A Population Pharmacokinetic Meta-analysis of Sunitinib Malate (SU11248) and Its Primary Metabolite (SU12662) in Healthy Volunteers and Oncology Patients

Abstract

Purpose: Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor approved for advanced renal cell carcinoma and imatinib-resistant or imatinib-intolerant gastrointestinal stromal tumor. Following administration, sunitinib is metabolized by cytochrome P450 3A4 to an active metabolite (SU12662). The objective of this analysis was to assess sunitinib and SU12662 pharmacokinetics and to identify covariates that might explain variability in exposure following oral administration. Experimental Design: Data from 590 subjects (73 volunteers and 517 patients) in 14 studies were analyzed. Plasma concentration-time data were analyzed using nonlinear mixed-effects modeling to estimate population pharmacokinetic parameters, as well as relationships between these parameters and gender, race, age, weight, creatinine clearance, Eastern Cooperative Oncology Group score, and tumor type. Simulations were done to determine the predicted effect of these covariates on exposure.Results: Separate models were developed for sunitinib and SU12662 (each a two-compartment model with first-order absorption and elimination). Sunitinib parameters were estimated as CL/F, 51.8 L/h andVd/F central , 2,030 liters. SU12662 parameters were estimated as CL/F, 29.6 L/h and Vd/F central , 3,080 liters. Tumor type (except acute myeloid leukemia), Asian race, gender, body weight, and elevated Eastern Cooperative Oncology Group score described a portion of the variability in CL/F for sunitinib and metabolite; gender and body weight explained some of the variability in Vd/F central for sunitinib and metabolite. Among patients, the predicted changes in sunitinib and metabolite AUC and C max as a result of the individual covariates ranged up to 17%. Conclusion: The magnitude of the predicted changes in exposure with the covariates studied minimizes the necessity for dose adjustment in any of these subpopulations.

Assessment of ethnic differences in sunitinib outcome between Caucasian and Asian patients with metastatic renal cell carcinoma: a meta-analysis

“…The effect sizes of above-mentioned factors are relatively small compared to the inter-individual variability of pharmacokinetic characteristics of 32.2% and 42.9% in clearance of sunitinib and SU12662 reported by Diekstra et al [55], and even higher variability published by Houk et al (37.9% and 52.2%, respectively) [44].…”

“…As to the pharmacokinetics of sunitinib, Houk et al assessed the population pharmacokinetics of sunitinib and SU12662 including patients with mRCC, gastrointestinal stromal tumor and other solid tumors. It was shown that the dug exposure (indicated as AUC) and the maximal plasma drug concentration (Cmax) for both sunitinib and SU12662 in Asian patients were about 15% higher compared to other ethnical groups [44]. In addition, Nagata et al [45] reported that the total trough level of sunitinib in six Japanese RCC patients using 50mg daily 4/2 schedule was higher than 100 ng/ml, whereas the average concentration of total sunitinib in Caucasian male patients (body weight: 77 kg, 50 mg daily dose) stated by Houk et al [44] was 30-90 ng/ml.…”

“…Compared to the Caucasian population, Asian people in general have a relatively lower body surface area (BSA), and as a result drug exposure in Asian patients may be higher after a standard dose. However, no or only a relatively small effect of BSA on sunitinib pharmacokinetics was identified in both Caucasian [44] and Japanese patients [46]. In contrast, the lean body mass (LBM) has recently been identified to be related with sunitinib and SU12662 exposure in 92 patients with solid tumors.…”

Practical Recommendations for Therapeutic Drug Monitoring of Kinase Inhibitors in Oncology

“…In RCC, increasing AUC has been related to higher response rates, longer PFS, and OS 74, 75, 76, 77. A meta‐analysis found AUC of sunitinib combined with its active metabolite N‐desethylsunitinib to be significantly associated with PFS and OS in both GIST ( n = 401) and RCC ( n = 169), all P < 0.01 76.…”

Current Perspectives on Sunitinib Targeted Therapy for Tumors

“…The pharmacokinetics of sunitinib and sunitinib malate have been evaluated in 135 healthy volunteers and in 266 patients with solid tumors [17,19]. The study have shown that following a single oral dose, peak plasma sunitinib concentrations occur between 6 and 12 hours post-dose [16,20]. In addition, sunitinib and SU12662 have previously been shown to display linear pharmacokinetics and have prolonged half-lives of 40 and 80 hours, respectively [21].…”