A comparison of the renal function biomarkers serum creatinine, pro-enkephalin and cystatin C to predict clearance of pemetrexed.

Abstract

For drugs with a narrow therapeutic window, there is a delicate balance between efficacy and toxicity, thus it is pivotal to administer the right dose from the first administration onwards. Exposure of pemetrexed, a cytotoxic drug used in lung cancer treatment, is dictated by kidney function. To facilitate optimized dosing of pemetrexed, accurate prediction of drug clearance is pivotal. Therefore, the aim of this study was to investigate the performance of the kidney function biomarkers serum creatinine, cystatin C and pro-enkephalin in terms of predicting the elimination of pemetrexed. We performed a population pharmacokinetic analysis using a dataset from two clinical trials containing pharmacokinetic data of pemetrexed and measurements of all three biomarkers. A three-compartment model without covariates was fitted to the data and the obtained individual empirical Bayes estimates for pemetrexed clearance were considered the "true" values (Cltrue). Subsequently, the following algorithms were tested as covariates for pemetrexed clearance: the Chronic Kidney Disease Epidemiology Collaboration equation using creatinine (CKD-EPICR), cystatin C (CKD-EPICYS), a combination of both (CKD-EPICR-CYS), pro-enkephalin as an absolute valueor in a combined algorithm with age and serum creatinine, and lastly, a combination of pro-enkephalin with cystatin C. The dataset consisted of 66 subjects with paired observations for all three kidney function biomarkers. Inclusion of CKD-EPICR-CYS as a covariate on pemetrexed clearance resulted in the best model fit, with the largest decrease in objective function (p < 0.00001) and explaining 35% of the total inter-individual variability in clearance. The predictive performance of the model to containing CKD-EPICR-CYS to predict pemetrexed clearance was good with a normalized root mean squared error and mean prediction error of 19.9% and 1.2%, respectively. In conclusion, this study showed that the combined CKD-EPICR-CYS performs best in terms predicting pharmacokinetics of pemetrexed. Despite the hypothesized disadvantages, creatinine remains to be a suitable and readily available marker to predict pemetrexed clearance in clinical practice.