Embryo-fetal developmental toxicity study design for pharmaceuticals.

Assessment of potential developmental and reproductive toxicity of human pharmaceuticals is currently guided by the International Conference on Harmonization (ICH) S5(R2) document (available at http://www.ich.org). The studies that assess developmental hazard are generally conducted in rodents and rabbits. Based on the authors' collective experience, adequate designs (including range-finding studies) and the presentation of data for these studies are described in detail. In addition, the suggested initiation and then total duration of these studies in relation to clinical studies that enroll women of childbearing potential are described. Optional parameters that may be included in the studies are discussed, as are study designs that combine assessments of fertility and developmental toxicity. New methods that may replace or enhance current procedures are outlined. The details described herein will assist all laboratories performing these studies, individuals who need to plan for the studies, and regulatory agencies that ultimately review these studies.

Juvenile animal toxicity study designs to support pediatric drug development.

The objective of juvenile animal toxicity studies of pharmaceuticals is to obtain safety data, including information on the potential for adverse effects on postnatal growth and development. Studies in juvenile animals may assist in identifying postnatal developmental toxicities or other adverse effects that are not adequately assessed in the routine toxicity evaluations and that cannot be safely or adequately measured in pediatric clinical trials. Unlike the traditional reproductive and developmental toxicology studies that have been discussed in the accompanying reports, the design requirements for toxicity studies in juvenile animals are not explicitly defined in regulatory guidance. However, studies in juvenile animals can be useful in providing safety information necessary to enable pediatric clinical trials in pediatric patients or when there are special concerns for toxicities that cannot be safely or adequately measured in clinical trials. These juvenile animal toxicity studies are designed on a case-by-case basis. General design considerations and examples of study designs for assessment of juvenile animal toxicity are discussed.

Hematology and clinical chemistry values in pregnant Wistar Hannover rats compared with nonmated controls.

BACKGROUND: The Wistar Hannover rat has been considered as an alternative animal model to the Sprague-Dawley rat in the safety evaluation of candidate pharmaceuticals for potential reproductive and developmental toxicity. Hematology and clinical chemistry results may provide useful evidence of maternal toxicity in the absence of fetal effects. OBJECTIVE: The purpose of this study was to evaluate differences in routine laboratory values between nonmated and pregnant (near-term)Wistar Hannover rats during a control developmental study. METHODS: One hundred fifty pregnant female Wistar Hannover rats (Tac:Glx:WlfBR) were dosed orally once per day with distilled water from gestation days (GDs) 6 through 17. An additional 150 nonmated (nonpregnant) females used as age-matched controls were dosed from study days (SDs) 7 through 18. Blood samples were collected on GD 18 or 19 (SD 19 or 20) for routine hematology and plasma clinical chemistry tests. Reference intervals were established for pregnant and nonmated animals. RESULTS: On GD 18/19, pregnant rats had a lower RBC count, hemoglobin concentration, and HCT, and higher MCH, MCHC, reticulocyte percentage, and platelet, WBC, absolute reticulocyte, segmented neutrophil, lymphocyte, and monocyte counts compared with nonmated rats. Pregnant rats had lower albumin, glucose, urea, and chloride concentrations, lower creatine kinase and alkaline phosphatase activities, higher total bilirubin, cholesterol, triglyceride, calcium, phosphorus, and globulin concentrations, and higher ALT activity than nonmated rats. Serum triglyceride concentration was approximately fourfold higher in pregnant rats compared with nonmated controls. CONCLUSION: Differences in hematology and chemistry values in pregnant Wistar Hannover rats are similar to those in Sprague-Dawley rats and support use of the Wistar Hannover rat as an animal model in the assessment of maternal toxicity. Differences in laboratory values of pregnant rats should be considered when interpreting data following exposure to candidate pharmaceuticals.

An oral (gavage) control embryo-fetal development study in the Wistar Hannover rat.

Many of the studies conducted to examine the developmental and reproductive toxicity potential of candidate pharmaceuticals use the Sprague-Dawley rat as the animal model. This is due in part to the large database for this outbred rat available for comparison of litter data, and the low incidence of fetal malformations and variations. The following study was conducted to generate information on potential embryo-fetal developmental defects and litter data in another outbred stock of rat, the Wistar Hannover. One hundred fifty pregnant female Wistar Hannover rats (Tac:Glx:WIfBR) were dosed orally once per day with distilled water from Gestation Days (GD) 6 through 17 covering the time from implantation to closure of the hard palate (GD0 = day of insemination). Caesarean sections were performed on Day 20 of gestation. All fetuses were examined for external, visceral and skeletal malformations and variations. Macroscopic and histomorphologic examinations were also completed for the F0 females at termination. The percent pregnant (88%) and litter size (average 10.6) were found to be lower than that commonly reported for the Sprague-Dawley rat (Crl:CD (SD)BR; 95.4% and 14.6, respectively). Pre-implantation loss (14.1%), post-implantation loss (7.4%) and percent resorptions (7.2%) occurred at a higher incidence than typically seen in the Sprague-Dawley rat (5.9, 5.6 and 5.1%, respectively). The average fetal body weights for both the female and male rats were lower than those typically seen in the Sprague-Dawley rat. External, visceral and skeletal examination of the F1 fetuses revealed numerous malformations and variations which also occurred at higher incidences than those reported for the Sprague-Dawley rat. Routine macroscopic and histomorphologic examination showed there were no changes that would be interpreted to have impaired mating performance, fertility or gestation. Thus, this study provides information on the reproductive effects and the background incidence of embryo-fetal development defects that could be used for comparison to those identified when using this outbred rat for developmental and reproductive toxicity studies, as well as for comparison to the more commonly used rat stock, the Sprague-Dawley rat. For the parameters evaluated, the Wistar Hannover rat had greater variability and an increased incidence of spontaneous malformations as compared to the Crl:CD (SD)BR Sprague-Dawley rat. These findings should be considered if this stock of rat is selected in the conduct of developmental and reproductive toxicity studies.