Vincristine pharmacodynamics and pharmacogenetics in children with cancer: A limited‐sampling, population modelling approach

Moore, Andrew S.; Norris, Ross; Price, Gareth; Nguyễn, Thu Thủy; Ni, Ming; George, Roy; Breda, Karin van; Duley, John A.; Charles, Bruce G.; Pinkerton, Ross

doi:10.1111/j.1440-1754.2011.02103.x

Cited by 54 publications

(43 citation statements)

References 29 publications

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“…This is further supported by the high volume of distribution (1.76 L/kg) suggesting extensive tissue uptake of vincristine. The elimination half-life in the Tasmanian devil (approximately 11 h) is similar to adult and infant humans [19], [31], [32]. Plasma clearance of vincristine would have been expected to be more rapid than that observed in humans if rapid elimination of the drug played a role in their resistance to toxicity.…”

Section: Discussionmentioning

confidence: 89%

Vincristine Chemotherapy Trials and Pharmacokinetics in Tasmanian Devils with Tasmanian Devil Facial Tumor Disease

Phalen

Frimberger²,

Pyecroft

et al. 2013

PLoS ONE

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Tasmanian Devil Facial Tumor Disease (DFTD) is a transmissible cancer threatening to cause the extinction of Tasmanian Devils in the wild. The aim of this study was to determine the susceptibility of the DFTD to vincristine. Escalating dosage rates of vincristine (0.05 to 0.136 mg/kg) were given to Tasmanian devils in the early stages of DFTD (n = 8). None of these dosage rates impacted the outcome of the disease. A dosage rate of 0.105 mg/kg, a rate significantly higher than that given in humans or domestic animals, was found to the highest dosage rate that could be administered safely. Signs of toxicity included anorexia, vomiting, diarrhea and neutropenia. Pharmacokinetic studies showed that, as with other species, there was a rapid drop in blood concentration following a rapid intravenous infusion with a high volume of distribution (1.96 L/kg) and a relatively long elimination half life (11 h). Plasma clearance (1.8 ml/min/kg) was slower in the Tasmanian devil than in humans, suggesting that pharmacodynamics and not pharmacokinetics explain the Tasmanian devil’s ability to tolerate high dosage rates of vincristine. While providing base-line data for the use of vincristine in Tasmanian devils and possibly other marsupials with vincristine susceptible cancers, these findings strongly suggest that vincristine will not be effective in the treatment of DFTD.

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Section: Discussionmentioning

confidence: 89%

Vincristine Chemotherapy Trials and Pharmacokinetics in Tasmanian Devils with Tasmanian Devil Facial Tumor Disease

Phalen

Frimberger²,

Pyecroft

et al. 2013

PLoS ONE

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“…The effects of CYP3A5*3 on treatment outcomes were possibly a result of its involvement in vincristine metabolism rather than CPA metabolism. It has been demonstrated that CYP3A5 promotes the loss of the parent drug and formation of the major metabolite of vincristine, M1, in the liver . Doxorubicin has been reported to be an inhibitor, but not a substrate, of CYP3A.…”

Section: Discussionmentioning

confidence: 99%

Cytochrome P450 Genetic Variations Can Predict mRNA Expression, Cyclophosphamide 4-Hydroxylation, and Treatment Outcomes in Chinese Patients With Non-Hodgkin's Lymphoma

Shu

Chen

et al. 2017

The Journal of Clinical Pharmacology

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To investigate the impact of cytochrome P450 (CYP) genetic polymorphisms CYP2B6, CYP2C19, and CYP3A5 on mRNA expression, cyclophosphamide/4-hydroxycyclophosphamide pharmacokinetics, and treatment outcomes of the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in Chinese patients with non-Hodgkin's lymphoma, 567 cases were investigated. Plasma concentrations of cyclophosphamide/4-hydroxycyclophosphamide were determined using liquid chromatography-tandem mass spectrometry and pharmacokinetic parameters calculated. The frequencies of CYP2B6*1/*29 and CYP2B6*1/*30 were 18 (3.2%) and 30 (5.3%), respectively. Liver samples with CYP2B6*29/*30, CYP2C19*2, CYP2B6*6, or CYP3A5*3 had significantly lower target mRNA expression. Samples with CYP2B6*6 and/or CYP2C19*2 had lower exposure to 4-hydroxycyclophosphamide, whereas those with CYP2B6*1G/*1H had higher exposure. Multivariate model showed that samples with CYP2C19*2 or CYP2B6 785A>raG had worse treatment response than samples with CYP3A5*3. CYP2C19*2, CYP2B6*6, CYP2B6*29, and CYP2B6*30 were protective factors for toxicity in the multivariate model. The best model for gene-gene interactions for treatment response contained CYP2C19*2, CYP2B6 785A>G, and CYP3A5*3 (cross-validation consistency [CVC], 8/10; P = .0035). The best prediction model for grade 2-4 toxicities had CYP2C19*2, CYP2B6 785A>G, and 516 G>T (CVC, 10/10; P < .0001). In previous reports, we were the first to report that the frequency of copy-number variations in CYP2B6 is higher among Chinese than among other ethnic populations. Genetic variations in CYP2B6, CYP2C19, and CYP3A5 dramatically affected the mRNA expression of proteins, the pharmacokinetics of 4-hydroxycyclophosphamide, and the R-CHOP treatment response in Chinese subjects. Patients carrying CYP3A5*3 were more likely to have a better treatment response, whereas patients with CYP2C19*2 or CYP2B6 516G>T, or CYP2B6 785A>G had higher tolerance to treatment.

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“…This effect may be achieved by a lower ratio of vincristine to its’ primary metabolite (M1) [88]. Despite these intriguing results, two other studies, which enrolled a total of 86 patients, and evaluated the presence of CYP3A5*3 , CYP3A5*6 and ABCB1 SNPs failed to confirm a significant association with the occurrence of vincristine-induced side effects [89–91]. These studies are limited due to the small number of patients included.…”

Section: Vincristinementioning

confidence: 99%

Pharmacogenetics predictive of response and toxicity in acute lymphoblastic leukemia therapy

Mei¹,

Ontiveros²,

Griffiths³

et al. 2015

Blood Reviews

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Acute lymphoblastic leukemia (ALL) is a relatively rare disease in adults accounting for no more than 20% of all cases of acute leukemia. By contrast with the pediatric population, in whom significant improvements in long term survival and even cure have been achieved over the last 30 years, adult ALL remains a significant challenge. Overall survival in this group remains a relatively poor 20–40%. Modern research has focused on improved pharmacokinetics, novel pharmacogenetics and personalized principles to optimize the efficacy of the treatment while reducing toxicity. Here we review the pharmacogenetics of medications used in the management of patients with ALL, including L-asparaginase, glucocorticoids, 6-mercaptopruine, methotrexate, vincristine and tyrosine kinase inhibitors. Incorporating recent pharmacogenetic data, mainly from pediatric ALL, will provide novel perspective of predicting response and toxicity in both pediatric and adult ALL therapy.

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Vincristine pharmacodynamics and pharmacogenetics in children with cancer: A limited‐sampling, population modelling approach

Cited by 54 publications

References 29 publications

Vincristine Chemotherapy Trials and Pharmacokinetics in Tasmanian Devils with Tasmanian Devil Facial Tumor Disease

Vincristine Chemotherapy Trials and Pharmacokinetics in Tasmanian Devils with Tasmanian Devil Facial Tumor Disease

Cytochrome P450 Genetic Variations Can Predict mRNA Expression, Cyclophosphamide 4-Hydroxylation, and Treatment Outcomes in Chinese Patients With Non-Hodgkin's Lymphoma

Pharmacogenetics predictive of response and toxicity in acute lymphoblastic leukemia therapy

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