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Conditioning Regimens

Population pharmacokinetics of cyclophosphamide in patients with thalassemia major undergoing HSCT

Bone Marrow Transplantation volume 47, pages 1178–1185 (2012)Cite this article

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Abstract

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 (P<0.002) and thus the area under the concentration curve (P<0.05) 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.

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Acknowledgements

This study was supported by the Indo-French center for the promotion of advanced research (IFCPAR) grant no. 2403-2 and the Department of Biotechnology, India, grant no. BT/PR7596/MED/12/291/2006. We also acknowledge Prof. Jeannine McCune, University of Washington and Fred Hutchinson Cancer Research Center, Seattle, USA for kindly providing PK data for comparison and her grant support (R21- CA162059).

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Author notes

  1. S Desire

    Present address: Current address: PSG Center for Molecular Medicine and Therapeutics, PSG Institute of Medical Sciences and Research, Coimbatore, India.,

  2. M Chandy

    Present address: Current Address: Tata Medical Center, Kolkata, India.,

Authors and Affiliations

  1. Department of Haematology, Christian Medical College, Vellore, India

    P Balasubramanian, S Desire, K M Lakshmi, V Mathews, B George, A Viswabandya, M Chandy & A Srivastava

  2. Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA

    J C Panetta

  3. INSERM U 458, Hopital Robert Debre, Paris, France

    R Krishnamoorthy

  4. These authors contributed equally to this study.,

    P Balasubramanian, S Desire & J C Panetta

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Balasubramanian, P., Desire, S., Panetta, J. et al. Population pharmacokinetics of cyclophosphamide in patients with thalassemia major undergoing HSCT. Bone Marrow Transplant 47, 1178–1185 (2012). https://doi.org/10.1038/bmt.2011.254

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