Metabolism, Excretion, and Pharmacokinetics of Oral Brivanib in Patients with Advanced or Metastatic Solid Tumors

Mekhail, Tarek; Masson, Éric; Fischer, Bruce S.; Gong, Jiachang; Iyer, Ramaswamy A.; Gan, Jinping; Pursley, Janice; Patricia, Daniel; Williams, Daphne; Ganapathi, Ram

doi:10.1124/dmd.110.033951

Cited by 22 publications

(29 citation statements)

References 23 publications

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“…Urine and feces were collected from each patient over intervals through 288 h postdose. Further details of this study were reported by Mekhail et al (2010).…”

Section: 4]triazin-4-yloxy)-1h-indole-2-carboxylic Acid (M26) Were Smentioning

confidence: 99%

Metabolism and Disposition of [¹⁴C]Brivanib Alaninate after Oral Administration to Rats, Monkeys, and Humans

Gong

Gan²,

Caceres‐Cortes³

et al. 2011

Drug Metab Dispos

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]brivanib alaninate to intact rats, bile duct-cannulated (BDC) rats, intact monkeys, BDC monkeys, and humans. Fecal excretion was the primary route of elimination of drug-derived radioactivity in animals and humans. In BDC rats and monkeys, the majority of radioactivity was excreted in bile. Brivanib alaninate was rapidly and completely converted via hydrolysis to brivanib in vivo. The area under the curve from zero to infinity of brivanib accounted for 14.2 to 54.3% of circulating radioactivity in plasma in animals and humans, suggesting that metabolites contributed significantly to the total drug-related radioactivity. In plasma from animals and humans, brivanib was a prominent circulating component. All the metabolites that humans were exposed to were also present in toxicological species. On the basis of metabolite exposure and activity against VEGF and FGF receptors of the prominent human circulating metabolites, only brivanib is expected to contribute to the pharmacological effects in humans. Unchanged brivanib was not detected in urine or bile samples, suggesting that metabolic clearance was the primary route of elimination. The primary metabolic pathways were oxidative and conjugative metabolism of brivanib.

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“…Urine and feces were collected from each patient over intervals through 288 h postdose. Further details of this study were reported by Mekhail et al (2010).…”

Section: 4]triazin-4-yloxy)-1h-indole-2-carboxylic Acid (M26) Were Smentioning

confidence: 99%

Metabolism and Disposition of [¹⁴C]Brivanib Alaninate after Oral Administration to Rats, Monkeys, and Humans

Gong

Gan²,

Caceres‐Cortes³

et al. 2011

Drug Metab Dispos

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“…Brivanib, an oral, selective dual inhibitor of FGFR and VEGF receptor (VEGFR) tyrosine kinases, has shown antitumor activity in preclinical models of various cancers, including HCC (23)(24)(25)(26)(27). Brivanib has a half-life of 12 hours and is administered once daily at a dose of 800 mg.…”

Section: Introductionmentioning

confidence: 99%

Phase II, Open-Label Study of Brivanib as Second-Line Therapy in Patients with Advanced Hepatocellular Carcinoma

Finn

Kang

Mulcahy

et al. 2012

Clinical Cancer Research

165

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Purpose: Brivanib, a selective dual inhibitor of fibroblast growth factor and VEGF signaling, has recently been shown to have activity as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). This phase II open-label study assessed brivanib as second-line therapy in patients with advanced HCC who had failed prior antiangiogenic treatment.Experimental Design: Brivanib was administered orally at a dose of 800 mg once daily. The primary objectives were tumor response rate, time to response, duration of response, progression-free survival, overall survival (OS), disease control rate, time to progression (TTP), and safety and tolerability.Results: Forty-six patients were treated. Best responses to treatment with brivanib (N ¼ 46 patients) using modified World Health Organization criteria were partial responses for two patients (4.3%), stable disease for 19 patients (41.3%), and progressive disease for 19 patients (41.3%). The tumor response rate was 4.3%; the disease control rate was 45.7%. Median OS was 9.79 months. Median TTP as assessed by study investigators following second-line treatment with brivanib was 2.7 months. The most common adverse events were fatigue, decreased appetite, nausea, diarrhea, and hypertension.Conclusion: Brivanib had a manageable safety profile and is one of the first agents to show promising antitumor activity in advanced HCC patients treated with prior sorafenib.

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“…Brivanib has manageable safety profiles in long-term toxicology and clinical studies (Mekhail et al, 2010;Park et al, 2011). The toxicology profile of the enantiomeric metabolite was not directly studied in preclinical species.…”

Section: Metabolite Profiles Of Incubation Mixtures Of [mentioning

confidence: 99%

“…The biotransformation and disposition of brivanib in animals and humans have been characterized previously (Mekhail et al, 2010;Gong et al, 2011). After oral doses of [ 14 C]brivanib alaninate to rats, monkeys, and humans, the radioactive dose was mainly cleared by metabolism, and the majority of drug-derived radioactivity was excreted in feces (Gong et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Metabolic Chiral Inversion of Brivanib and Its Relevance to Safety and Pharmacology

et al. 2012

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ABSTRACT:Brivanib alaninate is an orally administered alanine prodrug of brivanib, a dual inhibitor of the vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) signaling pathways. It is currently in clinical trials for the treatment of hepatocellular carcinoma and colorectal cancer. Brivanib has a single asymmetric center derived from a secondary alcohol. The potential for chiral inversion was investigated in incubations with liver subcellular fractions and in animals and humans after oral doses of brivanib alaninate. Incubations of [ 14 C]brivanib alaninate with liver microsomes and cytosols from rats, monkeys, and humans followed by chiral chromatography resulted in two radioactive peaks, corresponding to brivanib and its enantiomer. The percentage of the enantiomeric metabolite relative to brivanib in microsomal and cytosolic incubations of different species in the presence of NADPH ranged from 11.6 to 15.8 and 0.8 to 3.1%, respectively. The proposed mechanism of inversion involves the oxidation of brivanib to a ketone metabolite, which is subsequently reduced to brivanib and its enantiomer. After oral doses of brivanib alaninate to rats and monkeys, the enantiomeric metabolite was a prominent drug-related component in plasma, with the percentages of area under the curve (AUC) at 94.7 and 39.7%, respectively, relative to brivanib. In humans, the enantiomeric metabolite was a minor circulating component, with the AUC <3% of brivanib. Pharmacological studies indicated that brivanib and its enantiomer had similar potency toward the inhibition of VEGF receptor-2 and FGF receptor-1 kinases. Because of low plasma concentration in humans, the enantiomeric metabolite was not expected to contribute significantly to target-related pharmacology of brivanib. Moreover, adequate exposure in the toxicology species suggested no specific safety concerns with respect to exposure to the enantiomeric metabolite.

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Metabolism, Excretion, and Pharmacokinetics of Oral Brivanib in Patients with Advanced or Metastatic Solid Tumors

Abstract: ABSTRACT:The goal of this study was to evaluate the pharmacokinetics, mass balance, metabolism, routes and extent of elimination, and safety of a single oral dose of 14

Cited by 22 publications

References 23 publications

Metabolism and Disposition of [¹⁴C]Brivanib Alaninate after Oral Administration to Rats, Monkeys, and Humans

Metabolism and Disposition of [¹⁴C]Brivanib Alaninate after Oral Administration to Rats, Monkeys, and Humans

Phase II, Open-Label Study of Brivanib as Second-Line Therapy in Patients with Advanced Hepatocellular Carcinoma

Metabolic Chiral Inversion of Brivanib and Its Relevance to Safety and Pharmacology

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Metabolism, Excretion, and Pharmacokinetics of Oral Brivanib in Patients with Advanced or Metastatic Solid Tumors

Abstract: ABSTRACT:The goal of this study was to evaluate the pharmacokinetics, mass balance, metabolism, routes and extent of elimination, and safety of a single oral dose of 14

Cited by 22 publications

References 23 publications

Metabolism and Disposition of [14C]Brivanib Alaninate after Oral Administration to Rats, Monkeys, and Humans

Metabolism and Disposition of [14C]Brivanib Alaninate after Oral Administration to Rats, Monkeys, and Humans

Phase II, Open-Label Study of Brivanib as Second-Line Therapy in Patients with Advanced Hepatocellular Carcinoma

Metabolic Chiral Inversion of Brivanib and Its Relevance to Safety and Pharmacology

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Metabolism and Disposition of [¹⁴C]Brivanib Alaninate after Oral Administration to Rats, Monkeys, and Humans

Metabolism and Disposition of [¹⁴C]Brivanib Alaninate after Oral Administration to Rats, Monkeys, and Humans