Pharmacokinetic Assessment of Cooperative Efflux of the Multitargeted Kinase Inhibitor Ponatinib Across the Blood-Brain Barrier

Laramy, Janice K.; Kim, Minjee; Parrish, Karen E.; Sarkaria, Jann N.; Elmquist, William F.

doi:10.1124/jpet.117.246116

Cited by 30 publications

(22 citation statements)

References 33 publications

(50 reference statements)

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“…Compartmental Analysis with a BBB Model. A compartmental model that includes a brain compartment (BBB model) was used to quantitatively assess the rate and extent of SAR405838 distribution into and out of the mouse brain (Liu et al, 2005;Laramy et al, 2018). The model was fit to the data in two steps.…”

Section: Pharmacokinetic Data Analysismentioning

confidence: 99%

Brain Distributional Kinetics of a Novel MDM2 Inhibitor SAR405838: Implications for Use in Brain Tumor Therapy

Kim

Laramy

Gampa³

et al. 2019

Drug Metab Dispos

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Achieving an effective drug concentration in the brain is as important as targeting the right pathway when developing targeted agents for brain tumors. SAR405838 is a novel molecularly targeted agent that is in clinical trials for various solid tumors. Its application for tumors in the brain has not yet been examined, even though the target, the MDM2-p53 interaction, is attractive for tumors that could occur in the brain, including glioblastoma and brain metastases. In vitro and in vivo studies indicate that SAR405838 is a substrate of P-glycoprotein (P-gp). P-gp mediated active efflux at the bloodbrain barrier plays a dominant role in limiting SAR405838 brain distribution. Even though the absence of P-gp significantly increases the drug exposure in the brain, the systemic exposure, including absorption and clearance processes, were unaffected by P-gp deletion. Model-based parameters of SAR405838 distribution across the blood-brain barrier indicate the CL out of the brain was approximately 40-fold greater than the CL in. The free fraction of SAR405838 in plasma and brain were found to be low, and subsequent Kp uu values were less than unity, even in P-gp/Bcrp knockout mice. These results indicate additional efflux transporters other than P-gp and Bcrp may be limiting distribution of SAR405838 to the brain. Concomitant administration of elacridar significantly increased brain exposure, also without affecting the systemic exposure. This study characterized the brain distributional kinetics of SAR405838, a novel MDM2 inhibitor, to evaluate its potential in the treatment of primary and metastatic brain tumors. SIGNIFICANCE STATEMENT This paper examined the brain distributional kinetics of a novel MDM2-p53 targeted agent, SAR405838, to see its possible application for brain tumors by using in vitro, in vivo, and in silico approaches. SAR405838 is found to be a substrate of P-glycoprotein (P-gp), which limits its distribution to the brain. Based on the findings in the paper, manipulation of the function of P-gp can significantly increase the brain exposure of SAR405838, which may give an insight on its potential benefit as a treatment for primary and metastatic brain cancer.

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Section: Pharmacokinetic Data Analysismentioning

confidence: 99%

Brain Distributional Kinetics of a Novel MDM2 Inhibitor SAR405838: Implications for Use in Brain Tumor Therapy

Kim

Laramy

Gampa³

et al. 2019

Drug Metab Dispos

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“…There are no data regarding the crossing of lenvatinib through the blood-brain barrier, but as regards other MTK inhibitors we can suppose a reduced transfer in the brain, and therefore a reduced concentration and activity at this level. [10][11][12][13] On the other hand, no locoregional recurrences in other sites of the body were present. Rather, lenvatinib appeared to exert very good locoregional control, inasmuch as CT/PET showed a very remarkable reduction of FDG uptake in the neck.…”

Section: Discussionmentioning

confidence: 92%

Low-intermediate dose of lenvatinib in anaplastic thyroid cancer is highly effective and safe

et al. 2020

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We report two cases of anaplastic thyroid cancer (ATC) which had a very good response to a treatment with lenvatinib at 14 mg. A 73-year-old man with ATC stage IVB was operated on, undergoing a near-total thyroidectomy, and the pathological remnant tissue showed a quick and partial response to treatment with the drug. The patient had a single metastasis in the brain after 9 months, but then died due to bronchopneumonia after undergoing a neurosurgical intervention for the complete removal of the lesion. A 74-year-old woman with ATC stage IV was operated on, undergoing a near-total thyroidectomy after a neoadjuvant treatment with the drug, that was continued after surgical treatment. She had a partial remission of the local disease and of distant metastasis, which lasted for 14 months. She then died 4 months later due to cancer progression. Lenvatinib at 14 mg appears to be effective, fast and well tolerated.

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“…These parameters can be calculated using the brain slice technique (discussed below) or the equilibrium dialysis method. 66,67 K p,uu measurements allow understanding of whether or not molecules are subject to influx or efflux processes within the BBB. Typically, at steady-state concentrations the values for K p,uu would be at unity.…”

Section: Brain Uptake Measurements Using Partition Coefficients At Steady State Conditionsmentioning

confidence: 99%

Understanding the brain uptake and permeability of small molecules through the BBB: A technical overview

Chowdhury

Noorani

Alqahtani

et al. 2021

J Cereb Blood Flow Metab

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The brain is the most important organ in our body requiring its unique microenvironment. By the virtue of its function, the blood-brain barrier poses a significant hurdle in drug delivery for the treatment of neurological diseases. There are also different theories regarding how molecules are typically effluxed from the brain. In this review, we comprehensively discuss how the different pharmacokinetic techniques used for measuring brain uptake/permeability of small molecules have evolved with time. We also discuss the advantages and disadvantages associated with these different techniques as well as the importance to utilize the right method to properly assess CNS exposure to drug molecules. Even though very strong advances have been made we still have a long way to go to ensure a reduction in failures in central nervous system drug development programs.

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Pharmacokinetic Assessment of Cooperative Efflux of the Multitargeted Kinase Inhibitor Ponatinib Across the Blood-Brain Barrier

Cited by 30 publications

References 33 publications

Brain Distributional Kinetics of a Novel MDM2 Inhibitor SAR405838: Implications for Use in Brain Tumor Therapy

Brain Distributional Kinetics of a Novel MDM2 Inhibitor SAR405838: Implications for Use in Brain Tumor Therapy

Low-intermediate dose of lenvatinib in anaplastic thyroid cancer is highly effective and safe

Understanding the brain uptake and permeability of small molecules through the BBB: A technical overview

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