The plasma and cerebrospinal fluid pharmacokinetics of sorafenib after intravenous administration in non-human primates

Kim, AeRang; McCully, Cindy; Cruz, Raphael; Cole, Diane E.; Fox, Elizabeth; Balis, Frank M.; Widemann, Brigitte C.

doi:10.1007/s10637-010-9585-1

Cited by 20 publications

(13 citation statements)

References 23 publications

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“…Our findings were similar to the CSF exposure of most other tyrosine kinase inhibitors (35, 36). Although drug levels in the CSF are commonly used as surrogates of brain parenchyma penetration, this assumption is not completely valid particularly for brain tumors with a disrupted blood-brain barrier.…”

Section: Discussionsupporting

confidence: 88%

Phase I Trial, Pharmacokinetics, and Pharmacodynamics of Vandetanib and Dasatinib in Children with Newly Diagnosed Diffuse Intrinsic Pontine Glioma

Broniscer

Baker

Wetmore

et al. 2013

Clinical Cancer Research

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Purpose Testing of promising drug combinations is crucial in the treatment of diffuse intrinsic pontine glioma (DIPG). Since the VEGF and PDGF pathways are critical in gliomas, we evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of vandetanib, a VEGFR-2 inhibitor, combined with dasatinib, a potent PDGFR inhibitor, during and after radiotherapy in children with newly diagnosed DIPG. Experimental Design Dasatinib was started concurrently with radiotherapy. Vandetanib was started 8 days later. We tested increasing doses of vandetanib (65 and 85 mg/m2 once daily) and dasatinib (65 and 85 mg/m2 twice daily). Dose-limiting toxicities were evaluated during the first six weeks of therapy. Plasma pharmacokinetics was obtained on days 8 and 42±3 in all patients and concomitantly with cerebrospinal fluid (CSF) when possible. Inhibition of targets of dasatinib in peripheral blood mononuclear cells (PBMCs) was evaluated. Results Twenty-five patients were treated. Treatment was well tolerated. The median duration of treatment was 184 days. Diarrhea was the most significant toxicity. Three patients experienced substantial myelosuppression. The steady-state plasma pharmacokinetics of vandetanib was comparable to previous studies. Although the plasma exposure to dasatinib decreased from days 8 to 42, it remained similar to adult studies. CSF to plasma exposure of vandetanib and dasatinib were approximately 2% in 2 patients. Phosphorylated 70S6K decreased during therapy in PBMCs. Conclusions The MTD of vandetanib and dasatinib in combination was 65 mg/m2 for each drug. Other studies are underway to test dasatinib and other PDGFR inhibitors alone or in combination for this deadly cancer.

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Section: Discussionsupporting

confidence: 88%

Phase I Trial, Pharmacokinetics, and Pharmacodynamics of Vandetanib and Dasatinib in Children with Newly Diagnosed Diffuse Intrinsic Pontine Glioma

Broniscer

Baker

Wetmore

et al. 2013

Clinical Cancer Research

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“…Blood was collected 12 hours after the last sorafenib dose, which was also used as the level immediately before the next dose, as well as 0.5, 1, 2, 3, 5, and 8 hours after the dose of sorafenib between days 14 and 28 of cycle 1. Sorafenib plasma concentrations were measured using the high-performance liquid chromatography tandem mass spectroscopic (HPLC/MS-MS) method adapted from an assay (17) with a lower limit of quantification of 5 ng/mL (18). …”

Section: Methodsmentioning

confidence: 99%

A Phase I Trial and Pharmacokinetic Study of Sorafenib in Children with Refractory Solid Tumors or Leukemias: A Children's Oncology Group Phase I Consortium Report

Widemann

Kim

Fox

et al. 2012

Clinical Cancer Research

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106

105

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Purpose To determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of sorafenib in children with refractory extracranial solid tumors and evaluate the tolerability of the solid tumor MTD in children with refractory leukemias. Experimental Design Sorafenib was administered orally every 12 hours for consecutive 28-day cycles. Pharmacokinetics (day 1 and steady-state) and pharmacodynamics were conducted during cycle 1. Results Of 65 patients enrolled, 60 were eligible. In the solid tumor cohort (n = 49), 4 of 6 patients experienced a DLT [hypertension, pain, rash/urticaria, thrombocytopenia, alanine aminotransferase (ALT)/ aspartate aminotransferase (AST)] at the starting dose (150 mg/m2/dose) which resulted in de-escalation to 105 mg/m2/dose. After eligibility criteria modification and dose re-escalation, the MTD was 200 mg/m2/ dose for solid tumors and 150 mg/m2/dose for leukemias. Sorafenib exposure was highly variable between patients but was within the ranges reported in adults. The apparent sorafenib clearance increased with patient age. Diarrhea, rash, fatigue, and increased ALT/AST were the most common sorafenib-related toxicities. Stable disease for 4 or more cycles was observed in 14 solid tumor patients, and 2 patients with acute myeloid leukemia (AML) and FLT3 internal tandem duplication (FLT3ITD) experienced a decrease in bone marrow blasts to less than 5%. Conclusions The recommended phase II dose of sorafenib administered every 12 hours continuously for children with solid tumors is 200 mg/m2/dose and 150 mg/m2/dose for children with leukemias. Sorafenib toxicities and distribution in children are similar to adults. The activity of sorafenib in children with AML and FLT3ITD is currently being evaluated, and a phase II study for select solid tumors is ongoing.

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“…To assess the blood-brain barrier (BBB) permeability of TKIs, cerebrospinal fluid (CSF) concentrations have been compared to blood-concentrations [50]. A number of TKI assays for the analysis and subsequent calculation of the CSF-penetration rate have been published for erlotinib, gefitinib, sorafenib and vandetanib [8,[51][52][53][54][55]. CSF is a relatively clean ultrafiltrate, with a low protein level of approximately 0.15 to 0.60 g/L (blood-plasma contains ca.…”

Section: Cerebrospinal Fluidmentioning

confidence: 99%

Recent developments in the chromatographic bioanalysis of approved kinase inhibitor drugs in oncology

Rood

Schellens

Beijnen

et al. 2016

Journal of Pharmaceutical and Biomedical Analysis

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The plasma and cerebrospinal fluid pharmacokinetics of sorafenib after intravenous administration in non-human primates

Abstract: Sorafenib is well tolerated in NHP and measurable in CSF after an IV dose. The CSF penetration of sorafenib is limited relative to total and free drug exposure in plasma.

Cited by 20 publications

References 23 publications

Phase I Trial, Pharmacokinetics, and Pharmacodynamics of Vandetanib and Dasatinib in Children with Newly Diagnosed Diffuse Intrinsic Pontine Glioma

Phase I Trial, Pharmacokinetics, and Pharmacodynamics of Vandetanib and Dasatinib in Children with Newly Diagnosed Diffuse Intrinsic Pontine Glioma

A Phase I Trial and Pharmacokinetic Study of Sorafenib in Children with Refractory Solid Tumors or Leukemias: A Children's Oncology Group Phase I Consortium Report

Recent developments in the chromatographic bioanalysis of approved kinase inhibitor drugs in oncology

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