Pharmacokinetically based dosing of weekly paclitaxel to reduce drug-related neurotoxicity based on a single sample strategy

Kraff, Stefanie; Nieuweboer, Annemieke J.M.; Mathijssen, Ron H.J.; Baty, Florent; Graan, Anne-Joy de; Schaik, Ron H.N. van; Jaehde, Ulrich; Joerger, Markus

doi:10.1007/s00280-015-2724-9

Cited by 22 publications

(15 citation statements)

References 27 publications

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“…Indeed, the median time to neuropathy onset seemed to be inversely correlated with the tighter administration schedule, 35 and 21 days for weekly and tri-weekly administration, respectively ( Tanabe et al, 2013 ). Consequently, the pharmacokinetics of taxanes impact their neurotoxicity and a pharmacokinetic-based dosing algorithm has been proposed to reduce paclitaxel-related neurotoxicity ( Kraff et al, 2015 ).…”

Section: Taxanesmentioning

confidence: 99%

Long-Term Effects, Pathophysiological Mechanisms, and Risk Factors of Chemotherapy-Induced Peripheral Neuropathies: A Comprehensive Literature Review

et al. 2017

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Neurotoxic anticancer drugs, such as platinum-based anticancer drugs, taxanes, vinca alkaloids, and proteasome/angiogenesis inhibitors are responsible for chemotherapy-induced peripheral neuropathy (CIPN). The health consequences of CIPN remain worrying as it is associated with several comorbidities and affects a specific population of patients already impacted by cancer, a strong driver for declines in older adults. The purpose of this review is to present a comprehensive overview of the long-term effects of CIPN in cancer patients and survivors. Pathophysiological mechanisms and risk factors are also presented. Neurotoxic mechanisms leading to CIPNs are not yet fully understood but involve neuronopathy and/or axonopathy, mainly associated with DNA damage, oxidative stress, mitochondria toxicity, and ion channel remodeling in the neurons of the peripheral nervous system. Classical symptoms of CIPNs are peripheral neuropathy with a “stocking and glove” distribution characterized by sensory loss, paresthesia, dysesthesia and numbness, sometimes associated with neuropathic pain in the most serious cases. Several risk factors can promote CIPN as a function of the anticancer drug considered, such as cumulative dose, treatment duration, history of neuropathy, combination of therapies and genetic polymorphisms. CIPNs are frequent in cancer patients with an overall incidence of approximately 38% (possibly up to 90% of patients treated with oxaliplatin). Finally, the long-term reversibility of these CIPNs remain questionable, notably in the case of platinum-based anticancer drugs and taxanes, for which CIPN may last several years after the end of anticancer chemotherapies. These long-term effects are associated with comorbidities such as depression, insomnia, falls and decreases of health-related quality of life in cancer patients and survivors. However, it is noteworthy that these long-term effects remain poorly studied, and only limited data are available such as in the case of bortezomib and thalidomide-induced peripheral neuropathy.

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Section: Taxanesmentioning

confidence: 99%

Long-Term Effects, Pathophysiological Mechanisms, and Risk Factors of Chemotherapy-Induced Peripheral Neuropathies: A Comprehensive Literature Review

et al. 2017

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“…A median number of 4 PK samples per patient was drawn in this cohort, ranging from 1 to 20 samples per patient (10). A more detailed description of study and patient characteristics have been reported previously (10,(14)(15)(16)(17)(18). In the current analysis, patients were excluded from the database if no neutrophil counts or only baseline neutrophil counts were available, or if accurate paclitaxel dosing information, especially concerning dates of paclitaxel treatment, could not be obtained.…”

Section: Data Collectionmentioning

confidence: 99%

Does Older Age Lead to Higher Risk for Neutropenia in Patients Treated with Paclitaxel?

et al. 2019

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Purpose There is ongoing concern regarding increased toxicity from paclitaxel in elderly patients, particularly of severe neutropenia. Yet, data so far is controversial and this concern is not supported by a clinically relevant age-dependent difference in pharmacokinetics (PK) of paclitaxel. This study assessed whether age is associated with increased risk for paclitaxel-induced neutropenia. Methods Paclitaxel plasma concentration-time data, pooled from multiple different studies, was combined with available respective neutrophil count data during the first treatment cycle. Paclitaxel pharmacokinetic-pharmacodynamic (PK-PD) data was modeled using a non-linear mixed effects approach and a semiphysiological neutropenia model, where

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“…The approach used in this study is unique compared to dose adjustment algorithms that have previously been proposed. For example, a pharmacokinetic‐based dosing algorithm to manage neuropathy based on time of paclitaxel concentration >0.05 µmol was proposed . This dosing algorithm was developed in 200 patients with various solid malignancies, primarily esophageal cancer (72.5%).…”

Section: Discussionmentioning

confidence: 99%

“…For example, a pharmacokinetic-based dosing algorithm to manage neuropathy based on time of paclitaxel concentration >0.05 µmol was proposed. 15 This dosing algorithm was developed in 200 patients with various solid malignancies, primarily esophageal cancer (72.5%). Neuropathy was measured using the Common Terminology Criteria for Adverse Events version 4.0, and there was no information on time at which neuropathy occurred.…”

Section: Discussionmentioning

confidence: 99%

Personalized Management of Chemotherapy‐Induced Peripheral Neuropathy Based on a Patient Reported Outcome: CALGB 40502 (Alliance)

Sharma

Mehrotra

Gray

et al. 2019

The Journal of Clinical Pharma

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Chemotherapy‐induced peripheral neuropathy (henceforth, neuropathy) is often dose limiting and is generally managed by empirical dose modifications. We aimed to (1) identify an early time point that is predictive of future neuropathy using a patient‐reported outcome and (2) propose a dose‐adjustment algorithm based on simulated data to manage neuropathy. In previous work, a dose‐neuropathy model was developed using dosing and patient‐reported outcome data from Cancer and Leukemia Group B 40502 (Alliance), a randomized phase III trial of paclitaxel, nanoparticle albumin–bound paclitaxel or ixabepilone as first‐line chemotherapy for locally recurrent or metastatic breast cancer. In the current work, an early time point that is predictive of the future severity of neuropathy was identified based on predictive accuracy of the model. Using the early data and model parameters, simulations were conducted to propose a dose‐adjustment algorithm for the prospective management of neuropathy in individual patients. The end of the first 3 cycles (12 weeks) was identified as the early time point based on a predictive accuracy of 75% for the neuropathy score after 6 cycles. For paclitaxel, nanoparticle albumin–bound paclitaxel, and ixabepilone, simulations with the proposed dose‐adjustment algorithm resulted in 61%, 48%, and 35% fewer patients, respectively, with neuropathy score ≥8 after 6 cycles compared to no dose adjustment. We conclude that early patient‐reported outcome data on neuropathy can be used to guide dose adjustments in individual patients that reduce the severity of future neuropathy. Prospective validation of this approach should be undertaken in future studies.

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Pharmacokinetically based dosing of weekly paclitaxel to reduce drug-related neurotoxicity based on a single sample strategy

Abstract: This simulation study proposes a pharmacokinetically based dosing algorithm for weekly paclitaxel and shows potential improvement of the benefit/risk ratio by using empirical Bayesian models.

Cited by 22 publications

References 27 publications

Long-Term Effects, Pathophysiological Mechanisms, and Risk Factors of Chemotherapy-Induced Peripheral Neuropathies: A Comprehensive Literature Review

Long-Term Effects, Pathophysiological Mechanisms, and Risk Factors of Chemotherapy-Induced Peripheral Neuropathies: A Comprehensive Literature Review

Does Older Age Lead to Higher Risk for Neutropenia in Patients Treated with Paclitaxel?

Personalized Management of Chemotherapy‐Induced Peripheral Neuropathy Based on a Patient Reported Outcome: CALGB 40502 (Alliance)

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