LBOVI‐B‐2

BACKGROUND Dihydropyrimidine dehydrogenase (DPD) deficiency leads to life-threatening 5-Fluorouracil toxicity. We developed a 2-13C-uracil (13C-Ura) breath test (BT) to rapidly screen cancer patients. Deficient patients have low breath 13CO2 concentrations due to reduced catabolism of 13C-Ura to 13C-dihydrouracil (13C-DHU) and 13CO2. AIM Develop a pharmacokinetic (PK) model to simultaneously describe 13C-Ura and catabolite concentrations in plasma and breath from normal and DPD deficient subjects. METHODS Blood and breath samples were collected for 3h after oral 13C-Ura (6 mg/kg) administration to 19 normal and 10 DPD deficient subjects. Plasma 13C-Ura, 13C-DHU, and breath 13CO2 concentrations were quantified. ADAPT II simultaneously fitted parent, metabolite, and breath concentration-time data. Akaike's Information Criterion was used to select the model. RESULTS A one compartment linear absorption/elimination parent/metabolite model with cumulative breath13CO2 elimination described concentration-time data of 13C-Ura, 13C-DHU, and 13CO2. Significant differences in modeled PK parameters between normal and DPD deficient subjects were observed. CONCLUSION This is the first model to simultaneously describe orally administered 13C-Ura disposition in normal and DPD deficient subjects. Bayesian parameter estimation and simulation studies will be used to identify an optimal limited sampling strategy to detect DPD deficiency in patients who aren't candidates for BT screening. (See Table) PK Parameter Normal Subjects (Mean ± SD) DPD Deficient Subjects (Mean ± SD) Mann-Whitney U Test p Value 13C-Ura Half-life (h) 0.18 ± 0.07 0.60 ± 0.67 ≤ 0.001 13C-Ura Clearance (L/kg/h) 1.54 ± 0.63 0.77 ± 0.30 ≤ 0.001 13C-DHU Formation Rate Constant (1/h) 3.23 ± 2.48 1.24 ± 0.64 ≤ 0.001 Clinical Pharmacology & Therapeutics (2005) 79, P83–P83; doi: 10.1016/j.clpt.2005.12.298