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- W2247747662 abstract "2506 Background: Irinotecan, a prodrug of SN-38, is mainly metabolized by CYP3A. Based on the known relationship between midazolam clearance, a measure of CYP3A activity, and irinotecan disposition (Mathijssen et al, JNCI 2004), a randomized trial was performed comparing the pharmacokinetics and toxicity of irinotecan following conventional BSA-based dosing and dosing based on a formula derived from midazolam clearance, γGT, and height. Methods: Forty patients were randomized 1:1 to receive irinotecan at a dose of 350 mg/m2 (arm A) or at a dose based on the formula (arm B). UGT1A1*28 status, blood samples for pharmacokinetics, and toxicities were obtained during the first course. Pharmacokinetic parameters were calculated using WinNonLin. Results: Patient characteristics (22 males/18 females; median age, 58 years) were balanced between both arms, including the UGT1A1*28 status (p = 0.87). Doses ranged from 480–780 mg (mean 645) in arm A and 380–1,060 mg (mean 698) in arm B. The mean area under the curve (AUC) of irinotecan (22.4 vs 21.1 μg×h/mL) and SN-38 (0.57 vs 0.51 μg×h/mL) did not differ significantly between both arms (p> 0.44). Although the variability in dose was higher in arm B (10 vs 26%), the interindividual variability in AUC was reduced by 19% for irinotecan (31 vs 25%) and 26% for SN-38 (46 vs 34%). In addition, a lower interindividual variability in the nadir of the absolute neutrophil count (ANC) was found (80 vs 55%). Compared to arm A, the incidence of grade 3–4 neutropenia decreased by 75% (42 vs 11%; p= 0.03), which was unrelated to UGT1A1*28 genotype status (p > 0.79). Similarly, the incidence of grade 4 neutropenia was reduced (26 vs 5%). The incidence of grade 3–4 diarrhea was equal in both arms (11%). Conclusions: Individualization of irinotecan dosage based on CYP3A phenotyping results in a substantially reduced interindividual pharmacokinetic variability for irinotecan and SN-38. The variability in nadir ANC and the incidence of severe neutropenia decline as well. In combination with UGT1A1*28 genotyping approaches to predict the extent of SN-38 inactivation, CYP3A phenotype-determination should be explored further as a strategy to identify patients that are at risk for experiencing severe side effects. No significant financial relationships to disclose." @default.
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- W2247747662 date "2008-05-20" @default.
- W2247747662 modified "2023-09-26" @default.
- W2247747662 title "CYP3A phenotype-based individualized dosing of irinotecan to reduce interindividual variability in pharmacokinetics and toxicity: Results from a randomized trial" @default.
- W2247747662 doi "https://doi.org/10.1200/jco.2008.26.15_suppl.2506" @default.
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