Pharmacokinetics of 5-Fluorouracil in Patients Treated With Capecitabine Carrying the c.1236G>A <i>DPYD</i> Variant Allele.
retrospective_cohort · Level III
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- Also identified by DOI 10.1200/PO-26-00090.
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Abstract
<i>DPYD</i>-guided fluoropyrimidine dosing effectively limits the risk of severe toxicity while maintaining clinical efficacy. However, recent data suggest that c.1236G>A variant carriers, starting with a 25% reduced dose, have shorter progression-free survival than wild-type patients receiving a full dose. Although overall survival was unaffected, further investigation is warranted. To address this, we retrospectively compared 5-fluorouracil (5-FU) exposure between c.1236G>A variant carriers and <i>DPYD</i> wild-type patients. Pharmacokinetic data from nine clinical trials involving capecitabine-treated patients were pooled. Blood samples were collected before and after administration of capecitabine to assess systemic levels of its metabolites, including 5-FU. Capecitabine dosages were reduced for c.1236G>A variant carriers in accordance with the clinical guidelines at the time of study execution and varied from no reduction (n = 11) to a 25% (n = 16) or 50% (n = 8) reduction. Pharmacokinetic exposure, expressed as area under the plasma concentration-time curve (AUC<sub>0-∞</sub>), was determined using noncompartmental analysis and dose-normalized to 850 mg/m<sup>2</sup>. In total, 35 heterozygous c.1236G>A patients and 66 <i>DPYD</i> wild-type patients were evaluable. Patients carrying c.1236G>A who received a 50% dose reduction had a lower dose-normalized geometric mean 5-FU exposure (234 ng·h/mL coefficient of variation [CV = 43%]) compared with fully dosed c.1236G>A carriers (553 ng·h/mL [CV = 51%]) and fully dosed <i>DPYD</i> wild-type patients (582 ng·h/mL [CV = 48%]; <i>P</i> < .001). All c.1236G>A carriers who received a 50% dose reduction had AUC<sub>0-∞</sub> values below the AUC<sub>0-∞</sub> range observed in the wild-type group. Our findings indicate that an upfront 25% dose reduction for capecitabine in c.1236G>A carriers is likely more appropriate than the currently recommended 50% dose reduction. We stress the importance of individual dose titration in c.1236G>A carriers to avoid both over- and undertreatment.