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

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 compartment (V4) were 55.7 L/d and 79.8 L, respectively, with weight effect exponents fixed to 0.75 and 1.0, respectively. This is the first PopPK model of brentuximab vedotin to semimechanistically link the PK of ADC and that of the unconjugated small molecule MMAE. Both ADC and MMAE PK data were adequately described by the final integrated model, which supports weight-based dosing of brentuximab vedotin in adult patients with CD30-expressing hematologic malignancies.

SUBMITTER: Li H

PROVIDER: S-EPMC5574006 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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

Li Hong H Han Tae H TH Hunder Naomi N NN Jang Graham G Zhao Baiteng B

Journal of clinical pharmacology 20170517 9

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 analys ...[more]

PMID: 28513851

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Project description:BackgroundBrentuximab vedotin is a CD30-directed antibody-drug conjugate. Retreatment with brentuximab vedotin monotherapy was investigated in patients with CD30-positive Hodgkin lymphoma (HL) or systemic anaplastic large cell lymphoma (ALCL) who relapsed after achieving complete or partial remission (CR or PR) with initial brentuximab vedotin therapy in a previous study (ClinicalTrials.gov NCT00947856).MethodsTwenty-one patients with HL and 8 patients with systemic ALCL were retreated; 3 patients with systemic ALCL were retreated twice. Patients generally received brentuximab vedotin 1.8 mg/kg intravenously approximately every 3 weeks over 30 minutes as an outpatient infusion. The primary objectives of this study were to assess safety and to estimate antitumor activity of brentuximab vedotin retreatment.ResultsThe objective response rate was 60% (30% CR) in HL patients and 88% (63% CR) in systemic ALCL patients. The estimated median duration of response for patients with an objective response was 9.5 months (range, 0.0+ to 28.0+ months) at the time of study closure. Of the 19 patients with objective response, 7 patients had not had an event of disease progression or death at the time of study closure; duration of response for these patients ranged from 3.5 to 28 months. Of the 11 patients with CR, 45% had response durations of over 1 year.Adverse events (AEs) occurring in ≥25% of patients during the retreatment period were generally similar in type and frequency to those observed in the pivotal trials of brentuximab vedotin monotherapy, with the exception of peripheral neuropathy, which is known to have a cumulative effect. Grade 3 or higher events were observed in 48% of patients; these were generally transient and managed by dose modifications or delays. Deaths due to AEs occurred in 3 HL patients; none were considered to be related to brentuximab vedotin retreatment.DiscussionWith the exception of a higher rate of peripheral motor neuropathy, retreatment with brentuximab vedotin was associated with similar side effects seen in the pivotal trials.ConclusionsRetreatment with brentuximab vedotin monotherapy is associated with response rates in 68% (39% CR) of patients with relapsed HL and systemic ALCL.Trial registrationUnited States registry and results database ClinicalTrials.gov NCT00947856.

Dataset Information

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

Publications

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

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