Population Pharmacokinetic Modeling of Gemtuzumab Ozogamicin in Adult Patients with Acute Myeloid Leukemia.

Background And Objective: Gemtuzumab ozogamicin is an antibody-drug conjugate composed of the anti-CD33 monoclonal antibody hP67.6 covalently linked to N-acetyl-gamma-calicheamicin dimethylhydrazide, a potent cytotoxic antibiotic. The aim of this study was to characterize the population pharmacokinetics of gemtuzumab ozogamicin, represented by total hP67.6 antibody and unconjugated calicheamicin, in adult patients with acute myeloid leukemia to support drug dosing strategies and explore intrinsic and extrinsic factors that may influence exposure. Pharmacokinetic data from seven previous phase I and II studies in adult patients with relapsed, refractory, or de novo acute myeloid leukemia were integrated and analyzed using nonlinear mixed-effects modeling.

Methods: The pharmacokinetics of total hP67.6 antibody was described in 407 patients (5643 concentrations) who received gemtuzumab ozogamicin doses ranging from 0.25 to 9 mg/m using a two-compartment model with linear and time-dependent clearance components. The pharmacokinetics of unconjugated calicheamicin was characterized in 338 patients (4281 concentrations) using a two-compartment model with an input rate of formation dependent on the amount of hP67.6 eliminated. No statistically significant baseline covariates (sex, albumin, bone marrow, and peripheral blast percentage) demonstrated a clinically meaningful impact.

Results And Conclusion: Total hP67.6 antibody disposition did not appear altered in patients with mild or moderate renal disease or hepatic impairment. Gemtuzumab ozogamicin was approved for the treatment of acute myeloid leukemia by the US Food and Drug Administration in September 2017. The model-based simulations described here provided a pharmacokinetic rationale for the approved dosing regimen of 3 mg/m on days 1, 4, and 7, and served as the basis for all exposure-response modeling included in the recent Biologics License Application submission. Clinical trials identifiers: 0903A1-101-US; 0903A1-103-JA; 0903B1-201-US/CA (NCT00003131); 0903B1-202-EU; 0903B1-203-US/EU (NCT00003673); 0903B1-205-US/EU/AU (NCT00037596); and 0903B1-206-US/EU/AU (NCT00037583).