Toxicity and toxicokinetics of the cyclin-dependent kinase inhibitor AG-024322 in cynomolgus monkeys following intravenous infusion

• Published in: Cancer chemotherapy and pharmacology 2008-11, Vol.62 (6), p.1091-1101
• Main Authors: Brown, Alan P., Courtney, Cynthia L., Criswell, Kay A., Holliman, Christopher L., Evering, Winston, Jessen, Bart A.
• Format: Article
• Language: English
• Subjects: Animals; Anorexia - chemically induced; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - toxicity; Ataxia - chemically induced; Benzimidazoles - administration & dosage; Benzimidazoles - pharmacokinetics; Benzimidazoles - toxicity; Biological and medical sciences; Blood Vessels - drug effects; Bone Marrow - drug effects; Bone Marrow - pathology; Cancer Research; Cyclin-Dependent Kinases - antagonists & inhibitors; Cynomolgus; Dose-Response Relationship, Drug; Female; Gastrointestinal Tract - drug effects; Gastrointestinal Tract - pathology; Hematologic Diseases - chemically induced; Indazoles - administration & dosage; Indazoles - pharmacokinetics; Indazoles - toxicity; Infusions, Intravenous; Kidney Tubules - drug effects; Kidney Tubules - pathology; Lethargy - chemically induced; Macaca fascicularis; Male; Medical sciences; Medicine; Medicine & Public Health; Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - toxicity; Self Mutilation; Stereotyped Behavior - drug effects; Vomiting - chemically induced
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-008-0771-1

Purpose Cyclin-dependent kinases (CDKs) play a significant role in the control of cell-cycle progression and exhibit aberrant regulation in various neoplastic diseases. AG-024322 is a potent inhibitor of CDK1, CDK2, and CDK4 that produces cell-cycle arrest and antitumor activity in preclinical models. This study evaluated the toxicity of AG-024322 when given by intravenous (IV) infusion to cynomolgus monkeys, including reversibility of effects. Methods Male and female monkeys received AG-024322 by 30-min IV infusion once daily for 5 days at doses of 2, 6, and 10 mg/kg (24, 72, and 120 mg/m 2 , respectively). Controls received vehicle alone which was aqueous 5% dextrose, pH 3.8. Three animals/sex/group were necropsied on day 6, and two animals/sex/group at 6 and 10 mg/kg were necropsied on day 22 (reversal cohort). Doses were based upon the results of a dose range-finding study in monkeys; decreased white blood cells occurred at ≥3 mg/kg and 12 mg/kg produced central nervous system effects and was above the maximum-tolerated dose. Results No deaths occurred and clinical signs of toxicity, including swelling at the IV administration site, were seen at ≥6 mg/kg. AG-024322 at ≥6 mg/kg produced pancytic bone marrow hypocellularity, lymphoid depletion, and vascular injury at the injection site. Renal tubular degeneration occurred at 10 mg/kg. These changes were either reversible or in a process of repair following the 17-day recovery period. Hematology changes included decreases in reticulocytes and/or granulocytes at ≥6 mg/kg, which were reversible and consistent with changes in the bone marrow. Lymphoid and bone marrow depletion are consistent with pharmacologic inhibition of CDKs by AG-024322 and were expected findings. On day 22, vacuolar degeneration of pancreatic acinar cells with increased serum amylase and lipase levels occurred in one female at 10 mg/kg. Neither sex-related differences in toxicokinetics nor plasma accumulation over 5 days of dosing were seen. Terminal phase overall mean half-life on day 5 ranged from 6.69 to 8.87 h (across dose levels) and was not dose dependent. Conclusion The no-adverse-effect dose of AG-024322 was 2 mg/kg and associated with overall mean plasma AUC(0–24.5) of 2.11 μg h/mL.