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R. Mathijssen
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P2.03a - Poster Session with Presenters Present (ID 464)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03a-011 - Population Pharmacokinetic/Pharmacodynamic Monitoring of Pemetrexed to Predict Survival in Patients with Advanced NSCLC (ID 6226)
14:30 - 14:30 | Author(s): R. Mathijssen
- Abstract
Background:
A major challenge in advanced non-small cell lung cancer (NSCLC) remains the identification of predictors of clinical benefit from pemetrexed. Total systemic exposure to pemetrexed and its metabolites could be predictive for progression-free and overall survival (PFS/OS). However, sampling times in population pharmacokinetic (PK) analyses of pemetrexed are limited. We performed population PK modeling of pemetrexed during total treatment period and evaluated total systemic exposure as a predictor.
Methods:
In a prospective observational multi-center study, treatment-naive patients with stage IIIB or IV NSCLC receiving pemetrexed/platinum treatment were enrolled. Pemetrexed, dosed based on body surface area (500mg/m[2]), was administered as a 10-minute intravenous infusion every 21 days. Prior to and weekly after each pemetrexed administration, plasma sampling was performed (cycle-PK). Simultaneously, glomerular filtration rate (GFR) was estimated using the Chronic Kidney Disease Epidemiology Collaboriation (CKD-EPI) formula. In a subgroup, blood samples were collected at 10, 30 minutes and 1,2,4, 8, 24 hours after start of pemetrexed infusion (24-hour-PK). We used a recently validated assay to quantify plasma pemetrexed concentrations (Stoop et al, J Pharm Biomed Anal 2016;128:1-8). Population PK analyses were performed using nonlinear mixed effects modeling (NONMEM version 7.2). The final model, based on both cycle-PK and 24-hour-PK, was used to estimate the area under the plasma concentration versus time curve during cycle 1 (AUC~cycle~). With a Cox-regression analysis we examined the relation between AUC~cycle~ and OS/PFS, adjusted for known prognostic factors (sex, disease stage, WHO performance-score).
Results:
For 97 of the 151 patients, concentrations of pemetrexed were quantified (24-hour-PK, n=15; cycle-PK, n=82). A two-compartment model parametrized (population estimate (%standard error of the estimate) in terms of clearance (CL; 5.44L/h (14.9%)), central distribution volume (V~1~; 19.6L (11.3%)), peripheral distribution volume (V~2~; 173L (32.7%)), intercompartimental clearance (Q; 0.19L/h (31.6%)) and incorporated between-patient variability of CL (10.7%), estimated cycle-PK appropriately. GFR and other covariates did not improve the estimation of the parameters. The AUC~cylce ~was significantly different between males (190.8±64.9mg·h/L) and females (165.4±47.2mg·h/L). When we stratified for sex, the highest quartile of AUC independently predicted worse OS (HR=3.06, 95%CI: 1.43-6.57) and PFS (HR=2.79 95%CI: 1.36-5.70), adjusted for the remaining prognostic factors, GFR and pemetrexed dosage.
Conclusion:
Paradoxically worse OS and PFS in patients with high plasma pemetrexed AUC may suggest lower intracellular levels of pemetrexed. Another possibility is that these patients poorly metabolize pemetrexed into its more effective metabolites, which inhibit tumor growth more strongly by prolonged intracellular retention and higher affinity to target enzymes.
