Dataset Information

Pharmacokinetics and Pharmacodynamics of Treosulfan in Patients With Thalassemia Major Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.

ABSTRACT: A treosulfan (Treo)-based conditioning regimen prior to hematopoietic stem cell transplantation (HSCT) has been successfully used in treating hematological malignant and nonmalignant diseases. We report Treo pharmacokinetics (PK) in patients with thalassemia major undergoing HSCT (n?=?87), receiving Treo at a dose of 14?g/m2 /day. Median Treo AUC and clearance (CL) was 1,326?mg*h/L and 10.8?L/h/m2 , respectively. There was wide interindividual variability in Treo AUC and CL (64 and 68%) which was not explained by any of the variables tested. None of the Treo PK parameters were significantly associated with graft rejection or toxicity; however, Treo CL <7.97?L/h/m2 was significantly associated with poor overall (hazard ratio (HR) 2.7, confidence interval (CI) (1.09-6.76), P?=?0.032) and event-free survival (HR 2.4, CI (0.98-5.73), P?=?0.055). Further studies in a larger cohort are warranted to identify the factors explaining the variation in Treo PK as well as to establish a therapeutic range of Treo for targeted dose adjustment to improve HSCT outcome.

SUBMITTER: Mohanan E

PROVIDER: S-EPMC6045930 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Pharmacokinetics and Pharmacodynamics of Treosulfan in Patients With Thalassemia Major Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.

Mohanan Ezhilpavai E Panetta John C JC Lakshmi Kavitha M KM Edison Eunice S ES Korula Anu A Na Fouzia F Abraham Aby A Viswabandya Auro A George Biju B Mathews Vikram V Srivastava Alok A Balasubramanian Poonkuzhali P

Clinical pharmacology and therapeutics 20180117 3

A treosulfan (Treo)-based conditioning regimen prior to hematopoietic stem cell transplantation (HSCT) has been successfully used in treating hematological malignant and nonmalignant diseases. We report Treo pharmacokinetics (PK) in patients with thalassemia major undergoing HSCT (n = 87), receiving Treo at a dose of 14 g/m<sup>2</sup> /day. Median Treo AUC and clearance (CL) was 1,326 mg*h/L and 10.8 L/h/m<sup>2</sup> , respectively. There was wide interindividual variability in Treo AUC and CL ...[more]

PMID: 29247522

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Project description:PurposeTo analyze factors influencing tacrolimus (TAC) trough concentration (C0) in β-thalassemia major (β-TM) pediatric patients after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) and to investigate the effects of genotype polymorphism and drug-drug interactions on TAC trough concentration in children with β-TM. Furthermore, to analyze the correlation between TAC C0 and efficacy and adverse reactions.Patients and methodsProspectively collection of demographic information and details of combined treatment of patients with β-TM receiving HSCT, and genotypes of CYP3A4, CYP3A5, and ABCB1 (rs1045642, rs1128503, rs2032582) were obtained for each patient. Univariate analysis and multiple linear regression analysis were used to investigate influencing factors on TAC C0. The impact of different genotypes and the co-administration of azole antifungal drugs on β-TM patients receiving TAC were evaluated, together with the correlation between acute graft-versus-host disease (aGVHD), infection, and liver injury of TAC C0.ResultsA total of 46 patients with 587 concentration data were included. The multiple linear regression results showed that the patient's sex, weight, postoperative time, hemoglobin, platelet count, serum cystatin C, and combined voriconazole were independent influencing factors of the infusion trough concentration/daily dose, C0/Div. Age, body surface area, postoperative time, co-administration of voriconazole, and CYP3A4*18B are independent influencing factors of C0/Dpo. Group comparisons showed that voriconazole can affect TAC C0 administered intravenously (IV) and orally in β-TM pediatric patients, while patient genotype can affect TAC C0 during oral administration. TAC C0 does not correlate with aGVHD or liver injury, but infection may be associated with TAC C0.ConclusionThe concentration of TAC should be closely monitored when co-administered with voriconazole. It is worth considering that the influence of genotype on the trough concentration of oral TAC and individualized drug administration warrant investigation. Finally, this study indicated that C0 is not suitable as an indicator of the efficacy of TAC.

Dataset Information

Pharmacokinetics and Pharmacodynamics of Treosulfan in Patients With Thalassemia Major Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.

Publications

Pharmacokinetics and Pharmacodynamics of Treosulfan in Patients With Thalassemia Major Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.

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