Modeling the 5‐Fluorouracil Area Under the Curve Versus Dose Relationship to Develop a Pharmacokinetic Dosing Algorithm for Colorectal Cancer Patients Receiving FOLFOX6

• Published in: The oncologist (Dayton, Ohio) Ohio), 2012-03, Vol.17 (3), p.296-302
• Main Authors: Kaldate, Rajesh R., Haregewoin, Abebe, Grier, Charles E., Hamilton, Stephanie A., McLeod, Howard L.
• Format: Article
• Language: English
• Subjects: 5‐fluorouracil; Academia-Pharma Intersect; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Area Under Curve; Area under the curve; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - pathology; Dose-Response Relationship, Drug; Female; Fluorouracil - administration & dosage; Fluorouracil - pharmacokinetics; Fluorouracil - therapeutic use; FOLFOX6; Humans; Leucovorin - therapeutic use; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds - therapeutic use; Pharmacokinetics; Regression Analysis; Retrospective Studies
• ISSN: 1083-7159; 1549-490X
• DOI: 10.1634/theoncologist.2011-0357

Background. 5‐Fluorouracil (5‐FU) is administered based on standard body surface area (BSA) dosing. BSA administration results in highly variable exposure, measured as the area under the concentration‐time curve (AUC). An immunoassay (OnDose®; Myriad Genetic Laboratories, Inc., Salt Lake City, UT) that measures plasma 5‐FU concentration and reports an AUC in mg · h/L has been developed to optimize therapy using pharmacokinetic (PK) dosing. The results of an analysis to model the 5‐FU AUC‐dose relationship are presented. Methods. A set of 589 sequential patients from a clinical database receiving 5‐FU, leucovorin, and oxaliplatin (the FOLFOX6 regimen) for colorectal cancer (CRC) treatment was analyzed. A subset including only patients who had at least two consecutive cycles tested, received 1,600–3,600 mg/m2 of continuous infusion 5‐FU during the initial test cycle, and had a blood sample collected after ≥18 hours, was used to conduct regression modeling of the change in AUC versus change in dose. Results. A simple regression model with R2 = 0.51 developed over n = 307 cycle‐pair observations characterizes the AUC‐Dose relationship as: change in AUC = 0.02063 * dose change. The model suggests that dose changes in the range of 145–727 mg/m2 would be sufficient to adjust the AUC to a potential therapeutic threshold of >20 mg · h/L for most patients. Conclusions. 5‐FU is an ideal candidate for PK dose optimization. Because individual factors other than dose change may also affect the change in AUC, longitudinal PK monitoring in all cycles and dose adjustment to ensure AUC in the desired range of 20–30 mg · h/L are recommended. Results of an analysis to model the 5‐fluorouracil area under the concentration–time curve versus dose change relationship from a clinical database of colorectal cancer patients are presented.