RESUMEN
The aim of embryo-fetal developmental toxicity assessments for pharmaceuticals is to inform potential risk of adverse pregnancy outcome, which has traditionally relied on studies in pregnant animals. Recent updates to international safety guidelines (ICH S5R3) have incorporated information on how to use weight of evidence and alternative assays to reduce animal use while still informing risk of fetal harm. Uptake of these alternative approaches has been slow due to limitations in understanding how alternative assays translate to in vivo effects and then relevance to human exposure. To understand the predictivity of new approach methodologies for developmental toxicity (DevTox NAMs), we used two pharmaceutical examples (glasdegib and lorlatinib) to illustrate the value of DevTox NAMs to complement weight of evidence (WoE) assessments while considering the relationship of concentration-effect levels in NAMs to in vivo studies. The in vitro results generated in a battery of assays (mEST, rWEC, zebrafish, and human based stem cells) confirmed the WoE based on literature and further confirmed by preliminary embryo-fetal development data. The data generated for these two compounds supports integrating DevTox NAMs into the developmental toxicity assessment for advanced cancer indications.
RESUMEN
BACKGROUND: Abrocitinib is a Janus kinase (JAK) 1 selective inhibitor approved for the treatment of atopic dermatitis. Female reproductive tissues were unaffected in general toxicity studies, but an initial female rat fertility study resulted in adverse effects at all doses evaluated. A second rat fertility study was conducted to evaluate lower doses and potential for recovery. METHODS: This second study had 4 groups of 20 females each administered abrocitinib (0, 3, 10, or 70 mg/kg/day) 2 weeks prior to cohabitation through gestation day (GD) 7. In addition, 2 groups of 20 rats (0 or 70 mg/kg/day) were dosed for 3 weeks followed by a 4-week recovery period before mating. All mated females were evaluated on GD 14. RESULTS: No effects were observed at ≤10 mg/kg/day. At 70 mg/kg/day (29x human exposure), decreased pregnancy rate, implantation sites, and viable embryos were observed. All these effects reversed 4 weeks after the last dose. CONCLUSIONS: Based on these data and literature on the potential role of JAK signaling in implantation, we hypothesize that these effects may be related to JAK1 inhibition and, generally, that peri-implantation effects such as these, in the absence of cycling or microscopic changes in nonpregnant female reproductive tissues, are anticipated to be reversible.
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Fertilidad , Janus Quinasa 1 , Pirimidinas , Sulfonamidas , Femenino , Animales , Embarazo , Ratas , Fertilidad/efectos de los fármacos , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 1/metabolismo , Pirimidinas/farmacología , Sulfonamidas/farmacología , Ratas Sprague-Dawley , Implantación del Embrión/efectos de los fármacos , Inhibidores de las Cinasas Janus/farmacología , Índice de EmbarazoRESUMEN
Achondroplasia is an autosomal disorder caused by point mutation in the gene encoding fibroblast growth factor receptor 3 (FGFR3) and resulting in gain of function. Recifercept is a potential disease modifying treatment for achondroplasia and functions as a decoy protein that competes for ligands of the mutated FGFR3. Recifercept is intended to restore normal bone growth by preventing the mutated FGFR3 from negative inhibitory signaling in pediatric patients with achondroplasia. Here we evaluated the potential effects of twice weekly administration of recifercept to juvenile cynomolgus monkeys (approximately 3-months of age at the initiation of dosing) for 6-months. No adverse effects were noted in this study, identifying the high dose as the no-observed-adverse-effect-level and supporting the use of recifercept in pediatric patients from birth. Considering that juvenile toxicity studies in nonhuman primates are not frequently conducted, and when they are conducted they typically utilize animals ≥9 months of age, this study demonstrates the feasibility of executing a juvenile toxicity study in very young monkeys prior to weaning.
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Acondroplasia , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos , Animales , Humanos , Niño , Lactante , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/metabolismo , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/farmacología , Macaca fascicularis/metabolismo , Acondroplasia/tratamiento farmacológico , Acondroplasia/genética , Acondroplasia/metabolismo , Desarrollo Óseo , Huesos/metabolismoRESUMEN
Ervogastat (PF-06865571) is a small molecule diacylglycerol acyltransferase 2 (DGAT2) inhibitor being developed for the oral treatment of nonalcoholic steatohepatitis (NASH) with liver fibrosis. DGAT2 is a key enzyme in triglyceride synthesis in tissues and in regulating energy metabolism. Fertility and developmental toxicity studies with ervogastat were conducted in female rats and rabbits. There were no effects on female rat fertility or rabbit embryo-fetal development. Administration of ervogastat to pregnant rats during organogenesis reduced fetal weight and caused higher incidences of bent bones in fetuses that were shown to resolve by postnatal day 28 and were therefore considered to be transient variations secondary to developmental delay. Extended dosing in rats through the end of gestation and lactation (pre- and post-natal development study) caused impaired skin development, reduced offspring viability, and growth retardation. The spectrum of developmental effects in rats is consistent with the intended pharmacology (altered triglyceride metabolism) and the transient nature of the skeletal findings, along with the late gestational window of sensitivity for the effects on skin barrier development, reduce the concern for potential adverse developmental effects following unintended early gestational exposure to ervogastat in humans where treatment can be discontinued once pregnancy is determined.
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Diacilglicerol O-Acetiltransferasa , Reproducción , Animales , Diacilglicerol O-Acetiltransferasa/metabolismo , Diacilglicerol O-Acetiltransferasa/farmacología , Femenino , Fertilidad , Embarazo , Conejos , Ratas , Ratas Sprague-Dawley , TriglicéridosRESUMEN
Bococizumab is an anti-PCSK9 monoclonal antibody that was intended for the treatment of hypercholesterolemia. After reviewing the 6-month rat toxicity study data, in which there was a low spontaneous tumor incidence, unrelated to bococizumab administration, the U.S. FDA granted a carcinogenicity waiver request based on a weight-of-evidence assessment of low carcinogenic risk. Subsequently, after reviewing 6-month rat toxicity study data from another anti-PCSK9 antibody, RN317, with a similar low tumor incidence (unrelated to RN317), the U.S. FDA rescinded the bococizumab carcinogenicity study waiver and requested a full 2-year rat carcinogenicity study be conducted. The resulting 2-year carcinogenicity study demonstrated no bococizumab-related increase in tumors, confirming the weight-of-evidence evaluation and alleviating concerns regarding the carcinogenic potential. Here we report the scientific and regulatory background that led to the request for a rat carcinogenicity study, the feedback on the design of the carcinogenicity study, and the results from this study which affirmed the original weight-of-evidence assessment of low carcinogenic risk.
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Carcinógenos , Hipercolesterolemia , Animales , Anticuerpos Monoclonales/toxicidad , Pruebas de Carcinogenicidad , Carcinógenos/toxicidad , LDL-Colesterol , Proproteína Convertasa 9 , RatasRESUMEN
A maternal Group B Streptococcus (GBS) six-valent polysaccharide conjugate vaccine (GBS6) is being developed to protect neonates and infants up to 3 months of age through passive transfer of antibodies from the mother to the infant. Fertility and developmental toxicity studies were conducted in female Sprague Dawley rats and New Zealand White rabbits with GBS6 (20 µg capsular polysaccharide/serotype formulated with or without AlPO4 , the highest clinical dose). Females were administered the full human dose of the GBS6 formulation intramuscularly twice prior to mating and twice during gestation, to ensure that high antibody levels were maintained throughout gestation and lactation. Approximately, half of the rats and rabbits were evaluated at the end of gestation, and the remainder were evaluated at the end of lactation. Maternal blood for GBS6 serology, to measure antibody titers to the GBS6 antigens, was collected prior to the first dose, prior to mating, and at each necropsy. Blood for serology was also collected from offspring at the end of gestation and lactation. In both species, there was no evidence of vaccine-related effects on fertility, embryo-fetal development, or postnatal development of the offspring, supporting regulatory guidance that single-species evaluation would have been sufficient. Functional serum antibodies to all six serotypes in the vaccine were confirmed in maternal animals and functional serum antibodies to one or more of the six serotypes was also confirmed in some rat offspring and most of the rabbit offspring. The results of these studies supported the safety of GBS6 vaccine administration to pregnant women.
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Inmunización , Streptococcus agalactiae , Animales , Femenino , Fertilidad , Humanos , Polisacáridos , Embarazo , Conejos , Ratas , Ratas Sprague-Dawley , Vacunas Conjugadas/toxicidadRESUMEN
BNT162b2 is a vaccine developed to prevent coronavirus disease 2019 (COVID-19). BNT162b2 is a lipid nanoparticle formulated nucleoside-modified messenger RNA (mRNA) encoding the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein locked in its prefusion conformation. A developmental and reproductive toxicity study was conducted in rats according to international regulatory guidelines. The full human BNT162b2 dose of 30 µg mRNA/dose (>300 times the human dose on a mg/kg basis) was administered intramuscularly to 44 female rats 21 and 14 days prior to mating and on gestation days 9 and 20. Half of the rats were subject to cesarean section and full fetal examination at the end of gestation, and the other half were allowed to deliver and were monitored to the end of lactation. A robust neutralizing antibody response was confirmed prior to mating and at the end of gestation and lactation. The presence of neutralizing antibodies was also confirmed in fetuses and offspring. Nonadverse effects, related to the local injection site reaction, were noted in dams as expected from other animal studies and consistent with observations in humans. There were no effects of BNT162b2 on female mating performance, fertility, or any ovarian or uterine parameters nor on embryo-fetal or postnatal survival, growth, physical development or neurofunctional development in the offspring through the end of lactation. Together with the safety profile in nonpregnant people, this ICH-compliant nonclinical safety data supports study of BNT162b2 in women of childbearing potential and pregnant and lactating women.
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Vacunas contra la COVID-19/toxicidad , Fertilidad , Desarrollo Fetal , Animales , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Vacuna BNT162 , Vacunas contra la COVID-19/farmacología , Cesárea , Femenino , Lactancia , Embarazo , Ratas , Ratas WistarRESUMEN
Traditionally, understanding potential developmental toxicity from pharmaceutical exposures has been based on the results of ICH guideline studies in two species. However, support is growing for the use of weight of evidence approaches when communicating the risk of developmental toxicity, where the intended pharmacologic mode of action affects fundamental pathways in developmental biology or phenotypic data from genetically modified animals may increasingly be included in the overall assessment. Since some concern surrounds the use of data from knockout (KO) mice to accurately predict the risk for pharmaceutical modulation of a target, a deeper understanding of the relevance and predictivity of adverse developmental effects in KO mice for pharmacological target modulation is needed. To this end, we compared the results of embryo-fetal development (EFD) studies for 86 drugs approved by the FDA from 2017 to 2019 that also had KO mouse data available in the public domain. These comparisons demonstrate that data from KO mouse models are overall highly predictive of malformations or embryo-fetal lethality (MEFL) from EFD studies, but less so of a negative outcome in EFD studies. This information supports the use of embryo-fetal toxicity data in KO models as part of weight of evidence approaches in the communication of developmental toxicity risk of pharmaceutical compounds.
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Anomalías Inducidas por Medicamentos , Evaluación Preclínica de Medicamentos/métodos , Modelos Animales , Teratógenos/toxicidad , Animales , Embrión de Mamíferos/efectos de los fármacos , Muerte Fetal/etiología , Ratones NoqueadosRESUMEN
Acetyl-CoA carboxylase (ACC) is an enzyme within the de novo lipogenesis (DNL) pathway and plays a role in regulating lipid metabolism. Pharmacologic ACC inhibition has been an area of interest for multiple potential indications including oncology, acne vulgaris, metabolic diseases such as type 2 diabetes mellitus, and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. A critical role for ACC in de novo synthesis of long-chain fatty acids during fetal development has been demonstrated in studies in mice lacking Acc1, where the absence of Acc1 results in early embryonic lethality. Following positive predictions of developmental toxicity in the alternative in vitro assays (positive in murine embryonic stem cell [mESC] assay and rat whole embryo culture, but negative in zebrafish), developmental toxicity (growth retardation and dysmorphogenesis associated with disrupted midline fusion) was observed with the oral administration of the dual ACC1 and 2 inhibitors, PF-05175157, in Sprague Dawley rats and New Zealand White rabbits. The results of these studies are presented here to make comparisons across the assays, as well as mechanistic insights from the mESC assay demonstrating high ACC expression in the mESC and that ACC-induced developmental toxicity can be rescued with palmitic acid providing supportive evidence for DNL pathway inhibition as the underlying mechanism. Ultimately, while the battery of alternative approaches and weight-of-evidence case were useful for hazard identification, the embryo-fetal development studies were necessary to inform the risk assessment on the adverse fetal response, as malformations and/or embryo-fetal lethality were limited to doses that caused near-complete inhibition of DNL.
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Acetil-CoA Carboxilasa , Diabetes Mellitus Tipo 2 , Acetil-CoA Carboxilasa/genética , Acetil-CoA Carboxilasa/metabolismo , Animales , Lipogénesis , Ratones , Conejos , Ratas , Ratas Sprague-Dawley , Pez Cebra/metabolismoRESUMEN
Traditionally, understanding potential developmental toxicity from pharmaceutical exposures has been based on the results of ICH guideline studies in two species. However, support is growing for the use of weight of evidence approaches when communicating the risk of developmental toxicity, where the intended pharmacologic mode of action affects fundamental pathways in developmental biology or phenotypic data from genetically modified animals may increasingly be included in the overall assessment. Since some concern surrounds the use of data from knockout (KO) mice to accurately predict the risk for pharmaceutical modulation of a target, a deeper understanding of the relevance and predictivity of adverse developmental effects in KO mice for pharmacological target modulation is needed. To this end, we compared the results of embryo-fetal development (EFD) studies for 86 drugs approved by the FDA from 2017 to 2019 that also had KO mouse data available in the public domain. These comparisons demonstrate that data from KO mouse models are overall highly predictive of malformations or embryo-fetal lethality (MEFL) from EFD studies, but less so of a negative outcome in EFD studies. This information supports the use of embryo-fetal toxicity data in KO models as part of weight of evidence approaches in the communication of developmental toxicity risk of pharmaceutical compounds.
Asunto(s)
Anomalías Inducidas por Medicamentos , Evaluación Preclínica de Medicamentos/métodos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Pérdida del Embrión , Muerte Fetal , Modelos Animales , Animales , Desarrollo Embrionario/efectos de los fármacos , Desarrollo Fetal/efectos de los fármacos , Ratones NoqueadosRESUMEN
We previously observed a cutaneous type IV immune response in nonhuman primates (NHP) with the mGlu5 negative allosteric modulator (NAM) 7. To determine if this adverse event was chemotype- or mechanism-based, we evaluated a distinct series of mGlu5 NAMs. Increasing the sp3 character of high-throughput screening hit 40 afforded a novel morpholinopyrimidone mGlu5 NAM series. Its prototype, (R)-6-neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (PF-06462894, 8), possessed favorable properties and a predicted low clinical dose (2 mg twice daily). Compound 8 did not show any evidence of immune activation in a mouse drug allergy model. Additionally, plasma samples from toxicology studies confirmed that 8 did not form any reactive metabolites. However, 8 caused the identical microscopic skin lesions in NHPs found with 7, albeit with lower severity. Holistically, this work supports the hypothesis that this unique toxicity may be mechanism-based although additional work is required to confirm this and determine clinical relevance.
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Regulación Alostérica/efectos de los fármacos , Compuestos Heterocíclicos con 3 Anillos/farmacología , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Piridinas/farmacología , Piridinas/farmacocinética , Receptor del Glutamato Metabotropico 5/antagonistas & inhibidores , Receptor del Glutamato Metabotropico 5/metabolismo , Animales , Femenino , Células HEK293 , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/química , Humanos , Masculino , Simulación del Acoplamiento Molecular , Piridinas/efectos adversos , Piridinas/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
A database of embryo-fetal developmental toxicity (EFDT) studies of 379 pharmaceutical compounds in rat and rabbit was analyzed for species differences based on toxicokinetic parameters of area under the curve (AUC) and maximum concentration (Cmax) at the developmental lowest adverse effect level (dLOAEL). For the vast majority of cases (83% based on AUC of n = 283), dLOAELs in rats and rabbits were within the same order of magnitude (less than 10-fold different) when compared based on available data on AUC and Cmax exposures. For 13.5% of the compounds the rabbit was more sensitive and for 3.5% of compounds the rat was more sensitive when compared based on AUC exposures. For 12% of the compounds the rabbit was more sensitive and for 1.3% of compounds the rat was more sensitive based on Cmax exposures. When evaluated based on human equivalent dose (HED) conversion using standard factors, the rat and rabbit were equally sensitive. The relative extent of embryo-fetal toxicity in the presence of maternal toxicity was not different between species. Overall effect severity incidences were distributed similarly in rat and rabbit studies. Individual rat and rabbit strains did not show a different general distribution of systemic exposure LOAELs as compared to all strains combined for each species. There were no apparent species differences in the occurrence of embryo-fetal variations. Based on power of detection and given differences in the nature of developmental effects between rat and rabbit study outcomes for individual compounds, EFDT studies in two species have added value over single studies.
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Embrión de Mamíferos/fisiología , Desarrollo Embrionario/efectos de los fármacos , Preparaciones Farmacéuticas , Animales , Relación Dosis-Respuesta a Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Embrión de Mamíferos/efectos de los fármacos , Conejos , RatasRESUMEN
Regulatory non-clinical safety testing of human pharmaceuticals typically requires embryo-fetal developmental toxicity (EFDT) testing in two species (one rodent and one non-rodent). The question has been raised whether under some conditions EFDT testing could be limited to one species, or whether the testing in a second species could be decided on a case-by-case basis. As part of a consortium initiative, we built and queried a database of 379 compounds with EFDT studies (in both rat and rabbit animal models) conducted for marketed and non-marketed pharmaceuticals for their potential for adverse developmental and maternal outcomes, including EFDT incidence and the nature and severity of adverse findings. Manifestation of EFDT in either one or both species was demonstrated for 282 compounds (74%). EFDT was detected in only one species (rat or rabbit) in almost a third (31%, 118 compounds), with 58% (68 compounds) of rat studies and 42% (50 compounds) of rabbit studies identifying an EFDT signal. For 24 compounds (6%), fetal malformations were observed in one species (rat or rabbit) in the absence of any EFDT in the second species. In general, growth retardation, fetal variations, and malformations were more prominent in the rat, whereas embryo-fetal death was observed more often in the rabbit. Discordance across species may be attributed to factors such as maternal toxicity, study design differences, pharmacokinetic differences, and pharmacologic relevance of species. The current analysis suggests that in general both species are equally sensitive on the basis of an overall EFDT LOAEL comparison, but selective EFDT toxicity in one species is not uncommon. Also, there appear to be species differences in the prevalence of various EFDT manifestations (i.e. embryo-fetal death, growth retardation, and dysmorphogenesis) between rat and rabbit, suggesting that the use of both species has a higher probability of detecting developmental toxicants than either one alone.
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Desarrollo Fetal/efectos de los fármacos , Sustancias Peligrosas/toxicidad , Modelos Animales , Pruebas de Mutagenicidad/métodos , Teratógenos/toxicidad , Anomalías Inducidas por Medicamentos , Animales , Conejos , RatasRESUMEN
Bococizumab is a humanized monoclonal IgG2Δa antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9) for the treatment of hyperlipidemia. The evaluation of potential effects on embryo-fetal development was conducted in the rat. In a pharmacokinetic/pharmacodynamic study bococizumab was administered intravenously to pregnant Sprague-Dawley (SD) rats (n = 8/group) at 0, 10, 30, and 100 mg/kg during organogenesis. Maternal and fetal bococizumab, total cholesterol and HDL concentrations were determined. Bococizumab was well tolerated and there were no effects on ovarian or uterine parameters. Maternal and fetal bococizumab exposure increased with increasing dose, with a corresponding dose-dependent decrease in fetal cholesterol levels. Maternal cholesterol levels were decreased significantly, with reductions that were of a similar magnitude regardless of dose. In the definitive embryo-fetal development study bococizumab was administered to pregnant SD rats (n = 20/group) at 0, 10, 30, and 100 mg/kg and no adverse maternal or developmental effects were observed up to 100 mg/kg. These studies have provided an appropriate and relevant safety assessment of bococizumab in pregnant rats to inform human risk assessment, demonstrating no adverse effects on embryo-fetal development at magnitudes greater than anticipated clinical exposure and in the presence of maximal reductions in maternal cholesterol and dose-dependent reductions in fetal cholesterol.
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Anticuerpos Antiidiotipos/sangre , Anticuerpos Monoclonales Humanizados/administración & dosificación , Colesterol/sangre , Desarrollo Fetal/fisiología , Intercambio Materno-Fetal/fisiología , Serina Endopeptidasas/sangre , Animales , Anticuerpos Monoclonales Humanizados/toxicidad , Relación Dosis-Respuesta a Droga , Femenino , Desarrollo Fetal/efectos de los fármacos , Intercambio Materno-Fetal/efectos de los fármacos , Embarazo , Efectos Tardíos de la Exposición Prenatal/sangre , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Proproteína Convertasa 9 , Ratas , Ratas Sprague-DawleyRESUMEN
Three orally administered metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulators caused skin lesions consistent with delayed type-IV hypersensitivity in cynomolgus macaques in 2- and 12-week toxicity studies. Several monkeys developed macroscopic skin lesions in multiple locations after 8 to 9 days of dosing; the most prominent effects involved the genital region of males and generalized erythema occurred in both sexes. Microscopic lesions occurred in both clinically affected and unaffected areas and were characterized by lymphocytic interface inflammation, subepidermal bullae, and individual keratinocyte vacuolation/necrosis. In the 12-week study, clinical effects in 2 animals resolved with continued dosing, whereas in others the inflammatory process progressed with 1 female exhibiting systemic lymphocytic inflammation in multiple tissues. The inflammatory infiltrate consisted of CD3 and CD4 positive T lymphocytes with minimal CD68 positive macrophages and only rare CD8 positive T lymphocytes. A subset of animals given a dosing holiday was subsequently rechallenged with similar lesions developing but with a more rapid clinical onset. These skin lesions were consistent with type-IV delayed hypersensitivity with some features comparable to bullous drug eruptions in humans. A relationship between these findings and the intended mode of action for these compounds could not be ruled out, given the occurrence across different chemotypes.
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Antiparkinsonianos/toxicidad , Erupciones por Medicamentos/etiología , Erupciones por Medicamentos/patología , Compuestos Heterocíclicos con 3 Anillos/toxicidad , Compuestos Heterocíclicos de 4 o más Anillos/toxicidad , Piridinas/toxicidad , Receptor del Glutamato Metabotropico 5/antagonistas & inhibidores , Animales , Femenino , Inmunohistoquímica , Macaca fascicularis , MasculinoRESUMEN
Testicular degeneration was observed in exploratory toxicity studies in Wistar rats treated with several mGluR5 negative allosteric modulators. To determine if these testis effects were influenced by animal age, these compounds were administered to male Wistar rats of different ages (8, 10, and 12 weeks old) for 2 weeks followed by evaluation of male reproductive organ weights, testis histopathology, and inhibin B levels. Overall, seminiferous tubule degeneration was observed in 2/15, 5/15, and 0/15 compound treated rats from the 8, 10, and 12 week old cohorts and inhibin B was decreased in 8 and 10 week old animals, but not in 12 week old rats, suggesting that there is an age-related component to this testis toxicity. The gene expression profiles of drug transporters in the testis of rats aged PND 38 through PND 91 were very similar, indicating that immaturity of these transporters is an unlikely factor contributing to the age-related toxicity.
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Receptor del Glutamato Metabotropico 5/antagonistas & inhibidores , Testículo/efectos de los fármacos , Envejecimiento , Regulación Alostérica/efectos de los fármacos , Animales , Inhibinas/sangre , Masculino , Ratas , Ratas Wistar , Maduración Sexual , Testículo/crecimiento & desarrollo , Testículo/patologíaRESUMEN
Given the increasing use of Wistar Han (WH) rats in regulatory toxicology studies, these studies were performed to characterize the onset of sexual maturation in maturing WH rats as compared to Sprague-Dawley (SD) rats. Beginning on postnatal day (PND) 38 through PND 91 groups (n=8) of untreated WH rats were evaluated for maturation of the male reproductive system. Testicular spermatid head counts increased beginning on PND 42 until PND 70. Sperm were detected in the caput, corpus, and cauda epididymis on PND 45, 49, and 49, respectively, and counts increased through PND 91. Sperm motility was at adult levels by PND 63. The morphology of the testis/epididymis of all animals at day 70 or older was consistent with qualitative sexual maturity. Based on these endpoints, WH rats were determined to be sexually mature at PND 70, and many of these endpoints evaluated in SD rats exhibited nearly identical trends.
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Maduración Sexual , Animales , Epidídimo/anatomía & histología , Masculino , Tamaño de los Órganos , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Recuento de Espermatozoides , Testículo/anatomía & histologíaRESUMEN
An important aspect of the enhanced pre- and postnatal developmental (ePPND) toxicity study in nonhuman primates (NHP) is that it combines in utero and postnatal assessments in a single study. However, it is unclear if NHP ePPND studies are suitable to perform all of the evaluations incorporated into rodent PPND studies. To understand the value of including cognitive assessment in a NHP ePPND toxicity study, we performed a power analysis of object discrimination reversal task data using a modified Wisconsin General Testing Apparatus (ODR-WGTA) from two NHP ePPND studies. ODR-WGTA endpoints evaluated were days to learning and to first reversal, and number of reversals. With α = 0.05 and a one-sided t-test, a sample of seven provided 80% power to predict a 100% increase in all three of the ODR-WGTA endpoints; a sample of 25 provided 80% power to predict a 50% increase. Similar power analyses were performed with data from the Cincinnati Water Maze (CWM) and passive avoidance tests from three rat PPND toxicity studies. Groups of 5 and 15 in the CWM and passive avoidance test, respectively, provided 80% power to detect a 100% change. While the power of the CWM is not far superior to the NHP ODR-WGTA, a clear advantage is the routine use of larger sample size, with a group of 20 rats the CWM provides ~90% power to detect a 50% change. Due to the limitations on the number of animals, the ODR-WGTA may not be suitable for assessing cognitive impairment in NHP ePPND studies.
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Trastornos del Conocimiento/diagnóstico , Discriminación en Psicología , Desarrollo Embrionario , Macaca fascicularis/embriología , Macaca fascicularis/crecimiento & desarrollo , Estadística como Asunto , Animales , Animales Recién Nacidos , Reacción de Prevención , Femenino , Masculino , Aprendizaje por Laberinto , Ratas , Ratas Sprague-Dawley , Tamaño de la Muestra , Análisis y Desempeño de TareasRESUMEN
BACKGROUND: Sunitinib (SUTENT, Pfizer Inc., New York, NY) is a multitargeted inhibitor of selected receptor tyrosine kinases, which produces an antiproliferative and antiangiogenic effect by blocking pathways fundamental to tumor growth and survival. We investigated the effects of sunitinib on male and female fertility and early embryonic development in the rat. METHODS: In the female fertility and early embryonic development phase, untreated males were paired with treated females dosed at 0 (control), 0.5, 1.5, and 5 mg/kg/day from 14 days premating, through mating, to gestation day 7. In the male fertility phase, the same males were then treated 58 days at doses of 0 (control), 1, 3, and 10 mg/kg/day, mated with untreated females, with continued daily dosing for a total of 74 days. RESULTS: There was no systemic toxicity- or treatment-related effects on fertility in female rats. Females exposed at 5 mg/kg/day had an increase in the number of early resorptions with associated decrease in viable embryos. In the males, body weight and food consumption were decreased at 10 mg/kg/day compared to the controls. Male reproductive capacity, as assessed by copulation, fertility, and conception indices, was not impacted at any dose level. Sperm morphology, concentration, and motility were also unaffected by treatment. CONCLUSIONS: There were no effects on male reproduction. An increase in corpora lutea and an increase in early resorptions with associated reduction in viable embryos was noted in the females dosed 5 mg/kg/day. Sunitinib at doses up to 1.5 and 10 mg/kg/day had no effects on female and male reproduction, respectively.
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Indoles/toxicidad , Inhibidores de Proteínas Quinasas/toxicidad , Pirroles/toxicidad , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Reproducción/efectos de los fármacos , Pruebas de Toxicidad/métodos , Animales , Peso Corporal/efectos de los fármacos , Desarrollo Embrionario/efectos de los fármacos , Epidídimo/anatomía & histología , Epidídimo/efectos de los fármacos , Ciclo Estral/efectos de los fármacos , Femenino , Fertilidad/efectos de los fármacos , Masculino , Tamaño de los Órganos/efectos de los fármacos , Embarazo , Ratas , Ratas Sprague-Dawley , Espermatozoides/efectos de los fármacos , Espermatozoides/metabolismo , Sunitinib , Testículo/anatomía & histología , Testículo/efectos de los fármacosRESUMEN
The critical periods of axial skeletal development in rats and mice have been well characterized, however the timing of skeletal development in rabbits is not as well known. It is important to have a more precise understanding of this timing of axial skeletal development in rabbits due to the common use of this species in standard nonclinical studies to assess embryo-fetal developmental toxicity. Hydroxyurea, a teratogen known to induce a variety of fetal skeletal malformations, was administered to New Zealand White rabbits as a single dose (500 mg/kg) on individual days during gestation (gestation day, GD 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 19) and fetal external, visceral, and skeletal morphology was examined following cesarean sections on GD 29. A wide range of fetal skeletal effects was observed following hydroxyurea treatment, with a progression of malformations from anterior to posterior structures over time, as well as from proximal to distal structures over time. The sensitive window of axial skeletal development was determined to be GD 8 to 13, while disruption of appendicular and cranio-facial skeletal development occurred primarily from GD 11 to 16 and GD 11 to 12, respectively. The results of this study provide a better understanding of the critical developmental window for different segments of the rabbit skeleton, which will aid in the design of window studies to investigate teratogenicity in rabbits.