Pharmacokinetics of 5-azacitidine given with phenylbutyrate in patients with refractory solid tumors or hematologic malignancies

Abstract

2061 Background: 5-azacitidine (5AC, Vidaza), a cytidine nucleoside analogue, has anticancer properties and has been utilized in the treatment of various malignancies. Despite FDA approval, 5AC pharmacokinetics (PK) has not been previously described. Sequential addition of histone deacetylase inhibitors to cells preincubated with DNA methyltransferase inhibitors synergistically reactivates the expression of genes silenced through promoter methylation. The combination of 5AC and phenylbutyrate, a histone deaceytlase inhibitor, was taken into clinical trials. The purpose was to characterize the PK behavior of 5AC when given with phenylbutyrate. Methods: PK data were obtained from two trials involving patients with solid tumor and hematologic malignancies. 5AC at doses ranging from 10 to 75 mg/m2 was administered once daily as a subcutaneous injection for varying duration in combination with phenylbutyrate administered as a continuous intravenous infusion every 28 or 35 days. Serial plasma samples were collected up to 24 hours after 5AC administration. 5AC was quantitated using a validated LC/MS/MS method (M Zhao, J Chrom B 2004). PK was assessed using noncompartmental Methods: Results: The PK were performed on 24 patients with 30 PK periods. 5AC was rapidly absorbed with the mean Tmax occurring at 0.47 h. Average Cmax and AUC0-t values increased in a dose-proportionate manner with increasing dose. The mean ± SD Cmax at 10 and 75 mg/m2/d was 187.8 ± 114.0 ng/mL (766.8 ± 465.5 nM) and 1192.8 ± 342.4 ng/mL (4870.6 ± 1398.1 nM), respectively. The mean ± SD AUC0-t at 10 and 75 mg/m2/d was 202.9 ± 89.8 h*ng/mL (828.5 ± 366.7 h*nM) and 1454.8 ± 371.8 h*ng/mL (5940.4 ± 1518.2 h*nM), respectively. Interpatient variation in AUC was 1.7- to 3.4-fold. Despite a short t1/2 of 1.6 ± 2.4 h, 5AC inhibits DNA methyl transferase activity in tumors of patients. Conclusions: 5AC is rapidly absorbed and eliminated when administered subcutaneously. Sufficient 5AC exposure is achieved to produce pharmacodynamic effects in tumors. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pharmion Pharmion