A phase I pharmacokinetic study of metronomic vinorelbine and sorafenib using two schedules in Asian non-small cell lung cancer (NSCLC) patients

Abstract

Background: A recent Phase I study of metronomic oral vinorelbine (60mg, 90mg and 120mg) per week and 200mg BID sorafenib inAsian NSCLC patients performedby our group showed that the combinationof 60mg/week vinorelbine and 200mg BID sorafe-nib correlated with better survival and response. We herein report the pharmacoki-netics (PK) profile of metronomic vinorelbine at these three doses in combination with 200mg BID sorafenib in Asian NSCLC patients to better understand the pharmacology of this low dose combination treatment. Methods: Thirty-five NSCLC patients were randomly allocated into two treatment schedules S1 (N= 19) and S2 (N = 16) and sub-grouped to receive either oral vinorel-bine at three dose levels on Day 1 followed by 200mg sorafenib BID on Day 17 (S1) and vice-versa (S2). PK analysis of samples collected at steady-state on Days 15 and 29 from each group were quantified using LC-MS/MS. PK parameters were derived using non-compartmental analysis. Statistical analyses were performed on GraphPad Prism 6.0c. Results: Higher exposure of vinorelbine as determined by these PK parameters (average vinorelbine concentrations (Cav), area under the plasma-concentration curve (AUC0-1) and vinorelbine clearance (CL/F)) was observed in 60mg/week cohort compared to that of 90mg/week group in S1 on Day 15. [60mg/week vs 90mg/week respectively Cav: 2.62 ng/mL vs0.57 ng/mL, P=0.016; AUC0-1: 277.7 h.ng/mL vs 41.2h.ng/mL, P=0.06; CL/F: 158.77 L/h vs 1094.0 L/h, P=0.016]. Similar trends in Cav, AUC0-1 and CL/F were also observed from steady-state samples collected at Day 29 in both schedules; probably suggesting a lack of drug-drug interactions between vinorelbine and sorafe-nib. Due to insufficient sampling collection, analysis could not be performed for the 120mg/week cohort. No significant changes in sorafenib PK parameters were discernible in either S1 or S2. Conclusions: This pilot study illustrates that 60mg/week vinorelbine confers a more superior PK profile and improved clinical response compared to 90mg/week or 120mg/week. Future studies should investigate the combined therapeutic effect of 60mg/week vinorelbine and 200mg BID sorafenib in a Phase II efficacy trial.