safety pharmacology studies are performed to evaluate the potential for undesirable secondary pharmacological actions of vaccines if there is data to suggest that such studies are needed; this evaluation is made on a case by case basis. In the absence of specific guidance the design of studies for therapeutic vaccines follows the same general principles as those for anti-infective vaccines.


PubMed | CiToxLAB France
Type: Journal Article | Journal: Drug metabolism letters | Year: 2014

As the liver is generally considered the organ most involved in metabolic transformations, metabolism in other organs is often overlooked and in vitro screening systems largely adopted in drug discovery are generally based on liver tissue fractions. First pharmacokinetics of new chemical entities (NCEs) are initially based on preclinical species; rat is used in the majority of the cases to assess early in vitro-in vivo correlation (IVIVC). It is important, in this perspective, to address as early as possible the relevant differences between rat and human and the limits using pharmacokinetic studies in this species as a model for the human PK. In this paper the author reports at least three clear examples in drug discovery where the use of hepatic in-vitro systems resulted in a very poor IVIVC due to relevant extrahepatic metabolism in rats.

Loading CiToxLAB France collaborators
Loading CiToxLAB France collaborators