Association of cyclophosphamide pharmacokinetics to polymorphic cytochrome P450 2C19

Timm, Ramona; Kaiser, Rolf; Lötsch, Jörn; Heider, Ulrike; Sezer, Orhan; Weisz, Klaus; Montemurro, Michael; Roots, Ivar; Cascorbi, Ingolf

doi:10.1038/sj.tpj.6500330

Cited by 91 publications

(84 citation statements)

References 31 publications

(30 reference statements)

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“…CYP2C9*2 significantly increased CY AUC in this study, though previous reports have only shown association between CYP2B6*6 or CYP2C19*2 polymorphisms and CY PK. 46,56 These results are a bit different than the results when we just considered CY alone 57 where ALDH1A1 and CYP3A4*1B variant genotypes significantly influenced CY PK. This difference could be because of the fact that the CY PK in these results are influenced by HCY.…”

Section: Discussioncontrasting

confidence: 52%

Population pharmacokinetics of cyclophosphamide in patients with thalassemia major undergoing HSCT

Balasubramanian

Desire

Panetta

et al. 2012

Bone Marrow Transplant

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CY in combination with BU is a widely used conditioning regimen for haematopoietic SCT (HSCT). The aim of this study was to evaluate the pharmacokinetics (PK) of CY and its major metabolite 4-hydroxyCY (HCY) in patients with thalassemia undergoing HSCT. A total of 55 patients received BU (16 mg/kg) followed by CY (160 --200 mg/kg) both over 4 days before HSCT. A population PK model was developed to describe the disposition of CY and HCY and the inter-individual (IIV) and inter-occasion variability (IOV). The model was also used to determine the effects covariates including: demographics, Lucarelli classification and polymorphisms in enzymes involved in the metabolism or biotransformation of CY had on CY and HCY disposition. Overall, 17 --114% IIV and 12 --103% IOV in CY and HCY PK parameters were observed. Body weight and age were the main covariates, which explained the largest portion of the IIV. In addition, CYP2C9*2 explained a significant portion of the IIV in the clearance (Po0.002) and thus the area under the concentration curve (Po0.05) of CY. This covariate model may be used to design and plan targeted dose therapy in this group of pediatric patients, if clinical outcome association with CY PK are proved and target range established.Bone Marrow Transplantation (2012) 47, 1178 --1185; doi:10.1038/bmt.2011.254; published online 9 January 2012Keywords: CY; pharmacokinetics; thalassemia, HSCT INTRODUCTION CY in combination with BU has been a commonly used conditioning regimen in HSCT for malignant and non-malignant diseases. 1 --3 Even though advances in transplantation practices including reducing the intensity of the conditioning regimen have improved the outcome of HSCT in recent years, 4,5 doselimiting toxicities such as sinusoidal obstruction syndrome (SOS) and hemorrhagic cystitis 6,7 remain as the major problems associated with BU-CY-based myeloablative-conditioning regimen. We and others have previously shown that BU pharmacokinetics (PK) influences toxicity and outcome associated with HSCT in patients with thalassemia major treated with BU/CY conditioning. 8 --10 The PK and pharmacodynamics of CY in pediatric patients receiving myeloablative doses of CY are limited and to the best of our knowledge, there is no report on CY PK in pediatric patients undergoing HSCT with myeloablative BU/CY-conditioning regimen. A recent study on the PK of CY and its metabolites in pediatric patients receiving high-dose myeloablative therapy 11 showed very little inter-patient variation in CY elimination, which is largely accounted for by body surface area, suggesting that high-dose chemotherapy resulted in minimal differences in CY PK as compared with more conventional dosage regimens. A population PK model was developed for the first time in children with neuroblastoma, 12 which showed substantial inter-patient variability in the PK of CY and its metabolites. Neither of these two studies described any pharmacodynamics associations. Several studies in adult patients have shown association between the incidence of SO...

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Section: Discussioncontrasting

confidence: 52%

Population pharmacokinetics of cyclophosphamide in patients with thalassemia major undergoing HSCT

Balasubramanian

Desire

Panetta

et al. 2012

Bone Marrow Transplant

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“…36 In a pharmacogenetic study performed in the setting of non-Hodgkin's lymphoma treated with cyclophosphamidecontaining regimens, CYP2C19 rs4244285 has been shown to modulate cyclophosphamide conversion to active metabolites. 37 This observation, however, has not been correlated with outcome or toxicity. 37 In our study, among all SNPs involved in cyclophosphamide pharmacokinetics and including CYP2C19 rs4244285, only GSTA1 rs3957357 displayed a clinical relevance.…”

Section: Discussionmentioning

confidence: 91%

“…37 This observation, however, has not been correlated with outcome or toxicity. 37 In our study, among all SNPs involved in cyclophosphamide pharmacokinetics and including CYP2C19 rs4244285, only GSTA1 rs3957357 displayed a clinical relevance. Overall, our pharmacogenetic data indirectly suggest that detoxification of cyclophosphamide active metabolites by GSTA1 rs3957357, rather than cyclophosphamide bioactivation by CYP2C19 rs4244285, is clinically relevant in the setting of DLBCL treated with R-CHOP21.…”

Section: Discussionmentioning

confidence: 91%

Analysis of the host pharmacogenetic background for prediction of outcome and toxicity in diffuse large B-cell lymphoma treated with R-CHOP21

et al. 2009

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Knowledge on the impact of pharmacogenetics in predicting outcome and toxicity in diffuse large B-cell lymphoma (DLBCL) is scant. We tested 106 consecutive DLBCL treated with R-CHOP21 for 19 single nucleotide polymorphisms (SNPs) from 15 genes potentially relevant to rituximab-CHOP (R-CHOP) pharmacogenetics. Associations of SNPs with event-free survival (EFS) and toxicity were controlled for multiple testing. Genotypic variants of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase p22phox (CYBA rs4673) and alpha1 class glutathione S-transferase (GSTA1 rs3957357) were independent predictors of EFS (CYBA rs4673 TT genotype: HR 2.06, P ¼ 0.038; GSTA1 rs3957357 CT/TT genotypes: HR 0.38, P ¼ 0.003), after adjusting for International Prognostic Index (IPI). CYBA rs4673 and GSTA1 rs3957357 also predicted outcome in DLBCL subgroups by IPI. Impact of SNPs on toxicity was evaluated in 658 R-CHOP21 courses utilizing generalized estimating equations. NCF4 rs1883112 was an independent predictor against hematologic (odds ratios (OR): 0.45; P ¼ 0.018), infectious (OR: 0.46; P ¼ 0.003) and cardiac toxicity (OR: 0.37; P ¼ 0.023). Overall, host SNPs affecting doxorubicin pharmacodynamics (CYBA rs4673) and alkylator detoxification (GSTA1 rs3957357) may predict outcome in R-CHOP21-treated DLBCL. Also, NCF4 rs1883112, a SNP of NAD(P)H oxidase p40phox, may have a function in protecting against hematologic and nonhematologic toxicity. These results highlight the need to improve characterization of the host genetic background for a better prognostication of DLBCL.

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“…This cytostatic agent, widely used in conditioning regimens in combination with TBI or BU, is metabolized by CYP enzymes. 3,4 It is often speculated that the broad interindividual variability of cyclophosphamide's side effects and clinical efficacy might be due to differences in pharmacokinetics. Recently, cyclophosphamide-kinetics were analyzed for functionally relevant polymorphisms of the CYP metabolizing enzymes CYP2B6, CYP2C9, CYP2C19, CYP3A5 and glutathione-S-transferase A1.…”

Section: Discussionmentioning

confidence: 99%

“…Among the drugs which are metabolized by CYP2C19 enzymes are cytostatics, proton pump inhibitors, antidepressants, sedative, beta blockers, antiviral and anti-fungal agents. [2][3][4][5][6][7][8][9] Recently, it was demonstrated that PMs of CYP2C19 showed a decrease in platelet responsiveness to clopidogrel. 10 In another study, it was reported that patients treated with antidepressants and genotyped as PMs for CYP2D6 and CYP2C19, remained in hospital for longer (median 57.5 versus 40.0 days) compared to IMs.…”

Section: Introductionmentioning

confidence: 99%

Cytochrome P450 2C19 loss-of-function polymorphism is associated with an increased treatment-related mortality in patients undergoing allogeneic transplantation

Elmaagacli

Koldehoff

Steckel

et al. 2007

Bone Marrow Transplant

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The polymorphic gene expression of CYP2C19 causes individual variability in drug metabolism and thereby in pharmacologic and toxicologic responses. We genotyped 286 patients and their donors for the CYP2C19 gene who underwent allogeneic transplantation for various diseases and analyzed their outcome. Patients were classified as: poor metabolizers (PMs; 3.1%), intermediate metabolizers (IMs; 24.5%) and extensive metabolizers (EMs; 72.5%). Patients genotyped as PMs had significant higher hepato-and nephrotoxicities compared to IMs or EMs. Maximum bilirubin and serum creatinine levels measured after transplant were approximately twofold higher than those of EMs or IMs. The increased toxicity resulted in an increased 4-year estimate for transplant-related mortality (TRM) with 50718.6% for PMs compared to 25.173.7% for EMs (Po0.018) and 22.7 75.6% for IMs (Po0.042), whereas no significant influence for relapse rate, overall survival or incidence of acute graftversus-host disease grade 2-4 were found between the groups. Multivariate analysis including all potential factors that might influence TRM confirmed that the genotype of CYP2C19 is an independent factor, which influenced TRM significantly. These results suggest that genotyping for CYP450 2C19 can help to identify patients with higher risk for TRM.

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Association of cyclophosphamide pharmacokinetics to polymorphic cytochrome P450 2C19

Cited by 91 publications

References 31 publications

Population pharmacokinetics of cyclophosphamide in patients with thalassemia major undergoing HSCT

Population pharmacokinetics of cyclophosphamide in patients with thalassemia major undergoing HSCT

Analysis of the host pharmacogenetic background for prediction of outcome and toxicity in diffuse large B-cell lymphoma treated with R-CHOP21

Cytochrome P450 2C19 loss-of-function polymorphism is associated with an increased treatment-related mortality in patients undergoing allogeneic transplantation

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