A Population Pharmacokinetic Analysis Of A New Antibody Chemotherapeutic Agent: Gemtuzumab Ozogamicin.
J.A. Dowell, Ph.D., S.P. King, Ph.D., H.Liu, Ph.D., M.S. Berger, M.D., and J.M. Korth-Bradley, Pharm.D., Ph.D.
Wyeth-Ayerst Research, PA 19087 USA.
Gemtuzumab ozogamicin (GO) is a novel antibody-chemotherapeutic conjugate consisting of an engineered human anti-CD33 antibody (hP67.6) linked to a potent cytotoxic agent, N-acetyl-gamma calicheamicin DMH. A population pharmacokinetic analysis was performed using hP67.6 pharmacokinetic data from 180 patients with relapsed acute myelogenous leukemia (AML). NONMEM software was used to develop and estimate a model for hP67.6 plasma concentrations and to assess possible relationships between patient demography and hP67.6 pharmacokinetics. The majority of patients received two GO administrations that consisted of two-hour IV infusions of 9 mg/m2. The successfully developed model had a two-compartment structure with interindividual errors on CL (CV=92%) and V1 (CV=58%). Population parameter estimates were CL=0.114 L/h, V1= 6.58 L, Q=0.0474L/h, and V2=8.38 L. An increase in hP67.6 concentrations was observed after the second dose compared to the first dose, presumably due to changes in disease/ antigen burden. The change in pharmacokinetics was successfully modeled and empirically described by incorporating a proportional term on clearance (77.1%). There were no observed relationships between patient demographic variables (age, weight, and gender) and parameters.