Venetoclax Penetrates the Blood Brain Barrier: A Pharmacokinetic Analysis in Pediatric Leukemia Patients

Badawi, Mohamed; Menon, Rajeev; Place, Andrew E.; Palenski, Tammy L.; Sunkersett, Gauri; Arrendale, Richard F.; Deng, Rong; Federico, Sara M.; Cooper, Todd M.; Salem, Ahmed Hamed

doi:10.7150/jca.81795

Cited by 7 publications

(4 citation statements)

References 20 publications

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“…In addition, Badawi et al reported the pharmacokinetics of VEN in plasma and CSF samples from pediatric patients with R/R malignancies from a Phase 1 study, which demonstrates VEN's ability to cross into the central nervous system. 31 In light of these findings, VEN may have a role to play for patients with CNS complications. However, there is a need for further research in order to determine its utility in improving clinical outcomes.…”

Section: Discussionmentioning

confidence: 98%

Population Pharmacokinetic Models of Venetoclax in Hematologic Malignancies: A Systematic Review

Zhao,

Guo,

Zhu

et al. 2024

DDDT

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Several population pharmacokinetic (PPK) models of B cell lymphoma-2 (BCL-2) venetoclax (VEN) have been developed and published to characterize the influencing factors of pharmacokinetics in hematologic malignancies. This review described PPK models of VEN examining the magnitude and types of covariate effects in PK parameters, as well as identified areas that require further investigation in order to facilitate their use. Currently, there are six analyses on PPK models of VEN summarized in this review. Most analyses described the pharmacokinetics of VEN with a two-compartment model and all covariates are categorical. The median estimated apparent clearance (CL/F) was 446 L/Day and apparent volume of distribution of the central compartment (V 2 /F) was 114.5 L. The median IIV of CL/F reported was 39.5% and V 2 /F was 46.7%. Most commonly, CYP3A inhibitors, OATP1B3 inhibitors and rituximab co-administration were found to be significant covariates on CL/F. In addition, sex and population were influential covariates on V 2 /F. A detailed description of the characteristics of PPK models of VEN is provided in this review, as well as the effects of covariates on the PK parameters. For future development of the VEN PPK model, CYP3A inhibitors, rituximab co-administration, OATP1B1 transporter inhibitors, sex, population, and food might be considered. Further research and comprehensive investigations should be undertaken to explore reference ranges for therapeutic drug monitoring, define the potential role of patients with cerebrospinal fluid complications, and assess new or potential covariates. These endeavors will facilitate the development of personalized VEN therapy.

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Section: Discussionmentioning

confidence: 98%

Population Pharmacokinetic Models of Venetoclax in Hematologic Malignancies: A Systematic Review

Zhao,

Guo,

Zhu

et al. 2024

DDDT

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“… 17 The mean plasma‐to‐CSF ratio was 385 with a range of 44–1559, the mean is more than fourfold higher than the blood‐to‐brain ratio observed preclinically in mice, which suggests that other anatomical and/or physiological factors are involved in venetoclax disposition to the CSF. 17 …”

Section: Physicochemical Properties and Admementioning

confidence: 95%

“…Venetoclax can cross the blood–brain barrier as demonstrated in an open‐label, phase I study in 46 pediatric patients with relapsed/refractory (R/R) AML, acute lymphoblastic leukemia (ALL), or other hematological malignancies. Venetoclax concentrations in cerebrospinal fluid (CSF) were between <0.1 and 26 ng/mL with a mean concentration of 3.6 ng/mL 17 . The mean plasma‐to‐CSF ratio was 385 with a range of 44–1559, the mean is more than fourfold higher than the blood‐to‐brain ratio observed preclinically in mice, which suggests that other anatomical and/or physiological factors are involved in venetoclax disposition to the CSF 17 …”

Section: Physicochemical Properties and Admementioning

confidence: 99%

“…Venetoclax concentrations in cerebrospinal fluid (CSF) were between <0.1 and 26 ng/mL with a mean concentration of 3.6 ng/mL 17 . The mean plasma‐to‐CSF ratio was 385 with a range of 44–1559, the mean is more than fourfold higher than the blood‐to‐brain ratio observed preclinically in mice, which suggests that other anatomical and/or physiological factors are involved in venetoclax disposition to the CSF 17 …”

Section: Physicochemical Properties and Admementioning

confidence: 99%

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Clinical pharmacokinetics and pharmacodynamics of venetoclax, a selective B‐cell lymphoma‐2 inhibitor

Salem,

Menon

2024

Clinical Translational Sci

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Venetoclax, a highly potent BCL‐2 inhibitor, is indicated for treatment of some hematologic malignancies as monotherapy, and/or in combination with other agents. Venetoclax pharmacokinetics has been extensively characterized in patients and healthy participants. After oral dosing, the median time to reach maximum plasma concentration ranged from 5 to 8 h and harmonic mean half‐life ranged from 14 to 18 h. Food increases venetoclax bioavailability by 3–5‐fold and venetoclax should be administered with food to ensure adequate and consistent bioavailability. Venetoclax is eliminated via cytochrome P450 (CYP)3A metabolism, and a negligible amount of unchanged drug is excreted in urine. Strong CYP3A/P‐glycoprotein inhibitors increased venetoclax exposures (AUC) by 1.44‐ to 6.90‐fold while a significant decrease (71%) has been observed when dosed with strong CYP3 inducers. Venetoclax does not inhibit or induce CYP enzymes or transporters. Venetoclax pharmacokinetics is not appreciably altered by age, weight, sex, but the exposure is up to twofold higher in participants from Asian countries. Mild‐to‐severe renal impairment or end‐stage renal disease do not alter venetoclax exposures, and venetoclax is not cleared by dialysis. Although mild‐to‐moderate hepatic impairment does not affect venetoclax exposures, twofold higher exposure was observed in subjects with severe hepatic impairment. Venetoclax exposure is comparable across patients with different hematologic malignancies and healthy participants. Overall, venetoclax exposure is only affected by food and CYP3A modulators and is only higher in Asian subjects and subjects with severe hepatic impairment. Venetoclax exposure–response relationships are malignancy‐dependent and can be different between monotherapy and combination therapy.

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Recent Advances in Marine-Derived Nanoformulation for the Management of Glioblastoma

Devi,

Deka,

Das

et al. 2024

Mol Biotechnol

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Venetoclax Penetrates the Blood Brain Barrier: A Pharmacokinetic Analysis in Pediatric Leukemia Patients

Cited by 7 publications

References 20 publications

Population Pharmacokinetic Models of Venetoclax in Hematologic Malignancies: A Systematic Review

Population Pharmacokinetic Models of Venetoclax in Hematologic Malignancies: A Systematic Review

Clinical pharmacokinetics and pharmacodynamics of venetoclax, a selective B‐cell lymphoma‐2 inhibitor

Recent Advances in Marine-Derived Nanoformulation for the Management of Glioblastoma

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