Cabozantinib exposure –response analyses of efficacy and safety in patients with advanced hepatocellular carcinoma

AbstractCabozantinib, a multi-kinase inhibitor, is approved in the United States and European Union for treatment of patients with hepatocellular carcinoma following prior sorafenib treatment. In the Phase III CELESTIAL trial, hepatocellular carcinoma patients receiving cabozantinib showed longer overall survival (OS) and progression-free survival (PFS) than those receiving placebo. The approved cabozantinib (Cabometyx®) dose is 60  mg once daily with allowable dose modifications to manage adverse events (AE). Time-to-event Cox proportional hazard exposure–response (ER) models were developed to characterize the relationship between predicted cabozantinib exposure and the likelihood of various efficacy and safety endpoints. The ER models were used to predict hazard ratios (HR) for efficacy and safety endpoints for starting doses of 60, 40, or 20 mg daily. Statistically significant relationships between cabozantinib exposure and efficacy and safety endpoints were observed. For efficacy endpoints, predicted HR were lowe r for OS and PFS at 40 and 60 mg relative to the 20 mg dose: HR for death (OS) are 0.84 (40 mg) and 0.70 (60 mg); HR for disease progression/death (PFS) are 0.73 (40 mg) and 0.62 (60 mg). For safety endpoints, predicted HR were lower for palmar-plantar erythrodysaesthesia (PPE), diarrhea, and hypertension at 20 or 40 mg relative to the 60 mg dose: HR for PPE are 0.31 (20 mg) and 0.66 (40 mg); H...
Source: Journal of Pharmacokinetics and Pharmacodynamics - Category: Drugs & Pharmacology Source Type: research

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Source: Journal of Gastroenterology - Category: Gastroenterology Source Type: research
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Source: Medicine - Category: Internal Medicine Tags: Research Article: Observational Study Source Type: research
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Source: American Journal of Physiology. Gastrointestinal and Liver Physiology - Category: Physiology Authors: Tags: Am J Physiol Gastrointest Liver Physiol Source Type: research
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Source: Oncology Research - Category: Cancer & Oncology Tags: Oncol Res Source Type: research
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Source: Expert Review of Anticancer Therapy - Category: Cancer & Oncology Tags: Expert Rev Anticancer Ther Source Type: research
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Source: World Journal of Hepatology - Category: Gastroenterology Tags: World J Hepatol Source Type: research
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Source: Annals of Hepatology - Category: Gastroenterology Tags: Ann Hepatol Source Type: research
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Source: International Journal of Hyperthermia - Category: Internal Medicine Tags: Int J Hyperthermia Source Type: research
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Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Rattus norvegicus Source Type: research
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Source: Digestive and Liver Disease - Category: Gastroenterology Authors: Tags: Liver, Pancreas and Biliary Tract Source Type: research
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