Population pharmacokinetics of cyclophosphamide in patients with thalassemia major undergoing HSCT

Balasubramanian, Poonkuzhali; Desire, Salamun; Panetta, John C.; Km, Lakshmi; Mathews,; George, Biju; Viswabandya, Auro; Chandy, Mammen; Krishnamoorthy, R. V.; Srivastava, Alok

doi:10.1038/bmt.2011.254

Cited by 18 publications

(17 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Then, we compiled data from the literature on the blood concentrations of the two drugs from patients receiving high-dose cyclophosphamide or etoposide treatment. For high-dose cyclophosphamide treatment (1,850-7,000 mg/m 2 ), the maximum reported serum concentration (Cmax) was 2.664 mg/mL [24,25]. For high-dose etoposide treatment (1,480-1,665 mg/m 2 ), the reported Cmax was 0.1 mg/mL [26,27].…”

Section: Etoposide Increases Il-8 Secretion From Bmscs and Causes Lonmentioning

confidence: 99%

Etoposide-mediated interleukin-8 secretion from bone marrow stromal cells induces hematopoietic stem cell mobilization

Kang

Lee²,

Kim³

et al. 2020

Preprint

View full text Add to dashboard Cite

Abstract Background This study assessed the mechanism of hematopoietic stem cell (HSC) mobilization using etoposide with granulocyte-colony stimulating factor (G-CSF) and determined how it differed from that using cyclophosphamide with G-CSF or G-CSF alone.Methods The study analyzed data from 173 non-Hodgkin’s lymphoma patients who underwent autologous peripheral blood stem cell transplantation (auto-PBSCT), in vitro experiments using HSCs and bone marrow stromal cells (BMSCs), and in vivo mouse model studies.Results The etoposide with G-CSF mobilization group showed the highest yield of CD34+ cells and the lowest change in white blood cell counts during mobilization. Etoposide triggered interleukin (IL)-8 secretion from BMSCs and caused long-term BMSC toxicity, which were not observed with cyclophosphamide treatment. The expansion of CD34+ cells cultured in BMSC-conditioned medium containing IL-8 was more remarkable than that without IL-8. The expression of CXCR2, mTOR, and cMYC in HSCs was gradually enhanced at 1, 6, and 24 h after IL-8 stimulation. In animal studies, the etoposide with G-CSF mobilization group presented stronger expression of IL-8-related cytokines and MMP9 and scantier expression of SDF-1 in the bone marrow, compared to the other groups not treated with etoposide.Conclusion Collectively, the unique mechanism of etoposide with G-CSF-mediated mobilization is associated with the secretion of IL-8 from BMSCs, causing the enhanced proliferation and mobilization of HSCs in the bone marrow, which was not observed in the mobilization using cyclophosphamide with G-CSF or G-CSF alone. Moreover, the long-term toxicity of etoposide to BMSC emphasizes the need for further studies to develop more efficient and safe chemo-mobilization strategies.

show abstract

Section: Etoposide Increases Il-8 Secretion From Bmscs and Causes Lonmentioning

confidence: 99%

Etoposide-mediated interleukin-8 secretion from bone marrow stromal cells induces hematopoietic stem cell mobilization

Kang

Lee²,

Kim³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Higher urinary levels of Su and Ac were assumed if higher plasma levels were observed due to their water soluble nature. A recent population pharmacokinetic modeling with genetic covariates showed that CYP2C9 genotypes partly explained the variability in CY pharmacokinetics (Balasubramanian et al, 2012). It is possible that an increased rate of Ac formation is due to the normal function of CYP2C9.…”

Section: Discussionmentioning

confidence: 99%

The Association of Combined GSTM1 and CYP2C9 Genotype Status with the Occurrence of Hemorrhagic Cystitis in Pediatric Patients Receiving Myeloablative Conditioning Regimen Prior to Allogeneic Hematopoietic Stem Cell Transplantation

et al. 2017

View full text Add to dashboard Cite

Hemorrhagic cystitis (HC) is one of the complications of busulfan-cyclophosphamide (BU-CY) conditioning regimen during allogeneic hematopoietic stem cell transplantation (HSCT) in children. Identifying children at high risk of developing HC in a HSCT setting could facilitate the evaluation and implementation of effective prophylactic measures. In this retrospective analysis genotyping of selected candidate gene variants was performed in 72 children and plasma Sulfolane (Su, water soluble metabolite of BU) levels were measured in 39 children following treatment with BU-CY regimen. The cytotoxic effects of Su and acrolein (Ac, water soluble metabolite of CY) were tested on human urothelial cells (HUCs). The effect of Su was also tested on cytochrome P 450 (CYP) function in HepaRG hepatic cells. Cumulative incidences of HC before day 30 post HSCT were estimated using Kaplan–Meier curves and log-rank test was used to compare the difference between groups in a univariate analysis. Multivariate Cox regression was used to estimate hazard ratios with 95% confidence intervals (CIs). Multivariate analysis included co-variables that were significantly associated with HC in a univariate analysis. Cumulative incidence of HC was 15.3%. In the univariate analysis, HC incidence was significantly (p < 0.05) higher in children older than 10 years (28.6 vs. 6.8%) or in children with higher Su levels (>40 vs. <11%) or in carriers of both functional GSTM1 and CYP2C9 (33.3 vs. 6.3%) compared to the other group. In a multivariate analysis, combined GSTM1 and CYP2C9 genotype status was associated with HC occurrence with a hazards ratio of 4.8 (95% CI: 1.3–18.4; p = 0.02). Ac was found to be toxic to HUC cells at lower concentrations (33 μM), Su was not toxic to HUC cells at concentrations below 1 mM and did not affect CYP function in HepaRG cells. Our observations suggest that pre-emptive genotyping of CYP2C9 and GSTM1 may aid in selection of more effective prophylaxis to reduce HC development in pediatric patients undergoing allogeneic HSCT.Article summary:(1) Children carrying functional alleles in GSTM1 and CYP2C9 are at high risk for developing hemorrhagic cystitis following treatment with busulfan and cyclophosphamide based conditioning regimen.(2) Identification of children at high risk for developing hemorrhagic cystitis in an allogeneic HSCT setting will enable us to evaluate and implement optimal strategies for its prevention.Trial registration: This study is a part of the trail “clinicaltrials.gov identifier: NCT01257854.”

show abstract

“…1,38,39 Because the metabolism of cyclophosphamide is altered by different factors, such as drug interactions and liver or kidney disease, comprehensive studies of the pharmacokinetics of cyclophosphamide are needed to guide cyclophosphamide dosing strategies, as well as to increase treatment efficacy and to reduce side effects during treatment. The pharmacokinetics of cyclophosphamide and its main metabolites (carboxyethylphosphoramide mustard and 4-hydroxycyclophosphamide) as enantiomeric mixtures has been well documented in patients with cancer, [10][11][12]25,40 but no data regarding the enantiomeric mixture or individual enantiomers are available for patients with autoimmune diseases. The enantioselective pharmacokinetic properties of cyclophosphamide have been described by some authors in different situations; 19,33 however, the enantioselectivity in cyclophosphamide metabolism has not yet been evaluated.…”

Section: Discussionmentioning

confidence: 99%

Enantioselectivity in the Metabolism of Cyclophosphamide in Patients With Multiple or Systemic Sclerosis

Castro

Simões

Coelho

et al. 2017

The Journal of Clinical Pharmacology

View full text Add to dashboard Cite

The aim of this study was to evaluate the enantioselective pharmacokinetics of cyclophosphamide and its metabolites 4-hydroxycyclophosphamide and carboxyethylphosphoramide mustard in patients with systemic or multiple sclerosis. Patients with systemic sclerosis (n = 10) or multiple sclerosis (n = 10), genotyped for the allelic variants of CYP2C9*2 and CYP2C9*3 and of the CYP2B6 G516T polymorphism, were treated with 50 mg cyclophosphamide/kg daily for 4 days. Serial blood samples were collected up to 24 hours after administration of the last cyclophosphamide dose. Cyclophosphamide, 4-hydroxycyclophosphamide, and carboxyethylphosphoramide enantiomers were analyzed in plasma samples using liquid chromatography-tandem mass spectrometry coupled to chiral column Chiralcel OD-R or Chiralpak AD-RH. Cytokines IL-2, IL-4, IL-6, IL-8, IL-10, IL- 12p70, IL-17, TNF-α, and INT-δ in the plasma samples collected before cyclophosphamide infusion were analyzed by Milliplex MAP human cytokine/chemokine. Pharmacokinetic parameters showed higher plasma concentrations of (S)-(-)-cyclophosphamide (AUC 215.0 vs 186.2 μg·h/mL for multiple sclerosis patients and 219.1 vs 179.2 μg·h/mL for systemic sclerosis patients) and (R)-4-hydroxycyclophosphamide (AUC 5.6 vs 3.7 μg·h/mL for multiple sclerosis patients and 6.3 vs 5.6 μg·h/mL for systemic sclerosis patients) when compared to their enantiomers in both groups of patients, whereas the pharmacokinetics of the carboxyethylphosphoramide metabolite was not enantioselective. Cytokines' plasma concentrations were similar between multiple and systemic sclerosis groups. The pharmacokinetics of cyclophosphamide is enantioselective in patients with systemic sclerosis and multiple sclerosis, with higher plasma concentrations of the (S)-(-)-cyclophosphamide enantiomer due to the preferential formation of the (R)-4-hydroxycyclophosphamide metabolite.

show abstract

Population pharmacokinetics of cyclophosphamide in patients with thalassemia major undergoing HSCT

Cited by 18 publications

References 55 publications

Etoposide-mediated interleukin-8 secretion from bone marrow stromal cells induces hematopoietic stem cell mobilization

Etoposide-mediated interleukin-8 secretion from bone marrow stromal cells induces hematopoietic stem cell mobilization

The Association of Combined GSTM1 and CYP2C9 Genotype Status with the Occurrence of Hemorrhagic Cystitis in Pediatric Patients Receiving Myeloablative Conditioning Regimen Prior to Allogeneic Hematopoietic Stem Cell Transplantation

Enantioselectivity in the Metabolism of Cyclophosphamide in Patients With Multiple or Systemic Sclerosis

Contact Info

Product

Resources

About