title: Clinical pharmacokinetics of the CD19 receptor-directed tyrosine kinase inhibitor B43-Genistein in patients with B-lineage lymphoid malignancies.
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 5 patients 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 +/- 225 ng/ml, 291 +/- 37 mL/kg, and 9987 +/- 2021 micrograms x 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 micrograms x h/L vs. 7128 +/- 1156 micrograms x 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 micrograms x h/L vs. 12,044 +/- 2707 micrograms x 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.
authors.affiliation: Parker Hughes Cancer Center, Hughes Institute, St. Paul, Minnesota 55113, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Chen
authors.forename: A
authors.initials: A
authors.lastname: Levine
authors.forename: A
authors.initials: A
authors.lastname: Rao
authors.forename: K
authors.initials: K
authors.lastname: O'Neill
authors.forename: Y
authors.initials: Y
authors.lastname: Messinger
authors.forename: D E
authors.initials: DE
authors.lastname: Myers
authors.forename: F
authors.initials: F
authors.lastname: Goldman
authors.forename: C
authors.initials: C
authors.lastname: Hurvitz
authors.forename: J T
authors.initials: JT
authors.lastname: Casper
authors.forename: F M
authors.initials: FM
authors.lastname: Uckun
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D018941:Antigens, CD19 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D002648:Child; D005260:Female; D019833:Genistein / Q000493:pharmacokinetics*; D006801:Humans; D018796:Immunoconjugates / Q000493:pharmacokinetics; D008228:Lymphoma, Non-Hodgkin / Q000208:ethnology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000208:ethnology / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012727:Sex Characteristics
chemical_list: D018941:Antigens, CD19; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D019833:Genistein; D011505:Protein-Tyrosine Kinases