III-52 Rene Boosman

The pemetrexed exposure-neutropenia relationship, paving the way to a safe administration in patients with an impaired renal function

R.J. Boosman 1, T.P.C. Dorlo 1, N. de Rouw 2,3, , J.A. Burgers 1, A.C. Dingemans 4,5, M.M. van den Heuvel 2, L.E.L. Hendriks 4, B. Biesma 3, J.G.J.V. Aerts 5, S Croes 4, R.H.J. Mathijssen 5, A.D.R. Huitema 1,6,7, R. ter Heine 2

1 The Netherlands Cancer Institute, Amsterdam, the Netherlands; 2 Radboud University Medical Center, Nijmegen, the Netherlands; 3 Jeroen Bosch Hospital, ‘s-Hertogenbosch, the Netherlands; 4 Maastricht University Medical Center, Maastricht, the Netherlands; 5 Erasmus Medical Center, Rotterdam, the Netherlands; 6 University Medical Center Utrecht, Utrecht, the Netherlands; 7 Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands

Objectives: Pemetrexed is a widely used cytostatic agent for the treatment of non-small cell lung cancer (NSCLC) and mesothelioma. Dosing of pemetrexed is based on body surface area (500 mg/m2 every three weeks (Q3W)), although, renal function is the main determinant of systemic exposure. Pemetrexed is currently contraindicated in patients with a creatinine clearance <45mL/min and, therefore, about 30% of the population is withheld effective treatment. We recently included three patients in a study evaluating a novel AUC-based renal function-based dosing regimen for pemetrexed in patients with renal dysfunction (estimated glomerular filtration rates (eGFR) of 35, 36 and 8 mL/min). Unexpectedly, we observed a grade 1, 3 and 4 neutropenia, respectively, in these patients, indicating that the AUC-toxicity relationship is far from linear. To allow safe dosing of pemetrexed in this patient group, we set out to unravel the exposure-toxicity relationship of pemetrexed. The objective of this study is to investigate the pemetrexed exposure-neutropenia relationship.

Methods: Phase I pharmacokinetic (PK) data of pemetrexed and pharmacodynamic (PD) data on neutrophil counts after pemetrexed exposure were provided by the manufacturer and supplemented with data from our renal impairment study. Non-linear mixed effects modelling was performed using NONMEM (v. 7.4.3). A previously developed model with eGFR as covariate on clearance described the PK [1]. A semi-mechanistic chemotherapy-induced myelosuppression model was used to describe the neutrophil data [2]. The drug effect on the proliferation of the neutrophils was modelled either, as previously suggested, with a linear relation between drug concentration and proliferation rate [3] or as a threshold relation (using an Emax model with the hill coefficient fixed to 20) and vitamin supplementation as a binary covariate for IC50. The threshold relationship was based on the analogy to methotrexate that also exhibits threshold-driven toxicity [4]. Moreover, it was suggested by phase I studies, showing neutropenia after low but prolonged doses of pemetrexed [5-7]. External evaluation was performed using a trial simulation (n=1000) with data of the maximum tolerable doses assessed in these clinical studies [5-7]. After internal and external evaluation, the neutropenia-equivalent pemetrexed dose for a typical patient with impaired renal function (eGFR of 20mL/min) compared to a typical patient with an adequate renal function (eGFR of 90mL/min), dosed with the approved pemetrexed dose, was calculated.

Results: The final dataset included 556 pemetrexed plasma concentrations and 1513 neutrophil counts from 109 patients with eGFR ranging from 8 to 155 mL/min and vitamin supplementation in 78 patients. The threshold model described the neutrophil dynamics better than the linear relationship, indicated by a drop in Akaike Information Criterion of 33.6 points between both models. Typical values for Emax and IC50 were 1.16 (95% confidence interval (CI): 0.96-1.37) and 0.030mg/L (95% CI: 0.017-0.047), respectively. Vitamin supplementation increased the IC50 to 0.110 mg/L (95% CI: 0.092-0.146). Both models predicted similar frequencies of neutropenia for a pemetrexed dose of 600mg/m2 Q3W. However, neutropenia after low prolonged doses of pemetrexed or in patients with renal impairment was underpredicted by the linear model, while the predicted frequencies for the threshold model were in line with the observed frequencies in the clinical studies. Simulations with the threshold model showed that 20mg of pemetrexed in a patient with an eGFR of 20mL/min led to an equivalent neutropenic response as 1000mg (both with vitamin supplementation) of pemetrexed for a similar patient with an eGFR of 90mL/min. The calculated AUC of this low pemetrexed dose is approximately 13-fold lower compared to a typical patient with adequate renal function. 

Conclusions: We found that the pemetrexed exposure-neutropenia relationship is best described by a threshold model, showing both good internal and external validity in patients with a broad range of renal functions and doses. The clinical implications of our findings are that the dose in patients with impaired renal function has to be reduced to a potentially subtherapeutic dose. Therefore, prospective studies investigating prophylactic strategies to enable therapeutic dosing in this population are warranted.

References:

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Reference: PAGE 29 (2021) Abstr 9759 [www.page-meeting.org/?abstract=9759]

Poster: Drug/Disease Modelling - Other Topics