Toxicity of pemetrexed during renal impairment explained—Implications for safe treatment

Abstract

Pemetrexed is an important component of first line treatment in patients with non‐squamous non‐small cell lung cancer. However, a limitation is the contraindication in patients with renal impairment due to hematological toxicity. Currently, it is unknown how to safely dose pemetrexed in these patients. The aim of our study was to elucidate the relationship between pemetrexed exposure and toxicity to support the development of a safe dosing regimen in patients with renal impairment. A population pharmacokinetic/pharmacodynamic analysis was performed based on phase II study results in three patients with renal dysfunction, supplemented with data from 106 patients in early clinical studies. Findings were externally validated with data of different pemetrexed dosing regimens. Alternative dosing regimens were evaluated using the developed model. We found that pemetrexed toxicity was driven by the time above a toxicity threshold concentration. The threshold for vitamin‐supplemented patients was 0.110 mg/mL (95% CI: 0.092‐0.146 mg/mL). It was observed that in patients with renal impairment (estimated glomerular filtration rate [eGFR]: <45 mL/min) the approved dose of 500 mg/m2 would yield a high probability of severe neutropenia in the range of 51.0% to 92.6%. A pemetrexed dose of 20 mg for patients (eGFR: 20 mL/min) is shown to be neutropenic‐equivalent to the approved dose in patients with adequate renal function (eGFR: 90 mL/min), but would result in an approximately 13‐fold lower area under the concentration‐time curve. The pemetrexed exposure‐toxicity relationship is explained by a toxicity threshold and substantially different from previously thought. Without prophylaxis for toxicity, it is unlikely that a therapeutic dose can be safely administered to patients with renal impairment.

The Pharmacoeconomic Benefits of Pemetrexed Dose Individualization in Patients With Lung Cancer

“…The following parameters (lower limit; upper limit) were included in the sensitivity analyses: medication costs during admission (lower and upper limit determined in this study), costs of one extra WBC (lower and upper limit determined in this study), interindividual variability (IIV) of baseline eGFR (CV 16% as this is found in the study of de Rouw et al . 32 ; upper limit was not tested as a higher IIV is not found in previous studies), and IIV of baseline ANC (CV 30%; CV 45% 29 ).…”

“…The model is described in detail by Boosman et al . 29 A population of 500 participants was simulated for each scenario. Weights and heights were derived from the National Health and Nutrition Examination Survey (NHANES) database (median body mass index = 26.2 kg/m 2 , comparable to baseline body mass index of patients with lung cancer 30 ).…”

“…Baseline ANC was also simulated from a normal distribution based on the population described by Boosman et al . 29 (median 5.3 × 10 9 /L, CV 37%).…”

“…The pharmacokinetic model was coupled with a mechanistic myelosuppression model describing the time course of ANC during cytotoxic treatment, where the proliferation rate in the progenitor cell compartment was inhibited by the pemetrexed concentration. The model is described in detail by Boosman et al 29 A population of 500 participants was simulated for each scenario. Weights and heights were derived from the National Health and Nutrition Examination Survey (NHANES) database (median body mass index = 26.2 kg/m 2 , comparable to baseline body mass index of patients with lung cancer 30 ).…”

Optimized Dosing: The Next Step in Precision Medicine in Non-Small-Cell Lung Cancer

“…However, the development of an analytic method has proven to be challenging [106]. Although it is unclear how well the polyglutamylated forms of pemetrexed correlate to pemetrexed plasma concentrations, a plasma exposure-toxicity relationship has been well-established in a generally broad range of doses (126-1362 mg) [107][108][109]. In addition, doses of pemetrexed 900-1000 mg/m 2 did not improve efficacy of treatment compared with standard dosing of 500 mg/ m 2 Q3W [110].…”