Y. Zhao, Y. Ling, M. Poi, L. J. Schaaf, A. J. Johnson, J. C. Byrd, J. A. Jones, M. A. Phelps; Ohio State University, Columbus, OH
BACKGROUND: Cyclin dependent kinase inhibitors (CDKIs) have shown potent activity in patients with chronic lymphocytic leukemia (CLL) and other cancers. However, rapid CLL cell killing leads to hyper-acute tumor lysis syndrome (TLS) in some patients. In this study combining ofatumumab with the CDKI, dinaciclib, we evaluated relationships between dinaciclib pharmacokinetics (PK), TLS markers, and pharmacogenetics (PGx) of CYP3A4*22/CYP3A5*3.
METHODS: Dinaciclib was administered on 3 days from cycle 2 with doses escalating from 7 to 14 mg/m2. Dinaciclib and its glucuronide plasma concentration-time data were used to develop a population PK model. Blood potassium, lactate dehydrogenase (LDH), phosphate and uric acid levels were collected at multiple time points to monitor TLS. DNA was extracted from patient buccal swabs and peripheral blood mononuclear cells for 3A4*22/3A5*3 genotyping.
RESULTS: A total of 38 patients were accrued, and plasma PK data was obtained for 31 patients. Among patients Cmax and AUC ranged approximately 10- to 15-fold for both dinaciclib and dinaciclib glucuronide. Covariate analysis thus far yielded albumin as a significant factor on dinaciclib CL. There was only one TLS incidence. Increases in LDH and phosphate were observed after dinaciclib administration. Biochemical markers of TLS did not correlate with plasma exposures of dinaciclib or dinaciclib glucuronide. PGx data was available for 32 patients, and work is ongoing to evaluate CYP3A4*22/3A5*3 carriers tended to have higher dinaciclib Cmax and AUC compared to non-carriers.
CONCLUSION: Plasma exposure to both dinaciclib and its glucuronide varied 10-15 fold. Changes in biochemical markers of TLS were observed, but these changes are not associated with PK of dinaciclib or its glucuronide.