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


CONCLUSIONS
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.
Drug Safety Research and Development, Pfizer Global Research and Development, Ann Arbor, MI 48105, USA. abrown@namsa.com
Alan P
AP
Brown
Cynthia L
CL
Courtney
Kay A
KA
Criswell
Christopher L
CL
Holliman
Winston
W
Evering
Bart A
BA
Jessen
D000818:Animals; D000855:Anorexia / Q000139:chemically induced; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D001259:Ataxia / Q000139:chemically induced; D001562:Benzimidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D001808:Blood Vessels / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000473:pathology; D006402:Hematologic Diseases / Q000139:chemically induced; D007191:Indazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D007262:Infusions, Intravenous; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology; D053609:Lethargy / Q000139:chemically induced; D008252:Macaca fascicularis; D008297:Male; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D012652:Self Mutilation; D013239:Stereotyped Behavior / Q000187:drug effects; D014839:Vomiting / Q000139:chemically induced
D000970:Antineoplastic Agents; D001562:Benzimidazoles; D007191:Indazoles; C533671:N-((5-(3-(4,6-difluoro-1H-benzimidazol-2-yl)-1H-indazol-5-yl)-4-methylpyridin-3-yl)methyl)ethanamine; D047428:Protein Kinase Inhibitors; D018844:Cyclin-Dependent Kinases