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Gemtuzumab ozogamicin is currently approved to treat CD33-positive acute myeloid leukemia (AML) in first relapse in patients older than age 60 years. The objective of this study was to characterize the pharmacokinetics of gemtuzumab ozogamicin in pediatric patients with relapsed or refractory AML. The study population comprised 29 subjects younger than age 18 with AML in first relapse. Dosages of 6, 7.5, and 9 mg/m(2) were administered during the study. Pharmacokinetic parameters were determined following each dose for hP67.6, total calicheamicin derivatives, and unconjugated calicheamicin derivatives. hP67.6 pharmacokinetic parameters had a consistent and statistically significant change between the first and second doses. Increases in AUC and decreases in both CL and V(ss) from the first dose to the second dose were consistent with those of the adult population. Changes between dose periods for total calicheamicin derivatives and unconjugated calicheamicin derivatives were consistent with those of hP67.6. Changes in pharmacokinetic parameters between dose periods are attributed to saturation of CD33 binding sites and diminished clearance resulting from a lower peripheral blast burden and antigen. Children receiving 9 mg/m(2) had the following hP67.6 pharmacokinetic parameters: C(max), 3.47+/-1.04 mg/L; AUC, 136 +/- 107 mg x h/L; CL, 0.12 +/- 0.15 L/h/m(2); V(ss), 6.5 +/- 5.5 L; and t(1/2), 64 +/- 44 h after their first dose. Mean pharmacokinetic values are similar to values reported in adults. Individual children demonstrated large intersubject variability, similar to adults. The pharmacokinetics of gemtuzumab ozogamicin in pediatric patients closely follow the profile and variability of adult patients.

This paper discusses background information and the body of clinical data that has been accumulated to demonstrate the efficacy and safety of gemtuzumab ozogamicin (Mylotarg, Wyeth Pharmaceuticals, Philadelphia, PA). Based on these data, gemtuzumab ozogamicin was approved by the United States Food and Drug Administration for the treatment of patients with CD33-positive acute myeloid leukemia in first relapse who are 60 years of age or older and who are not considered candidates for other cytotoxic chemotherapy. The recommended dosage of gemtuzumab ozogamicin is 9 mg/m2, administered as a 2-hour intravenous infusion for a total of 2 doses with 14 days between doses.

The purpose of this study was to characterize the pharmacokinetics of gemtuzumab ozogamicin (Mylotarg; Wyeth-Ayerst Laboratories, St. Davids, PA) in patients with acute myeloid leukemia (AML) in first relapse. Gemtuzumab ozogamicin is an antibody-chemotherapeutic conjugate characterized as antibody-targeted chemotherapy, consisting of an engineered human anti-CD33 antibody (hP67.6) linked to a potent cytotoxic agent, N-acetyl-gamma calicheamicin DMH. The pharmacokinetics of gemtuzumab ozogamicin was evaluated in 59 adult AML patients in first relapse, enrolled in a phase II study. Plasma was collected following each dose at specified times, and the pharmacokinetics was characterized by measures of hP67.6, total calicheamicin derivatives, and unconjugated calicheamicin derivatives. After administration of the first 9 mg/m2 dose of gemtuzumab ozogamicin, the pharmacokinetic parameters (mean +/- SD) of hP67.6 following the first dose were as follows: peak plasma concentration, 2.86 +/- 1.35 mg/L; AUC, 123 +/- 105 mg x h/L; t 1/2, 72.4 +/- 42.0 hours; and clearance, 0.265 +/- 0.229L/h. Increased concentrations were observed after the second dose and are believed to be due to a decrease in clearance by CD33-positive blast cells, a result of the reduced tumor burden following the first dose. The concentration profiles of calicheamicin followed the same time course as hP67.6, evidence that calicheamicin remained conjugated to the antibody and delivered to leukemic cells. No relationship was found between plasma concentration and response at the recommended dose. The pharmacokinetics of gemtuzumab ozogamicin has been characterized in AML patients receiving doses at the proposed therapeutic level.

Study Objective: To determine the pharmacokinetic parameters of the components of gemtuzumab ozogamicin and to assess the possible influence of age and gender on the values., Design: Phase II, multicenter, open-label, nonrandomized, parallel study, Setting: Hospitals and outpatient oncology clinics., Patients: Fifty-eight patients with acute myeloid leukemia in first relapse participated. Demographic data included 29 men and 29 women; 34 were younger than 60 years of age (mean age 53+/-16 yrs)., Intervention: Patients received gemtuzumab ozogamicin as a single 2-hour infusion of 9 mg/m2. Serial plasma samples were collected over 10 days after the beginning of the infusion., Measurements and Main Results: Plasma concentrations of components of gemtuzumab ozogamicin (hP67.6 antibody, total and unconjugated calicheamicin derivatives) were measured by validated enzyme-linked immunosorbent assays. Pharmacokinetic parameters were determined by noncompartmental methods and comparisons between groups were made by analysis of variance. No significant differences were seen between men and women or between those over 60 and those less than 60 years of age in maximum concentration, time to maximum concentration, area under the curve, clearance, or volume of distribution for components of gemtuzumab ozogamicin., Conclusion: No differences occur in the pharmacokinetics of the components of gemtuzumab ozogamicin (hP67.6 or calicheamicin) based on gender or age.