N. de Rouw (1,2), R.J. Boosmann (3), H.J. Derijks (1,2), D.M. Burger (1), L.B. Hilbrands (4), M.M. van den Heuvel (5), R. ter Heine (1)
1 Radboud university medical center, Radboud Institute for Health Sciences, Department of Pharmacy, Nijmegen, The Netherlands, 2 Pharmacy Jeroen Bosch Hospital, ‘s-Hertogenbosch, The Netherlands, 3 Antoni van Leeuwenhoek – The Netherlands Cancer Institute, Department of Pharmacy & Pharmacology, Amsterdam, The Netherlands, 4 Radboud university medical center, Radboud Institute for Health Sciences, Department of Nephrology, Nijmegen, The Netherlands, 5 Radboud university medical center, Radboud Institute for Health Sciences, Department of Pulmonology, Nijmegen, The Netherlands
Introduction/objectives: In the era of chemo-immunotherapy, pemetrexed remains a pharmacotherapeutic cornerstone for treatment of lung cancer. Currently, pemetrexed dosing is based on body surface area (BSA), and contra-indicated in patients with creatinine clearance (CrCl) <45 ml/min (due to occurrence of fatal toxicity in a phase I study). As lung cancer patients are at high risk of renal impairment, effective therapy may be withheld from a substantial part of this patient group. To optimally benefit from pemetrexed-based cancer treatment, safe dosing strategies for these patients should be developed. Previous pharmacokinetic studies on pemetrexed did not include patients with renal dysfunction, but showed that renal function was a determinant for exposure. Altogether, to further explore pemetrexed dose optimization strategies to allow safe treatment in both patients with adequate as impaired renal function, knowledge of the pharmacokinetics in this patient group is essential. The aim of our study was to investigate population pharmacokinetics of pemetrexed in patients with various levels of renal function.
Methods: Phase I rich pharmacokinetic data of pemetrexed were obtained from Eli Lilly. From the available data, we estimated creatinine clearance (Cockcroft Gault formula) and estimated glomerular filtration rate (according to the CKD-EPI and MDRD formulas). A population pharmacokinetic analysis was performed. Volume of distribution and intercompartmental clearance were allometrically scaled to total body weight. The different measures for renal function (CrCl, CKD-EPI and MDRD) were tested as covariates for clearance. Models were evaluated with standard goodness-of-fit plots (GOF). Parameter uncertainty was assessed by means of sampling importance resampling. Lastly, the model published by the manufacturer of pemetrexed (Latz et al. (2006)) and the presented model were compared for target attainment at an AUC of 164mg*h/L ± 25%. A virtual population (age, heights and weights derived from NHANES database) with varying renal functions was simulated using Monte Carlo simulations. Dosing was based on BSA according to drug label. The population was divided in patients with impaired renal function (CrCl <45 mL/min) and adequate renal function (CrCl ≥45 mL/min) to assess the impact of renal function on exposure.
Results: The final dataset consisted of 47 individuals with CKD-EPI ranging from 14 to 146 mL/min. A three-compartment model with allometric scaling fitted the data best. Typical values for renal clearance (ClR) and non-renal clearance (ClNR; with relative standard error of estimate RSE%) were 3.42 L/h (8.7%) and 0.66 L/h (35%). For central volume of distribution (V1) and peripheral volume of distribution (V2 and V3) typical values were 6.70 L (6.0%), 8.01 L (5.6%) and 1.23 L (10.6%), respectively. Adding absolute CKD-EPI as a covariate resulted in the best model fit and was therefore included as a linear covariate on pemetrexed clearance in the final model. This reduced the interindividual variability (IIV) on clearance from 38.7 to 21.0%. In the simulation study, the model of Latz et al. showed low variability in exposure, independent of renal function. Our model showed high impact of renal function on pemetrexed exposure, with large variability and increased exposure with impaired renal function. Comparison of geometric mean AUCs showed that predicted exposure in patients with renal impairment is 1.7x higher when using our model.
Conclusions: This population pharmacokinetic analysis is the first to include patients with both severe renal impairment and adequate renal function. In comparison to the findings of Latz et al., we found that renal function is even more important for pemetrexed clearance. With our model we predict that in a patient with an impaired renal function of 20 mL/min, the clearance of pemetrexed is approximately 50% lower than previously thought. BSA-based dosing seems acceptable in individuals with adequate renal function, but results in toxic exposure in renal impairment. Our findings support that renal function based dosing should be applied for pemetrexed. Together with data on the pharmacokinetics/pharmacodynamics (PK/PD) of pemetrexed, this model can be used to develop safe dosing strategies for lung cancer patients irrespective of the presence of renal impairment.
References:
[1] Mita AC, Sweeney CJ, Baker SD, Goetz A, Hammond LA, Patnaik A, et al. Phase I and pharmacokinetic study of pemetrexed administered every 3 weeks to advanced cancer patients with normal and impaired renal function. J Clin Oncol. 2006;24(4):552-62
[2] European Medicine Agency (EMA). ALIMTA EPAR – Product Information. 2017
[3] Launay-Vacher V, Etessami R, Janus N, Spano JP, Ray-Coquard I, Oudard S, et al. Lung cancer and renal insufficiency: prevalence and anticancer drug issues. Lung. 2009;187(1):69-74.
[4] Latz JE, Chaudhary A, Ghosh A, Johnson RD. Population pharmacokinetic analysis of ten phase II clinical trials of pemetrexed in cancer patients. Cancer Chemother Pharmacol. 2006;57(4):401-11.
[5] Latz JE, Rusthoven JJ, Karlsson MO, Ghosh A, Johnson RD. Clinical application of a semimechanistic-physiologic population PK/PD model for neutropenia following pemetrexed therapy. Cancer Chemother Pharmacol. 2006;57(4):427-35.
Reference: PAGE () Abstr 9253 [www.page-meeting.org/?abstract=9253]
Poster: Clinical Applications