Clinical Pharmacokinetics of the CD19 Receptor-Directed Tyrosine Kinase Inhibitor B43-Genistein in Patients with B-Lineage Lymphoid Malignancies


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Abstract

The authors examined the pharmacokinetics of the CD19 receptor-directed tyrosine kinase inhibitor B43-Genistein in 17 patients (4 children, 13 adults) with B-lineage lymphoid malignancies, including 12 patients with acute lymphoblastic leukemia (ALL) and 5patients with non-Hodgkin's lymphoma (NHL). The immunoconjugate was administered intravenously as a 1-hour continuous infusion at a dose level of either 0.1 mg/kg (N = 12) or 0.18 mg/kg (N = 5), and the plasma concentration-time data were modeled by using the WinNonlin program to estimate the pharmacokinetic parameters. Pharmacokinetic analyses revealed a plasma half-life of 19 ± 4 hours, mean residence time of 22 ± 4 hours, and a systemic clearance of 18 ± 2 mL/h/kg. The average (mean ± SEM) values for the maximum plasma concentration Cmax, volume of distribution at steady state (Vss), and area under curve (AUC) were 1092 ± 225ng/ml, 291 ± 37mL/kg, and 9987 ± 2021 μg × h/L, respectively. The AUC values were higher at the 0.18 mg/kg dose level than at the 0.1 mg/kg dose level (16,848 ± 5118 μg × h/L vs. 7128 ± 1156 μg × h/L, p = 0.009). Patients with ALL had a significantly larger volume of distribution at steady state (332 ± 47 mL/kg vs. 191 ± 12 mL/kg, p = 0.04), faster clearance (21 ±3 mL/h/kg vs. 11 ±2 mL/h/kg, p = 0.03), and lower dose-corrected AUC than patients with NHL (6010 ±836 μg × h/L vs. 12,044 ± 2707 μg × h/L, p = 0.006). There was a trend toward faster clearance rates (23 ± 4 mL/h/kg vs. 16 ± 3 mL/h/kg, p = 0.1), shorter elimination half-lives (5.7 ± 3.6 hours vs. 13 ± 8.8 hours, p = 0.1), and shorter mean residence times (11 ± 3 hours vs. 25 ± 5 hours, p = 0.08) for non-Caucasian patients as compared to Caucasian patients. When compared to adult patients, pediatric patients showed a significantly larger volume of distribution at steady state (418 ± 82 mL/kg vs. 252 ± 34 mL/kg, p = 0.02) and a longer elimination half-lives (18.4 ± 13.6 hours vs. 8.7 ± 6.7 hours, p = 0.04). The pharmacokinetics of B43-Genistein was not affected by the gender of the patients or by bone marrow transplantation in past medical history. Overall, B43-Genistein showed favorable pharmacokinetics in this heavily pretreated leukemia/lymphoma patient population, which is reminiscent of its recently reported favorable pharmacokinetics in cynomolgus monkeys. To our knowledge, this is the first clinical pharmacokinetics study of a tyrosine kinase inhibitor containing immunoconjugate.

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