ABSTRACT
Glomerulopathy and body weight gain were noted after chronic oral administration of a novel nonsteroidal dissociated agonist of the glucocorticoid receptor compound, fosdagrocorat, to beagle dogs fed an ad libitum diet. To further investigate the role of diet and treatment with either fosdagrocorat or the glucocorticoid comparator, prednisone, on renal safety, a 13-week investigative study was conducted in beagle dogs. Renal histopathology, clinical chemistry, urinalysis, glomerular filtration rate (GFR), body weight, heart rate, blood pressure (BP), and hematology were investigated in restricted- and ad libitum-fed dogs administered prednisone (2.2 mg/kg/d), fosdagrocorat (5 mg/kg/d), or vehicle for 13 weeks. Glomerulopathy was primarily observed in fosdagrocorat- and prednisone-treated ad libitum but not in feed-restricted or ad libitum vehicle-treated dogs. Kidneys in dogs from the prednisone-treated ad libitum had the greatest incidence and severity of tubular degenerative changes. Increased urine volume and decreased urine-specific gravity were present in prednisone- and fosdagrocorat-treated dogs, regardless of diet. These changes were not associated with consistent changes in GFR. Fosdagrocorat or prednisone treatment ad libitum dogs had the greatest increase in body weight gain. Sporadic changes in systolic and diastolic BP were noted in fosdagrocorat- and prednisone-treated groups. Significant reductions in serum cortisol and absolute eosinophils were noted in both ad libitum- and restriction-fed prednisone- and fosdagrocorat-treated dogs. In conclusion, prednisone-treated dogs fed ad libitum had greater glucocorticoid-induced renal effects than those dosed with fosdagrocorat.
Subject(s)
Kidney/drug effects , Organophosphates/pharmacology , Phenanthrenes/pharmacology , Prednisone/pharmacology , Receptors, Glucocorticoid/agonists , Animals , Blood Pressure/drug effects , Body Weight/drug effects , Dogs , Eating/drug effects , Female , Food Deprivation , Glomerular Filtration Rate/drug effects , Heart Rate/drug effects , Kidney/pathology , Organophosphates/administration & dosage , Organophosphates/adverse effects , Phenanthrenes/administration & dosage , Phenanthrenes/adverse effects , Prednisone/adverse effects , Receptors, Glucocorticoid/drug effectsABSTRACT
Signaling through the erbB receptor family of tyrosine kinases contributes to the proliferation, differentiation, migration, and survival of a variety of cell types. Abnormalities in members of this receptor family have been shown to play a role in oncogenesis, thus making them attractive targets for anticancer treatments. PF-00299804 is a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor currently in phase I clinical trials. PF-00299804 is believed to irreversibly inhibit erbB tyrosine kinase activity through binding at the ATP site and covalent modification of nucleophilic cysteine residues in the catalytic domains of erbB family members. Oral administration of PF-00299804 causes significant antitumor activity, including marked tumor regressions in a variety of human tumor xenograft models that express and/or overexpress erbB family members or contain the double mutation (L858R/T790M) in erbB1 (EGFR) associated with resistance to gefitinib and erlotinib. Furthermore, PF-00299804 shows exceptional distribution to human tumor xenografts and excellent pharmacokinetic properties across species.
Subject(s)
Antineoplastic Agents/pharmacology , Antineoplastic Agents/pharmacokinetics , Quinazolinones/pharmacology , Quinazolinones/pharmacokinetics , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Xenograft Model Antitumor Assays , Amino Acid Substitution , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , ErbB Receptors/metabolism , Female , Humans , Mice , Mice, SCID , Mutation/genetics , Phosphorylation/drug effects , Species SpecificityABSTRACT
Renal dysplasia is a congenital renal malformation characterized by disruption of normal renal development with asynchronous differentiation of nephrons, collecting ducts, and parenchyma and abnormal patterning of cortical and medullary tissues. The present article describes unilateral renal dysplasia discovered in a cynomolgus monkey from a routine toxicology study. The affected kidney was small and characterized by extensive interstitial fibrosis with the formation of fibromuscular collars around glomeruli and tubules, immature nephrons, and persistent mesenchyme encompassing few collecting ducts. The present case is remarkable in that there is a paucity of reports describing histopathologic findings of spontaneously occurring renal dysplasia in preclinical test species for use in large animal toxicity studies.
Subject(s)
Kidney Diseases/congenital , Kidney Diseases/pathology , Kidney Diseases/veterinary , Monkey Diseases/congenital , Animals , Macaca fascicularis , Male , Monkey Diseases/pathologyABSTRACT
The discovery of two histamine H(3) antagonist clinical candidates is disclosed. The pathway to identification of the two clinical candidates, 6 (PF-03654746) and 7 (PF-03654764) required five hypothesis driven design cycles. The key to success in identifying these clinical candidates was the development of a compound design strategy that leveraged medicinal chemistry knowledge and traditional assays in conjunction with computational and in vitro safety tools. Overall, clinical compounds 6 and 7 exceeded conservative safety margins and possessed optimal pharmacological and pharmacokinetic profiles, thus achieving our initial goal of identifying compounds with fully aligned oral drug attributes, "best-in-class" molecules.