Pemetrexed exposure predicts toxicity in advanced non-small-cell lung cancer: A prospective cohort study

Background: We explored whether total exposure to pemetrexed predicts effectiveness and toxicity in advanced non-small-cell lung cancer (NSCLC). Furthermore, we investigated alternative dosing schedules. Methods: In this prospective cohort study, patients with advanced NSCLC receiving first-or second-line pemetrexed(/platinum) were enrolled. Plasma sampling was performed weekly (cyclePK) and within 24 h (24hPK) after pemetrexed administration. With population pharmacokinetic/pharmacodynamic modelling, total exposure to pemetrexed during cycle 1 (area under the curve during chemotherapy cycle 1 [AUC(1)]) was estimated and related to progression-free survival (PFS)/overall survival (OS). We compared mean AUC(1) (mg.h/L) in patients with and without severe chemotherapy-related adverse events (AEs) during total treatment. Second, different dosing schedules were simulated to minimise the estimated variability (coefficient of variation [CV]) of AUC. Results: For 106 of 165 patients, concentrations of pemetrexed were quantified (24hPK, n = 15; cyclePK, n = 106). After adjusting for prognostic factors, sex, disease stage and World Health Organisation performance score, AUC(1) did not predict PFS/OS in treatmentnaive patients (n = 95) (OS, hazard ratio [HR] = 1.05, 95% confidence interval [CI]: 1.00 -1.11; PFS, HR = 1.03, 95% CI: 0.98-1.08). Patients with severe chemotherapy-related AEs (n = 55) had significantly higher AUC1 values than patients without them (n = 51) (226 +/- 53 vs 190 +/- 31, p < 0.001). Compared with body surface areaebased dosing (CV: 22.5%), simulation of estimated glomerular filtration rate (eGFR)-based dosing (CV 18.5%) and fixed dose of 900 mg with 25% dose reduction, if the eGFR<60 mL/min (CV: 19.1%), resulted in less interindividual variability of AUC. Conclusions: Higher exposure to pemetrexed does not increase PFS/OS but is significantly associated with increased occurrence of severe toxicity. Our findings suggest that fixed dosing reduces interpatient pharmacokinetic variability and thereby might prevent toxicity, while preserving effectiveness. (C) 2019 Elsevier Ltd. All rights reserved.