PURPOSE: A toxicology and pharmacokinetic study of orally administered (po) IPdR (5-3iodo-2-pyrimidinone-2'deoxyribose, NSC-726188) was performed in Fischer-344 rats using a once daily (qd) x 28 days dosing schedule as proposed for an initial phase I clinical trial of IPdR as a radiosensitizer. METHODS: For the toxicology assessment, 80 male and female rats (10/sex/dosage group) were randomly assigned to groups receiving either 0, 0.2, 1.0 or 2.0 g kg(-1)day(-1) of po IPdR x 28 days and one-half were observed to day 57 (recovery group). Animals were monitored for clinical signs during and following treatment with full necropsy of one-half of each dosage group at day 29 and 57. For the plasma pharmacokinetic assessment, 40 rats (10/sex/dosage group) were randomly assigned to groups receiving either 0.2 or 1.0 g kg(-1)day(-1) of po IPdR x 28 days with multiple blood samplings on days 1 and 28 and single blood sampling on days 8 and 15. RESULTS: No drug-related deaths occurred. Higher IPdR doses resulted in transient weight loss and transient decreased hemoglobins but had no effect on white cells or platelets. Complete serum chemistry evaluation showed transient mild decreases in total protein, alkaline phosphatase, and serum globulin. Necropsy evaluation at day 29 showed minimal to mild histopathologic changes in bone marrow, lymph nodes and liver; all reversed by day 59. There were no sex-dependent differences in plasma pharmacokinetics of IPdR noted and the absorption and elimination kinetics of IPdR were found to be linear over the dose range studied. CONCLUSIONS: A once-daily dosing schedule of po IPdR for 28 days with doses up to 2.0 g kg(-1)day(-1) appeared to be well tolerated in Fischer-344 rats. Drug-related weight loss and microscopic changes in bone marrow, lymph nodes and liver were observed. These changes were all reversed by day 57. IPdR disposition was linear over the dose range used. However, based on day 28 kinetics it appears that IPdR elimination is enhanced following repeated administration. These toxicology and pharmacokinetic data were used when considering the design of our initial phase I trial of po IPdR as a clinical radiosensitizer.
PURPOSE: A toxicology and pharmacokinetic study of orally administered (po) IPdR (5-3iodo-2-pyrimidinone-2'deoxyribose, NSC-726188) was performed in Fischer-344 rats using a once daily (qd) x 28 days dosing schedule as proposed for an initial phase I clinical trial of IPdR as a radiosensitizer. METHODS: For the toxicology assessment, 80 male and female rats (10/sex/dosage group) were randomly assigned to groups receiving either 0, 0.2, 1.0 or 2.0 g kg(-1)day(-1) of po IPdR x 28 days and one-half were observed to day 57 (recovery group). Animals were monitored for clinical signs during and following treatment with full necropsy of one-half of each dosage group at day 29 and 57. For the plasma pharmacokinetic assessment, 40 rats (10/sex/dosage group) were randomly assigned to groups receiving either 0.2 or 1.0 g kg(-1)day(-1) of po IPdR x 28 days with multiple blood samplings on days 1 and 28 and single blood sampling on days 8 and 15. RESULTS: No drug-related deaths occurred. Higher IPdR doses resulted in transient weight loss and transient decreased hemoglobins but had no effect on white cells or platelets. Complete serum chemistry evaluation showed transient mild decreases in total protein, alkaline phosphatase, and serum globulin. Necropsy evaluation at day 29 showed minimal to mild histopathologic changes in bone marrow, lymph nodes and liver; all reversed by day 59. There were no sex-dependent differences in plasma pharmacokinetics of IPdR noted and the absorption and elimination kinetics of IPdR were found to be linear over the dose range studied. CONCLUSIONS: A once-daily dosing schedule of po IPdR for 28 days with doses up to 2.0 g kg(-1)day(-1) appeared to be well tolerated in Fischer-344 rats. Drug-related weight loss and microscopic changes in bone marrow, lymph nodes and liver were observed. These changes were all reversed by day 57. IPdR disposition was linear over the dose range used. However, based on day 28 kinetics it appears that IPdR elimination is enhanced following repeated administration. These toxicology and pharmacokinetic data were used when considering the design of our initial phase I trial of po IPdR as a clinical radiosensitizer.
Authors: Timothy Kinsella; Howard Safran; Susan Wiersma; Thomas DiPetrillo; Andrew Schumacher; Kayla Rosati; John Vatkevich; Lawrence W Anderson; Kimberly D Hill; Charles Kunos; Jerry M Collins Journal: Clin Cancer Res Date: 2019-07-23 Impact factor: 12.531
Authors: Shivaani Kummar; Larry Anderson; Kimberly Hill; Eva Majerova; Deborah Allen; Yvonne Horneffer; S Percy Ivy; Larry Rubinstein; Pamela Harris; James H Doroshow; Jerry M Collins Journal: Clin Cancer Res Date: 2013-02-12 Impact factor: 12.531