Impact of Venetoclax Exposure on Clinical Efficacy and Safety in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia

Freise, Kevin J.; Jones, Aksana K.; Eckert, Doerthe; Mensing, Sven; Wong, Shekman; Humerickhouse, Rod; Awni, Walid M.; Salem, Ahmed Hamed

doi:10.1007/s40262-016-0453-9

Cited by 50 publications

(58 citation statements)

References 38 publications

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“…With regard to safety, subjects receiving venetoclax doses up to 1200 mg once daily, where the exposures were approximately 2.5‐fold higher than those achieved at the approved dose of 400 mg once daily, did not experience dose‐limiting toxicities . Consistently, exposure–safety analyses indicated that higher venetoclax exposures had no effect on QT interval and were not associated with an increase in grade 3 or higher adverse events of neutropenia and infection . Based on these exposure–response relationships and assuming that a similar exposure–response relationship exists in Chinese subjects with CLL, the phase 2 open‐label study evaluating the venetoclax pharmacokinetics, efficacy, and safety in Chinese subjects with R/R CLL is being conducted at the 400‐mg once‐daily dose.…”

Section: Discussionmentioning

confidence: 86%

“…The approved therapeutic dosage regimen of venetoclax is 400 mg once daily in patients with CLL after the initial weekly ramp‐up. In an exposure–efficacy analysis conducted using data from subjects with CLL (predominantly whites), the rate of objective response was shown to be similar, with a 0.5‐ to 2.0‐fold change in venetoclax exposure from that typically achieved at the 400‐mg once‐daily dosage regimen . An exposure progression‐free survival (PFS) analysis demonstrated that higher exposures are likely to increase PFS .…”

Section: Discussionmentioning

confidence: 98%

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Pharmacokinetics of the BCL‐2 Inhibitor Venetoclax in Healthy Chinese Subjects

Cheung

Salem

Menon

et al. 2017

Clinical Pharm in Drug Dev

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Venetoclax has been approved in the United States, Europe, Canada, and Australia for appropriate patients with difficult-to-treat chronic lymphocytic leukemia (CLL). The objective of this phase 1 study was to evaluate the pharmacokinetics of venetoclax in Chinese subjects to inform the dose selection of venetoclax in a phase 2 study of patients with relapsed/refractory (R/R) CLL in China. Twelve healthy first-generation Han Chinese subjects received a single 100-mg dose of venetoclax following a low-fat breakfast. Pharmacokinetic parameters were estimated using noncompartmental methods. After a single dose of venetoclax in healthy Chinese subjects, the median time to peak concentration was 6 hours (range, 4 to 6 hours), and the mean ± SD C , AUC , and terminal half-life were 1.0 ± 0.32 μg/mL, 12.6 ± 5.4 μg·h/mL, and 18.4 ± 2.97 hours, respectively. On average, venetoclax C and AUC values were 94% and 66% higher, respectively, in Chinese subjects compared with those observed historically for non-Asian subjects receiving the same dose. Based on these pharmacokinetic results and the established exposure-response relationship of venetoclax in non-Asian CLL subjects, a 400-mg once-daily dosage regimen was selected for evaluating the venetoclax pharmacokinetics, efficacy, and safety in the venetoclax phase 2 open-label study in Chinese subjects with R/R CLL.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 98%

Pharmacokinetics of the BCL‐2 Inhibitor Venetoclax in Healthy Chinese Subjects

Cheung

Salem

Menon

et al. 2017

Clinical Pharm in Drug Dev

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“…Recently, venetoclax was approved by the US FDA for treatment of newly diagnosed AML in adults who are aged 75 years or older or who have comorbidities that preclude use of intensive induction chemotherapy in combination with HMAs or LDAC under accelerated approval pathway. Previous studies have evaluated the venetoclax exposure response relationships in subjects with CLL, non‐Hodgkin's lymphoma, or multiple myeloma . The findings of the analyses reported herein provide the rationale and justification for the dose of venetoclax used in the pivotal, global, randomized, double‐blind, placebo‐controlled phase III study in combination with azacitidine versus azacitidine alone (NCT02993523) and in combination with LDAC vs LDAC alone (NCT03069352), conducted in treatment‐naïve elderly patients with AML who are ineligible for standard induction therapy.…”

Section: Discussionmentioning

confidence: 99%

Optimizing venetoclax dose in combination with low intensive therapies in elderly patients with newly diagnosed acute myeloid leukemia: An exposure‐response analysis

Agarwal

Gopalakrishnan

Mensing

et al. 2019

Hematological Oncology

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The objective of this research was to characterize the venetoclax exposure‐efficacy and exposure‐safety relationships and determine its optimal dose in elderly patients with newly diagnosed acute myeloid leukemia (AML) receiving venetoclax in combination with low intensity therapies (hypomethylating agent [HMA; azacitidine or decitabine] or low‐dose cytarabine [LDAC]). A total of 212 patients from the HMA study and 92 patients from the LDAC study were included in the exposure‐safety analyses. Those who received at least one dose of venetoclax and had at least one measurable response (201 and 83 in the HMA and LDAC studies, respectively) were included in the exposure‐efficacy analyses. The probability of response based on International Working Group (IWG) for AML response criteria, adverse events of grade 3 or worse neutropenia or infection or a serious adverse event was modeled using logistic regression analyses to characterize the venetoclax exposure‐response relationships. In combination with an HMA, increasing concentrations of venetoclax, up to those associated with a less than or equal to 400‐mg once daily (QD) dose, were associated with a higher probability of response, with a trend for flat or decreasing probabilities of response thereafter. In combination with LDAC, increasing concentrations of venetoclax were associated with higher probabilities of response, with no plateau observed. Increasing concentrations of venetoclax were not associated with increasing probability of any safety event except for a slight increase in grade 3 or worse infections with HMAs; however, tolerability issues were observed at doses of greater than or equal to 800 mg QD in each study. Exposure‐response analyses support the use of venetoclax 400 mg QD in combination with an HMA and 600 mg QD in combination with LDAC (ie, the next highest dose evaluated below 800 mg in each combination) to safely maximize the probability of response in elderly patients with newly diagnosed AML.

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“…Concomitant use of moderate CYP3A inhibitors increased dose‐normalized venetoclax C max and AUC 0‐24 values by 40% to 60%. An exposure‐safety analyses of the adverse events (grade ≥ 3) in CLL patients indicated that higher average venetoclax concentrations were associated with a decrease in neutropenia rates likely due to disease improvement . However, because of the risk for tumor lysis syndrome during the ramp‐up phase, coadministration of venetoclax with moderate CYP3A inhibitors should be avoided, or the venetoclax dose should be reduced during the ramp‐up phase in CLL patients.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Venetoclax, a Novel BCL‐2 Inhibitor, in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Non‐Hodgkin Lymphoma

Salem

Agarwal

Dunbar

et al. 2016

The Journal of Clinical Pharma

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Venetoclax is a selective BCL-2 inhibitor that is approved in the United States for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least 1 prior therapy. The aim of this analysis was to characterize venetoclax pharmacokinetics in the plasma and urine of patients with hematological malignancies and evaluate the effect of dose proportionality, accumulation, weak and moderate CYP3A inhibitors, as well as low- and high-fat meals on venetoclax pharmacokinetics. Patients received a once-daily venetoclax dose of 20 to 1200 mg. Pharmacokinetic parameters were estimated using noncompartmental methods. Venetoclax peak exposures were achieved at 5 to 8 hours under low-fat conditions, and the mean terminal-phase elimination half-life ranged between 14.1 and 18.2 hours at different doses. Venetoclax steady-state exposures showed minimal accumulation and increased proportionally over the dose range of 300 to 900 mg. Low-fat and high-fat meals increased venetoclax exposures by approximately 4-fold relative to the fasting state. Moderate CYP3A inhibitors increased venetoclax exposures by 40% to 60%, whereas weak CYP3A inhibitors had no effect. A negligible amount of venetoclax was excreted in the urine. In summary, venetoclax exhibits a pharmacokinetic profile that is compatible with once-daily dosing with food regardless of fat content. Concomitant use of venetoclax with moderate CYP3A inhibitors should be avoided or venetoclax dose should be reduced during the venetoclax initiation and ramp-up phase in CLL patients. Renal excretion plays a minimal role in the elimination of venetoclax.

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Impact of Venetoclax Exposure on Clinical Efficacy and Safety in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia

Abstract: The exposure-response analyses indicated that a venetoclax dosage regimen of 400 mg daily results in a high (>80 %) probability of achieving OR in R/R CLL/SLL patients, with minimal probability of increasing neutropenia or infection with higher exposures.

Cited by 50 publications

References 38 publications

Pharmacokinetics of the BCL‐2 Inhibitor Venetoclax in Healthy Chinese Subjects

Pharmacokinetics of the BCL‐2 Inhibitor Venetoclax in Healthy Chinese Subjects

Optimizing venetoclax dose in combination with low intensive therapies in elderly patients with newly diagnosed acute myeloid leukemia: An exposure‐response analysis

Pharmacokinetics of Venetoclax, a Novel BCL‐2 Inhibitor, in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Non‐Hodgkin Lymphoma

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