Application of pharmacokinetic (PK)-guided 5-fluorouracil (FU) in clinical practice.

Abstract

2595 Background: Body surface area (BSA)-based dosing of FU results in up to 100-fold inter-individual PK variability. PK-guided FU compared to BSA-based dosing resulted in higher response rates and decreased rate of toxicities in two randomized clinical trials. A paucity of data exists on PK-guided FU dosing in the clinical setting. Methods: A total of 70 colorectal cancer (CRC) patients (pts) from 6 academic and community sites received mFOLFOX6 (FU 2,400 mg/m2over 46 h every 2 wks) +/- bevacizumab. Peripheral blood was obtained 2-44 h after start of FU infusion and AUCs were estimated using an immunoassay at Myriad Genetics. FU doses for cycles 2-4 (C2-4) were adjusted algorithmically to target an area under the concentration-time curve (AUC) of 20-25 mg*h/L. The primary outcome was the % of pts within target AUC by C4, with a secondary outcome of toxicity rates compared to historical data. Comparisons between cycles were made using generalized linear models, accounting for repeated observations within pt. Results: The % of pts within target AUC post C1 and C4 was 30% (17/57, 95%CI: 18-43%) and 46% (24/52, 95%CI: 32-61%), respectively (OR=2.16, p=0.05). For each subsequent cycle, the odds of a pt being within range increases by 28% (p=0.04) (Table). The median dose needed to achieve target AUC at C4 was 2,580 (range 1,920-3,484) mg/m2. The median AUC post C1 and C4 was 19 and 21 mg*h/L, respectively. Less grade 3/4 mucositis and diarrhea were seen compared to historical data (3 v 15% and 6 v 12%, respectively); however, no difference in grade 3/4 neutropenia was noted (27 v 33%). Nine pts were non-evaluable by protocol for PK analysis, largely due to sampling/processing errors. Conclusions: PK-guided FU resulted in a greater number of pts achieving the targeted AUC and fewer pts under-dosed at C4 compared to C1. Individualization of FU dosing in the front-line, community and academic, setting is achievable for the treatment of CRC; however, larger clinical trials are needed to define the clinical utility of PK-guided FU. Clinical trial information: NCT01164215. [Table: see text]