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

Abstract

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 > or =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 > or =6 mg/kg. AG-024322 at > or =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 > or =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 microg h/mL.

• Authors: Alan P Brown, Cynthia L Courtney, Kay A Criswell, Christopher L Holliman, Winston Evering, Bart A Jessen
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 62 Issue 6 Pg. 1091-101 (Nov 2008) ISSN: 1432-0843 [Electronic] Germany
• PMID: 18509643 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Benzimidazoles
• Indazoles
• N-((5-(3-(4,6-difluoro-1H-benzimidazol-2-yl)-1H-indazol-5-yl)-4-methylpyridin-3-yl)methyl)ethanamine
• Protein Kinase Inhibitors
• Cyclin-Dependent Kinases

Topics

• Animals
• Anorexia (chemically induced)
• Antineoplastic Agents (administration & dosage, pharmacokinetics, toxicity)
• Ataxia (chemically induced)
• Benzimidazoles (administration & dosage, pharmacokinetics, toxicity)
• Blood Vessels (drug effects)
• Bone Marrow (drug effects, pathology)
• Cyclin-Dependent Kinases (antagonists & inhibitors)
• Dose-Response Relationship, Drug
• Female
• Gastrointestinal Tract (drug effects, pathology)
• Hematologic Diseases (chemically induced)
• Indazoles (administration & dosage, pharmacokinetics, toxicity)
• Infusions, Intravenous
• Kidney Tubules (drug effects, pathology)
• Lethargy (chemically induced)
• Macaca fascicularis
• Male
• Protein Kinase Inhibitors (administration & dosage, pharmacokinetics, toxicity)
• Self Mutilation
• Stereotyped Behavior (drug effects)
• Vomiting (chemically induced)