Abstract
The primary objective of this study is to evaluate the capacity of concentration-guided sorafenib dosing protocols to increase the proportion of patients that achieve a sorafenib maximal concentration (Cmax) within the range 4.78 to 5.78 μg/mL. A full physiologically based pharmacokinetic model was built and validated using Simcyp® (version 19.1). The model was used to simulate sorafenib exposure in 1000 Sim-Cancer subjects over 14 days. The capacity of concentration-guided sorafenib dose adjustment, with/without model-informed dose selection (MIDS), to achieve a sorafenib Cmax within the range 4.78 to 5.78 μg/mL was evaluated in 500 Sim-Cancer subjects. A multivariable linear regression model incorporating hepatic cytochrome P450 (CYP) 3A4 abundance, albumin concentration, body mass index, body surface area, sex and weight provided robust prediction of steady-state sorafenib Cmax (R2 = 0.883; p < 0.001). These covariates identified subjects at risk of failing to achieve a sorafenib Cmax ≥ 4.78 μg/mL with 95.0% specificity and 95.2% sensitivity. Concentration-guided sorafenib dosing with MIDS achieved a sorafenib Cmax within the range 4.78 to 5.78 μg/mL for 38 of 52 patients who failed to achieve a Cmax ≥ 4.78 μg/mL with standard dosing. In a simulation setting, concentration-guided dosing with MIDS was the quickest and most effective approach to achieve a sorafenib Cmax within a designated range.
Highlights
Sorafenib is an orally administered small molecule kinase inhibitor (KI) used in the treatment of advanced hepatocellular (HCC) and renal cell (RCC) carcinomas
The primary objective of this study is to evaluate the capacity of concentration-guided sorafenib dose adjustment, with and without model-informed dose selection (MIDS), to increase the proportion of patients that achieve a sorafenib Cmax within a concentration range of 4.78 to 5.78 μg/mL
The present study demonstrated that concentration-guided dosing with MIDS facilitates therapeutic sorafenib exposure in 99% of subjects within 28 days while minimising the number of additional subjects at risk of supra-therapeutic dosing compared to concentration-guided dosing alone
Summary
Sorafenib is an orally administered small molecule kinase inhibitor (KI) used in the treatment of advanced hepatocellular (HCC) and renal cell (RCC) carcinomas. Variability in sorafenib exposure between individuals and within an individual over time has been identified as a potential source of heterogeneity in treatment efficacy and tolerability [1,2]. Variability in gastrointestinal absorption due to limited and pH dependent solubility has been proposed as a major source of variability in exposure [6], concomitant proton pump inhibitor (PPI) use, which is reported to reduce KI absorption [7], has been demonstrated to have no impact on survival outcomes in HCC [8] and RCC [9,10].
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