Population Pharmacokinetics of Brentuximab Vedotin in Patients With CD30-Expressing Hematologic Malignancies

Journal of Clinical Pharmacology
Hong LiBaiteng Zhao

Abstract

Brentuximab vedotin, a CD30-directed antibody-drug conjugate (ADC), is approved for treating certain patients with CD30-expressing hematologic malignancies. Its primary mechanism of action is the targeted delivery of a microtubule-disrupting agent, monomethyl auristatin E (MMAE), to CD30-expressing cells. A population pharmacokinetic (PopPK) analysis was conducted to characterize the PK of ADC and unconjugated MMAE in patients with CD30-expressing hematologic malignancies by compartmental analysis and to evaluate the effects of covariates on PK of the ADC. A nonlinear mixed-effects modeling approach was used to evaluate data from 314 patients in 5 clinical studies. ADC PK was described by a linear, 3-compartment model with first-order elimination. MMAE PK was described by a semimechanistic, linear, 2-compartment model with first-order elimination. The estimated typical values for a 75-kg male patient were 1.56 L/d and 4.29 L for ADC systemic clearance (CL) and volume of central compartment (V1), respectively, with weight effect exponents of 0.698 and 0.503, respectively. Typical V1 in 75-kg females was 87% of that in males, with no impact on systemic ADC exposure. Typical values of MMAE clearance (CLM ) and volume of central co...Continue Reading

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Citations

Sep 18, 2017·Journal of Pharmacokinetics and Pharmacodynamics·Matts KågedalChunze Li
Sep 20, 2017·Pharmaceutical Research·Paul MalikJonathan Blay
Dec 12, 2018·Expert Review of Hematology·Carrie Van Der WeydenH Miles Prince
Aug 23, 2019·Expert Review of Hematology·Yun Choi, Catherine S Diefenbach
Feb 7, 2018·Antibodies·Andrew T LucasWilliam C Zamboni
Feb 11, 2020·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Angelo PaciSophie Broutin
Jun 3, 2021·Antibodies·Iftekhar Mahmood

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Clinical Trials Mentioned

NCT00430846
NCT00649584
NCT00848926
NCT00866047
NCT01026415

Software Mentioned

PopPK
NONMEM
R
NONMEM VII

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