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

INTRODUCTION: 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. METHODS: 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 value or in a combined algorithm with age and serum creatinine, and lastly, a combination of pro-enkephalin with cystatin C. RESULTS: 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. CONCLUSIONS: 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.

Cumulative pemetrexed dose increases the risk of nephrotoxicity.

INTRODUCTION: Pemetrexed is a pharmacotherapeutic cornerstone in the treatment of non-small cell lung cancer. As it is primarily eliminated by renal excretion, adequate renal function is essential to prevent toxic exposure. There is growing evidence for the nephrotoxic potential of pemetrexed, which even becomes a greater issue now combined immuno-chemotherapy prolongs survival. Therefore, the aim of this study was to describe the incidence of nephrotoxicity and related treatment consequences during pemetrexed-based treatment. METHODS: A retrospective cohort study was conducted in the Jeroen Bosch Hospital, Den Bosch, the Netherlands. All patients that received at least 1 cycle of pemetrexed based therapy were included in the dataset. The primary outcome was defined as a ≥25 % reduction in eGFR. Additionally, the treatment consequences of decreased renal function were assessed. Logistic regression was used to identify risk factors for nephrotoxicity during treatment with pemetrexed. RESULTS: Of the 359 patients included in this analysis, 21 % patients had a clinically relevant decline in renal function after treatment and 8.1 % of patients discontinued treatment due to nephrotoxicity. Cumulative dose (≥10 cycles of pemetrexed based therapy) was identified as a risk factor for the primary outcome measure (adjusted OR 5.66 (CI 1.73-18.54)). CONCLUSION: This study shows that patients on pemetrexed-based treatment are at risk of developing renal impairment. Risk significantly increases with prolonged treatment. Renal impairment is expected to become an even greater issue now that pemetrexed-based immuno-chemotherapy results in longer survival and thus longer treatment duration.

Pharmacokinetically-guided dosing of pemetrexed in a patient with renal impairment and a patient requiring hemodialysis.

OBJECTIVES: Pemetrexed is indicated for non-small cell lung cancer and mesothelioma. Dosing is based on body surface are (BSA), while renal function is the only determinant for exposure and thus toxicity. BSA-based dosing introduces large variability in exposure and may lead to (hemato)toxicity in patients with impaired renal function. Therefore, pemetrexed is contraindicated in renal impairment. The presented cases provide proof-of-concept for pharmacokinetically-guided dosing of pemetrexed in a haemodialysis patient and a patient with mild renal impairment. METHODS: The pharmacokinetic target was an area under the concentration-time curve (AUC) of 123-205 mg·h/L. Using a previously developed population pharmacokinetic model, individual pharmacokinetics were estimated. RESULTS: Both patients had an exposure above target after the initial dose, but a proportional dose reduction resulted in a therapeutic exposure in both patients (185 and 166 mg·h/L, respectively), that was well-tolerated. Interestingly, a threefold increase in systemic clearance of pemetrexed was observed during hemodialysis (from 1.00 L/h to 3.01 L/h), which approximates the population clearance of pemetrexed. CONCLUSION: Altogether, we showed that pharmacokinetically-guided dosing of pemetrexed may be a feasible strategy for patients with lung cancer and renal impairment.