Pharmacokinetic/Pharmacodynamic Modeling to Support the Re‐approval of Gemtuzumab Ozogamicin

Gemtuzumab ozogamicin (Mylotarg; Pfizer, New York, NY) was the first antibody–drug conjugate to be approved for CD33‐positive acute myeloid leukemia (AML). However, it was voluntarily withdrawn from the US market due to lack of clinical benefit in the confirmatory phase III trial. In 2012, several investigator cooperative studies using a different dosing regimen showed efficacy, but pharmacokinetic (PK) data were not collected in these trials. Through simulation of expected concentrations for new dosing regimens, PK/pharmacodynamic modeling was able to support the safety and efficacy of these regimens. Significant exposure–response relationships were found for the attainment of complete remission with and without platelet recovery, attainment of blast‐free status, the time course of myelosuppression, several grade ≥ 3 hepatic adverse events, and veno‐occlusive disease. Gemtuzumab ozogamicin received full approval by the US Food and Drug Administration (FDA) in September 2017 for newly diagnosed and relapsed AML in adult patients and relapsed AML in pediatric patients aged 2–17 years.