Factors Affecting Pharmacokinetics of Sunitinib and Its Metabolite, SU12662: A Systematic Review of Population Pharmacokinetic Studies.
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BACKGROUND AND OBJECTIVE: Sunitinib malate is used to treat advanced renal cell carcinoma, gastrointestinal stromal, and pancreatic tumors. Wide variability in drug exposure is reported for both sunitinib and its active metabolite (SU12662). This review aimed to summarize reported population pharmacokinetics studies of sunitinib and to identify the factors affecting the pharmacokinetics of sunitinib and SU12662. METHODS: A systematic search was undertaken using Scopus, Web of Science, and PubMed databases following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Studies were included in the review if population pharmacokinetic modeling approach was used for sunitinib and/or SU12662 in adult and/or pediatric population. Data quality was assessed using the percent compliance rate of each study. RESULTS: A total of 1820 articles were retrieved, and subsequently, 14 studies that met the inclusion criteria were included in the systematic review. Most of the studies reported two-compartment model with first-order absorption and elimination to describe sunitinib and SU12662. Body surface area, age, sex, ethnicity, tumor type, and ABCB1 and ABCG2 genotype were the significant covariates that affected the pharmacokinetics of sunitinib and SU12662. CONCLUSIONS: According to the published data from the reported studies, various covariates alter sunitinib and SU12662 exposure and thus have the potential to influence the clinical outcome of sunitinib treatment. Predictive performance assessment of these published models should be performed before implementing these models during the routine clinical practice. The summarized significant covariates affecting pharmacokinetics (PK) of sunitinib and SU12662 will facilitate model-informed precision dosing of sunitinib therapy in a clinical setting.