ABSTRACT
BACKGROUND: Plasma exposure of sunitinib shows large inter-individual variation. Therefore, a pharmacokinetic (PK) study was performed to determine safety and feasibility of sunitinib dosing based on PK levels. METHODS: Patients were treated with sunitinib 37.5 mg once daily. At days 15 and 29 of treatment, plasma trough levels of sunitinib and N-desethyl sunitinib were measured. If the total trough level (TTL) was <50 ng ml(-1) and the patient did not show any grade ⩾3 toxicity, the daily sunitinib dose was increased by 12.5 mg. If the patient suffered from grade ⩾3 toxicity, the sunitinib dose was lowered by 12.5 mg. RESULTS: Twenty-nine out of 43 patients were evaluable for PK assessments. Grade ⩾3 adverse events were experienced in seven patients (24%) at the starting dose and in nine patients (31%) after dose escalation. TTLs were below target in 15 patients (52%) at the starting dose. Of these, five patients (17%) reached target TTL after dose escalation without additional toxicity. CONCLUSIONS: In a third of the patients that were below target TTL at standard dose, the sunitinib dose could be increased without additional toxicities. This could be the basis for future studies and the implementation of a PK-guided dosing strategy in clinical practice.
Subject(s)
Antineoplastic Agents/administration & dosage , Indoles/administration & dosage , Neoplasms/drug therapy , Protein Kinase Inhibitors/administration & dosage , Pyrroles/administration & dosage , Salvage Therapy , Adult , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/blood , Antineoplastic Agents/pharmacokinetics , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Monitoring , Fatigue/chemically induced , Feasibility Studies , Female , Gastrointestinal Diseases/chemically induced , Hematologic Diseases/chemically induced , Humans , Indoles/adverse effects , Indoles/blood , Indoles/pharmacokinetics , Male , Middle Aged , Neoplasms/enzymology , Nervous System Diseases/chemically induced , Pilot Projects , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/blood , Protein Kinase Inhibitors/pharmacokinetics , Pyrroles/adverse effects , Pyrroles/blood , Pyrroles/pharmacokinetics , SunitinibABSTRACT
Interpatient variability in the pharmacokinetics (PK) of sunitinib is high. Single nucleotide polymorphisms (SNPs) in PK candidate genes have been associated with the efficacy and toxicity of sunitinib, but whether these SNPs truly affect the PK of sunitinib remains to be elucidated. This multicenter study involving 114 patients investigated whether these SNPs and haplotypes in genes encoding metabolizing enzymes or efflux transporters are associated with the clearance of sunitinib and its active metabolite SU12662. SNPs were tested as covariates in a population PK model. From univariate analysis, we found that the SNPs in CYP3A4, CYP3A5, and ABCB1 were associated with the clearance of both sunitinib and SU12662. In multivariate analysis, CYP3A4*22 was found to be eliminated last with an effect size of -22.5% on clearance. Observed effect sizes are below the interindividual variability in clearance and are therefore too limited to directly guide individual dosing of sunitinib.
