Regina Demlová1, Miroslav Turjap2, Ondřej Peš3, Katarína Kostolanská3, Jan Juřica4,5. 1. Department of Pharmacology, Medical Faculty, Masaryk University, Brno. 2. Department of Clinical Pharmacy, University Hospital Ostrava, Ostrava. 3. Department of Biochemistry, Medical Faculty, Masaryk University. 4. Department of Pharmacology, Medical Faculty, Masaryk University, Masaryk Memorial Cancer Institute; and. 5. Department of Human Pharmacology and Toxicology, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic.
Abstract
BACKGROUND: Sunitinib is an inhibitor of multiple receptor tyrosine kinases and is a standard-of-care treatment for advanced and metastatic renal cell carcinoma and a second-line treatment in locally advanced inoperable and metastatic gastrointestinal stromal tumors. A fixed dose of the drug, however, does not produce a uniform therapeutic outcome in all patients, and many face adverse effects and/or toxicity. One of the possible causes of the interindividual variability in the efficacy and toxicity response is the highly variable systemic exposure to sunitinib and its active metabolite. This review aims to summarize all available clinical evidence of the treatment of adult patients using sunitinib in approved indications, addressing the necessity to introduce proper and robust therapeutic drug monitoring (TDM) of sunitinib and its major metabolite, N-desethylsunitinib. METHODS: The authors performed a systematic search of the available scientific literature using the PubMed online database. The search terms were "sunitinib" AND "therapeutic drug monitoring" OR "TDM" OR "plasma levels" OR "concentration" OR "exposure." The search yielded 520 journal articles. In total, 447 publications were excluded because they lacked sufficient relevance to the reviewed topic. The remaining 73 articles were, together with currently valid guidelines, thoroughly reviewed. RESULTS: There is sufficient evidence confirming the concentration-efficacy and concentration-toxicity relationship in the indications of gastrointestinal stromal tumors and metastatic renal clear-cell carcinoma. For optimal therapeutic response, total (sunitinib + N-desethylsunitinib) trough levels of 50-100 ng/mL serve as a reasonable target therapeutic range. To avoid toxicity, the total trough levels should not exceed 100 ng/mL. CONCLUSIONS: According to the current evidence presented in this review, a TDM-guided dose modification of sunitinib in selected groups of patients could provide a better treatment outcome while simultaneously preventing sunitinib toxicity.
BACKGROUND:Sunitinib is an inhibitor of multiple receptor tyrosine kinases and is a standard-of-care treatment for advanced and metastatic renal cell carcinoma and a second-line treatment in locally advanced inoperable and metastatic gastrointestinal stromal tumors. A fixed dose of the drug, however, does not produce a uniform therapeutic outcome in all patients, and many face adverse effects and/or toxicity. One of the possible causes of the interindividual variability in the efficacy and toxicity response is the highly variable systemic exposure to sunitinib and its active metabolite. This review aims to summarize all available clinical evidence of the treatment of adult patients using sunitinib in approved indications, addressing the necessity to introduce proper and robust therapeutic drug monitoring (TDM) of sunitinib and its major metabolite, N-desethylsunitinib. METHODS: The authors performed a systematic search of the available scientific literature using the PubMed online database. The search terms were "sunitinib" AND "therapeutic drug monitoring" OR "TDM" OR "plasma levels" OR "concentration" OR "exposure." The search yielded 520 journal articles. In total, 447 publications were excluded because they lacked sufficient relevance to the reviewed topic. The remaining 73 articles were, together with currently valid guidelines, thoroughly reviewed. RESULTS: There is sufficient evidence confirming the concentration-efficacy and concentration-toxicity relationship in the indications of gastrointestinal stromal tumors and metastatic renal clear-cell carcinoma. For optimal therapeutic response, total (sunitinib + N-desethylsunitinib) trough levels of 50-100 ng/mL serve as a reasonable target therapeutic range. To avoid toxicity, the total trough levels should not exceed 100 ng/mL. CONCLUSIONS: According to the current evidence presented in this review, a TDM-guided dose modification of sunitinib in selected groups of patients could provide a better treatment outcome while simultaneously preventing sunitinibtoxicity.