Pharmacokinetic (PK) - pharmacodynamic (PD) study of gemcitabine (G) in a randomised phase II trial of carboplatin (C) combined with G at standard rate infusion or fixed dose rate infusion in patients with advanced non-small-cell lung cancer (NSCLC)

Abstract

2024 Background: Preclinical and clinical data have reported intracellular G triphosphate (dFdCTP) levels can be optimised by administering G at a constant rate infusion of 10mg/m2/min. A randomised phase II study was conducted to compare the response rate (RR), toxicity and PK/PD relationships of G given at standard infusion (30 min) versus constant rate infusion of 10mg/m2/min in combination with C. Methods: Chemonaive advanced stage NSCLC patients were randomised to C (AUC 5) day 1 and G 10 mg/m2/min over 75 min days 1 and 8 q3w (Arm A) or C (AUC 5) day 1 and G 1000mg/m2 over 30 min days 1 and 8 q3w (Arm B). Plasma dFdC, dFdU and peripheral mononuclear cell dFdCTP were measured; genotyping of CDA, DCK, and RR was performed for pharmacogenetic correlations. Results: 76 patients were randomised and treated in arms A (n=38) and B (n=38). Median age was 55 years and stage IV 82% (Arm A) and 62 years and 82% (Arm B). Haematologic toxicity was similar in both arms (neutropenia grade 3/4 in 68% vs 74% and thrombocytopenia 3/4 in 68% vs 50% of patients). Response rate was 37% (95% CI 22–53%) in arm A and 44% (95% CI 29–60%) in arm B. Median survival was 212 days (95%CI 176–263 days) in arm A and 287 days (95% CI 191–394 days) in arm B. dFdCTP saturation was reached in Arm B but not in Arm A. dFdCTP Cmax, AUC and clearance was 173.9 +/- 77.3 uM, 35079 +/-18216 uM*min and 0.14 +/- 0.06 L/min respectively (Arm A, n= 15) and 224.8 +/- 71.8 uM, 32546.9 +/- 11927.7uM*min and 0.18 +/- 0.07 L/min respectively (Arm B, n= 18). Conclusions: Constant rate infusion of G at 10mg/m2/min in combination with C had similar response rates, haematological toxicity and dFdCTP AUC compared with standard infusion rate of G and C. High interindividual dFdCTP variability was seen in both schedules. Constant rate infusion of G at 10mg/m2/min may be a suitable alternative to standard infusion G. No significant financial relationships to disclose.