AML-259 Pharmacokinetics and Bioequivalence of Two Formulations of GFH009 Maleate Injection in Sprague Dawley Rats

Abstract

Cyclin-dependent kinase 9 (CDK9) is a serine/threonine kinase that regulates the expression of short-lived oncogene products, such as MYC and MCL1, which are key influencers of tumor cell proliferation and survival. CDK9 deregulation has been reported in leukemia and other hematological malignancies. GFH009 is a potent, highly selective, clinical-stage, small molecule that inhibits CDK9. The objective of this study was to characterize the preclinical pharmacokinetic (PK) profiles of two different formulations of GFH009 maleate (pH 4.5 and 6.0). Sprague Dawley (SD) rats were randomized to receive a single dose of one formulation of GFH009 maleate (4 mg/kg) intravenously (IV) at a volume of 5 mL/kg. Blood samples were obtained at pre-dose and pre-specified timepoints post-dose. Plasma concentration of GFH009 was quantitated by a validated LC-MS/MS method, and PK parameters were assessed by non-compartmental analysis approach. Twelve SD rats per group were included. The plasma concentrations of the GFH009 formulations were within 90% to 110% of the nominal concentrations, and the coefficient of variation was <5.0%. The mean plasma concentration peaked at 5 min post-dose (479 ng/mL and 486 ng/mL in groups 1 and 2, respectively) and gradually decreased in a similar profile. The LLOQ was 1.000 ng/mL. In group 1, C0 (mean ± SD) was 586 ± 109 ng/mL, AUClast was 825 ± 73.8 h-ng/mL; AUCInf was 842 ± 75.0 h-ng/mL, clearance (CL) was 4780 ± 429 mL/h/kg, and t1/2 was 5.45 ± 0.649 h. In group 2, C0 was 572 ± 147 ng/mL, AUClast was 924 ± 144 h-ng/mL, AUCInf was 946 ± 145 h-ng/mL, CL was 4310 ± 607 mL/h/kg, and t1/2 was 5.66 ± 0.973 h. Bioequivalence analysis showed that the 90% CI values for C0, AUClast, and AUCInf were within the acceptable range (80-125%). The PK profiles of GFH009 were comparable following single IV administration of two formulations of GFH009 maleate injection in SD rats, which supported application of the pH 6.0 formulation in Phase I trials in patients with relapsed/refractory hematologic conditions, including AML and lymphoma.