Clinical application of a semimechanistic-physiologic population PK/PD model for neutropenia following pemetrexed therapy

Latz, Jane E.; Rusthoven, James J.; Karlsson, Mats O.; Ghosh, A.K.; Johnson, Robert D.

doi:10.1007/s00280-005-0035-2

Cited by 41 publications

(69 citation statements)

References 26 publications

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“…As described previously (20,21), patient-specific factors that affect either the systembased parameters or the drug-related in this model result in changes to the ANC-time profile. Thus, patient-specific factors were evaluated as covariates with respect to each of the four model parameters.…”

Section: Translational Relevancementioning

confidence: 99%

“…A full model was developed using established covariate search and model development strategies (20,21). Potential covariates were added to the model sequentially based on the change in the MOF for the individual covariate; those covariates that reduced the objective function the most were added to the model first.…”

Section: Translational Relevancementioning

confidence: 99%

“…The established semimechanistic-physiologic structural model (20,21) was fit to the ANC time data without covariates. Four structural pharmacodynamic parameters were estimated: baseline ANC (BAS), mean transit time (MTT) that quantifies the maturation time of a committed stem progenitor cell to a mature circulating neutrophil, dose stimulus variable (DS) that quantifies the effect of systemic pemetrexed exposure, and a feedback parameter (FP) that quantifies the strength of the feedback action resulting from release of endogenous colony-stimulating factors.…”

Section: Translational Relevancementioning

confidence: 99%

“…The current analyses applied the same analytic approach as that in the previous population pharmacokinetic/pharmacodynamic analyses (20,21) but incorporated data from five additional studies in Western and Japanese patients, the majority (>90%) of whom received pemetrexed with vitamin supplementation. Specific objectives were to (a) characterize the time course of neutropenia in Japanese and Western patients after pemetrexed administration using an established semimechanistic-physiologic model, (b) characterize the relationship between pemetrexed systemic exposure and neutropenia in these patients, and (c ) describe differences in neutropenic response by vitamin supplementation status and between Japanese and Western patients.…”

mentioning

confidence: 99%

“…The model was used previously to analyze data from eight cancer trials in which patients received pemetrexed, 500 or 600 mg/m 2 without vitamin supplementation, to examine neutropenic response [absolute neutrophil count (ANC) versus time, including the time course, severity (nadir depth), and recovery time of ANC] after single-agent pemetrexed administration and to identify patient characteristics associated with variability in neutropenic response (20,21). These previous population pharmacokinetic/ pharmacodynamic analyses identified factors affecting the severity and time course of neutropenia following pemetrexed administered without vitamin supplementation to Western patients (predominantly Caucasian).…”

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confidence: 99%

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Population Pharmacokinetic/Pharmacodynamic Analyses of Pemetrexed and Neutropenia: Effect of Vitamin Supplementation and Differences between Japanese and Western Patients

Latz

Schneck

Nakagawa

et al. 2008

Clinical Cancer Research

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Purpose:The objectives of the analysis were to characterize the time course of neutropenia after pemetrexed administration using an established semimechanistic-physiologic model, characterize the relationship between pemetrexed exposure and neutropenia, and describe differences in neutropenic response by vitamin supplementation status and between Japanese and Western patients. Experimental Design: An eight-compartment population pharmacokinetic/pharmacodynamic model was used to describe the absolute neutrophil count (ANC)-time profile (neutropenic response) following pemetrexed doses of 300 to 1,400 mg/m 2 administered every 21days. The analyses pooled data from 13 studies including 279 patients (161 supplemented with oral folic acid and intramuscular vitamin B 12 , and 118 unsupplemented; 248 Western and 31 Japanese) who received 857 treatment cycles. Results: Vitamin supplementation status, ethnic origin, and drug exposure were the dominant predictors of neutropenic response. Vitamin supplementation diminishes neutropenic response to pemetrexed. Model-predicted ANC nadirs for the ''typical'' Western patient receiving 500 mg/m 2 pemetrexed F vitamin supplementation were 2.74 Â 10 9 /L and 1.70 Â 10 9 /L, respectively. Japanese patients had a less pronounced neutropenic response to pemetrexed relative to Western patients. The model-predicted ANC nadir for Japanese patients receiving 500 mg/m 2 pemetrexed with vitamin supplementation was 2.66 Â 10 9 /L. Values for the 1,000 mg/m 2 dose with vitamin supplementation were 1.91 Â 10 9 /L and 1.34 Â 10 9 /L for Japanese and Western patients, respectively. Increased albumin, decreased cystathionine, and decreased body surface area were also associated with increased neutropenic response. Conclusions: The neutropenic response to higher pemetrexed doses administered with vitamin supplementation is tolerable. All other factors equal, Japanese patients have a lesser neutropenic response to pemetrexed relative to Western patients.

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Section: Translational Relevancementioning

confidence: 99%

Section: Translational Relevancementioning

confidence: 99%

Section: Translational Relevancementioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Population Pharmacokinetic/Pharmacodynamic Analyses of Pemetrexed and Neutropenia: Effect of Vitamin Supplementation and Differences between Japanese and Western Patients

Latz

Schneck

Nakagawa

et al. 2008

Clinical Cancer Research

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

Rouw

Boer

Boosman

et al. 2022

Clin Pharma and Therapeutics

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Neutropenia is a dose-related treatment-limiting and costly adverse event of pemetrexed. We postulate that individualized dosing reduces the incidence of neutropenia. The aims of this study were (i) to investigate the costs of pemetrexed-related neutropenia and (ii) to determine the pharmacoeconomic benefits of individualized dosing of pemetrexed in terms of budget impact, yearly cost savings, and reduction in severe neutropenia. Retrospective data on the treatment of grade 3 or higher neutropenia during pemetrexed-based chemotherapy were collected from three Dutch hospitals to determine the mean healthcare consumption during a neutropenic episode. Subsequently, Monte Carlo simulations were performed using a validated pharmacokinetic/pharmacodynamic model to predict the neutropenia incidence during four cycles for standard dosing of pemetrexed and individualized dosing. The mean costs per neutropenia and the expected neutropenia incidence were combined to calculate the budget impact and cost savings. We found that the average costs per pemetrexed-associated neutropenic episode to be €1,490 (US $1,674). The neutropenia incidence for the standard and individualized pemetrexed dosing strategies were 12.7% and 9.9%, respectively. This resulted in total expected neutropenia-related costs of ~ €3.0 million (US $3.372 million) and €2.4 million (US $2.697 million), respectively. Taking the number of patients eligible for pemetrexed treatment into account, individualized dosing could result in saving €686,000 (US $770,995) on a yearly basis in the Netherlands alone. Individualized dosing of pemetrexed can decrease the incidence of neutropenia and thus result in a significant decrease in neutropenia-related costs and decreased risk of hospitalization or even death while maintaining therapeutic exposure.

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

Boosman

Dorlo

Rouw

et al. 2021

Intl Journal of Cancer

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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.

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Clinical application of a semimechanistic-physiologic population PK/PD model for neutropenia following pemetrexed therapy

Cited by 41 publications

References 26 publications

Population Pharmacokinetic/Pharmacodynamic Analyses of Pemetrexed and Neutropenia: Effect of Vitamin Supplementation and Differences between Japanese and Western Patients

Population Pharmacokinetic/Pharmacodynamic Analyses of Pemetrexed and Neutropenia: Effect of Vitamin Supplementation and Differences between Japanese and Western Patients

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

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

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