Population Pharmacokinetics of Gemtuzumab Ozogamicin in Pediatric Patients with Relapsed or Refractory Acute Myeloid Leukemia

• Published in: Clinical pharmacokinetics Vol. 58; no. 2; pp. 271 - 282
• Main Authors: Masters, Joanna C., Barry, Elly, Knight, Beverly
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-02-2019; Springer Nature B.V
• Subjects: Adolescent; Adults; Antineoplastic Agents, Immunological - pharmacokinetics; Chemotherapy; Child; Child, Preschool; Children & youth; Clinical trials; Drug dosages; Drug Resistance, Neoplasm; Female; Gemtuzumab - pharmacokinetics; Humans; Immunotherapy; Infant; Internal Medicine; Leukemia; Leukemia, Myeloid, Acute - metabolism; Lymphoma; Male; Medicine; Medicine & Public Health; Models, Biological; Monoclonal antibodies; Neoplasm Recurrence, Local - metabolism; Original Research Article; Pediatrics; Pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy; Population; Recurrence; Sialic Acid Binding Ig-like Lectin 3 - antagonists & inhibitors; Studies; Targeted cancer therapy; United States > US
• ISSN: 0312-5963; 1179-1926
• DOI: 10.1007/s40262-018-0694-x

Background and Objective
To date, the population pharmacokinetics (popPK) of gemtuzumab ozogamicin (GO), a CD33-directed antibody–drug conjugate consisting of hP67.6 antibody linked to
N
-acetyl gamma calicheamicin used in the treatment of acute myeloid leukemia (AML), has not been characterized in pediatric patients. This report describes the popPK of GO following intravenous administration in 29 pediatric patients aged ≤ 17 years with relapsed or refractory AML who were enrolled in the 0903A1-102-US phase I/II study.
Methods
The pharmacokinetics (PK) of GO, as represented by total hP67.6 antibody, were described by a two-compartment model with two clearance components: a linear clearance (CL
1
) and time-dependent clearance that includes a decay coefficient. The PK of unconjugated calicheamicin (UC; payload) were described by a two-compartment model with CL
1
and an input rate of formation based on antibody rate of elimination. Allometric scaling was included in both models, with baseline body weight as a fixed effect on CL
1
and central volume.
Results and Conclusions
PK parameters for hP67.6 and UC were not significantly affected by any of the available demographic factors and safety laboratory values tested as covariates (except baseline body weight). Simulations to compare GO dosing regimens (6, 7.5, and 9 mg/m
2
on days 1 and 15 versus, 3 mg/m
2
fractionated dosing on days 1, 4, and 7) were performed, showing that total antibody and UC trough concentrations were maintained at higher concentrations during treatment following the more frequent dosing than following the original regimen.
Study Identifier
0903A1-102-US.