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Morford L.L.,Lilly Research Laboratories | Bowman C.J.,Pfizer | Bogh I.B.,Novo Nordisk AS | Chellman G.J.,Charles River Preclinical Services | And 3 more authors.
Birth Defects Research Part B - Developmental and Reproductive Toxicology

Evaluation of pharmaceutical agents in children is now conducted earlier in the drug development process. An important consideration for this pediatric use is how to assess and support its safety. This article is a collaborative effort of industry toxicologists to review strategies, challenges, and current practice regarding preclinical safety evaluations supporting pediatric drug development with biopharmaceuticals. Biopharmaceuticals include a diverse group of molecular, cell-based or gene therapeutics derived from biological sources or complex biotechnological processes. The principles of preclinical support of pediatric drug development for biopharmaceuticals are similar to those for small molecule pharmaceuticals and in general follow the same regulatory guidances outlined by the Food and Drug Administration and European Medicines Agency. However, many biopharmaceuticals are also inherently different, with limited species specificity or immunogenic potential which may impact the approach taken. This article discusses several key areas to aid in the support of pediatric clinical use, study design considerations for juvenile toxicity studies when they are needed, and current practices to support pediatric drug development based on surveys specifically targeting biopharmaceutical development. © 2011 Wiley-Liss, Inc. Source

Ganderup N.C.,Ellegaard Gottingen Minipigs | Harvey W.,Charles River Preclinical Services | Mortensen J.T.,CiToxLAB Scantox | Harrouk W.,U.S. FDA
International Journal of Toxicology

Over the past 3 decades minipigs have moved from being an obscure alternative to dogs and nonhuman primates to being a standard animal model in regulatory toxicity studies. This article covers the use of minipigs as a model in the context of nonclinical drug safety and provides an overview of the minipig's developmental history and relates minipigs to other animal species commonly used in toxicology; and the minipig's translational power is supported by 43 case studies of marketed drug products covered. Special focus is given to criteria for selecting minipigs in nonclinical programs supporting the development of new medicines; the use of swine in the assessment of food additives, agrochemicals, and pesticides; as well as a regulatory perspective on the use of minipigs in Food and Drug Administration (FDA)-regulated products. This article presents the main points conveyed at a symposium held at the 2010 American College of Toxicology meeting in Baltimore, Maryland. © 2012 The Author(s). Source

Beckman D.,Novartis | Barbeau S.,Charles River Preclinical Services | Mclean L.A.,Novartis | Yan J.-H.,Novartis | Hoffmann P.,Novartis
Birth Defects Research Part B - Developmental and Reproductive Toxicology

BACKGROUND: Aliskiren is the first orally bioavailable direct renin inhibitor approved for the treatment of hypertension in adults. Juvenile toxicity studies in rats were initiated to support treatment in the pediatric population. METHODS: In Study 1, aliskiren oral administration was initiated on postpartum day (PPD) 14, after nephrogenesis was completed, and continued through PPD 70 at doses of 0, 30, 100, and 300 mg/kg/day. In-life, clinical pathology, anatomic pathology, developmental, behavioral, reproductive, and toxicokinetics evaluations were performed. In Study 2, oral administration was initiated on PPD 8, before completion of nephrogenesis, and continued through PPD 35/36. In-life, clinical pathology, anatomic pathology, developmental, and toxicokinetics evaluations were performed. RESULTS: With dosing initiated on PPD 8, mortality at 100 and 300 mg/kg/day and slightly increased kidney weight at 100 mg/kg/day occurred. Decreased absolute lymphocyte count at 300 mg/kg/day at the end of dosing occurred with dosing initiated on PPD 14. There were clinical signs and transient effects on body weight gains in both studies. There were no changes in other parameters. Systemic exposure was much higher on PPD 8 and 14 compared with adult rats on PPD 64. CONCLUSIONS: All effects produced by aliskiren, including kidney effects, were reversible. Increased exposure in very young animals is considered to be the result of immature drug transporter systems. © 2014 Wiley Periodicals, Inc. Source

Perin E.C.,Texas Heart Institute | Silva G.V.,Texas Heart Institute | Vela D.C.,Texas Heart Institute | Zheng Y.,Texas Heart Institute | And 7 more authors.
Journal of Cardiac Failure

Background: Hepatocyte growth factor (HGF) may stimulate angiogenesis. We examined the safety and therapeutic potential of the HGF plasmid (VM202) in pigs with chronic myocardial ischemia. Methods and Results: We delivered VM202 or vehicle transendocardially to 4 groups of pigs: vehicle control (n = 9); high-dose VM202 (n = 9); low-dose VM202 (n = 3); and normal control (no ischemia; n = 1). Pigs were killed 3, 30, and 60 days after injection. No adverse events were associated with VM202 treatment or delivery. Quantitative polymerase chain reaction indicated that heart injection sites had the highest levels of VM202 (day 3), which became almost undetectable by 30-60 days. Most nontarget tissues showed clearance of VM202 plasmid by day 30. Control and VM202-treated pigs did not differ in global functional data. Dobutamine-stressed myocardial-contrast echocardiogram suggested that VM202 may help preserve microvascular perfusion at 30 days; reperfusion velocity in ischemic myocardium decreased significantly in control (baseline to follow-up, 5.1 ± 1.9 to 2.7 ± 1.0; P = .031) but not in VM202 groups (high-dose: 3.1 ± 1.1 vs 3.1 ± 1.5 [P = .511]; low-dose: 3.8 ± 1.1 vs 3.9 ± 1.5 [P = .559]). Linear local shortening increased significantly from day 0 to 30 in VM202-treated versus control pigs (5.0 ± 4.7% vs 9.2 ± 7.5% vs 0.9 ± 5.8% [high-dose, low-dose, control, respectively]; P = .021). Conclusions: Transendocardial delivery of VM202 was safe and may help to preserve microcirculatory perfusion and improve wall motion. © 2011 Elsevier Inc. All rights reserved. Source

Smith S.Y.,Charles River Preclinical Services | Jolette J.,Charles River Preclinical Services | Chouinard L.,Charles River Preclinical Services | Komm B.S.,Pfizer
Journal of Bone and Mineral Metabolism

Bazedoxifene (BZA) is a novel selective estrogen receptor modulator in clinical development for the prevention and treatment of postmenopausal osteoporosis. This preclinical study evaluated the efficacy and safety of BZA in preventing ovariectomy (OVX)-induced bone loss in aged cynomolgus monkeys. Animals (18 per group) underwent OVX and were administered BZA (0.2, 0.5, 1, 5, or 25 mg/kg/day) or vehicle, or were sham-operated and administered vehicle, by daily oral gavage for 18 months. Biochemical markers of bone turnover were assessed at 6, 12, and 18 months, along with bone densitometry using dual energy X-ray absorptiometry and peripheral quantitative computed tomography. Animals were killed after 18 months. Uterine and pituitary weights were determined, and histomorphometric and biomechanical measurements were performed. OVX vehicle controls showed increases in bone turnover associated with cancellous and cortical bone osteopenia (in vivo), and slight decreases (not statistically significant) in biomechanical strength parameters at the lumbar spine and femoral neck. BZA partially preserved cortical and cancellous bone mass by preventing the OVX-induced increases in bone turnover. Although the response was often similar among BZA-treated groups, the strongest efficacy was generally seen at 25 mg/kg/day. Treatment with BZA did not adversely affect measures of bone strength and was well tolerated; there was no evidence of uterotrophic activity, mammary tissue was unaffected, and there were no adverse effects on plasma lipids. Treatment of ovariectomized animals with BZA partially prevented changes in bone remodeling that correlated with increases in bone mineral density, while maintaining bone strength and a favorable safety profile. © 2014 The Japanese Society for Bone and Mineral Research and Springer Japan. Source

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