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Population pharmacokinetics of treosulfan and development of a limited sampling strategy in children prior to hematopoietic stem cell transplantation.

ABSTRACT: There is an increasing interest in use of treosulfan (TREO), a structural analogue of busulfan, as an agent in conditioning regimens prior to hematopoietic stem cell transplantation (HSCT), both in pediatric and adult populations. The aim of this study was to develop a population pharmacokinetic model and to establish limited sampling strategies (LSSs) enabling accurate estimation of exposure to this drug.The study included 15 pediatric patients with malignant and non-malignant diseases, undergoing conditioning regimens prior to HSCT including TREO administered as a 1 h or 2 h infusion at daily doses of 10, 12, or 14 g/m2. A population pharmacokinetic model was developed by means of non-linear mixed-effect modeling approach in Monolix® software. Multivariate regression analysis and Bayesian method were used to develop 2- and 3-point strategies for estimation of exposure to TREO.Pharmacokinetics of TREO was best described with a two-compartmental linear model with proportional residual error. Following sampling schedules allowed accurate estimation of exposure to TREO: 1 h and 6 h or 1 h, 2 h, and 6 h for a TREO dose 12 g/m2 in a 1 h infusion, or at 2 h and 6 h or 2 h, 4 h, and 8 h for a TREO dose of 12 g/m2 and 14 g/m2 in a 2 h infusion.A two-compartmental population pharmacokinetic model of TREO was developed and successfully used to establish 2- and 3-point LSSs for accurate and precise estimation of TREO AUC0??.

SUBMITTER: Danielak D

PROVIDER: S-EPMC5748442 | biostudies-other | 2018 Jan

REPOSITORIES: biostudies-other

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Population pharmacokinetics of treosulfan and development of a limited sampling strategy in children prior to hematopoietic stem cell transplantation.

Danielak Dorota D Twardosz Jadwiga J Kasprzyk Anna A Wachowiak Jacek J Kałwak Krzysztof K Główka Franciszek F

European journal of clinical pharmacology 20171003 1

<h4>Purpose</h4>There is an increasing interest in use of treosulfan (TREO), a structural analogue of busulfan, as an agent in conditioning regimens prior to hematopoietic stem cell transplantation (HSCT), both in pediatric and adult populations. The aim of this study was to develop a population pharmacokinetic model and to establish limited sampling strategies (LSSs) enabling accurate estimation of exposure to this drug.<h4>Methods</h4>The study included 15 pediatric patients with malignant and ...[more]

PMID: 28975382

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Project description:The presence of active viral infections has an impact on the prognosis of patients undergoing hematopoietic stem cell transplantation (HSCT). Nevertheless, the number of reports of cytomegalovirus infection in patients with inborn errors of immunity (IEI) who undergo HSCT is relatively low. To analyze the effect of cytomegalovirus infection acquired prior to curative treatment on patient survival in 123 children with IEI. An observational and retrospective study was performed with patients younger than 18 years diagnosed with IEI who were candidates for HSCT, gene therapy, or thymus transplantation at five hospitals in Spain between 2008 and 2019. We included 123 children, 25 infected by cytomegalovirus prior to undergoing curative treatment (20.3%). At IEI diagnosis, 24 of the patients were already infected, 21 of whom had symptomatic cytomegalovirus disease (87%), while the other three patients developed disease before undergoing curative treatment. The patients with cytomegalovirus infection had higher mortality than those without (p = 0.006). Fourteen patients developed refractory cytomegalovirus infection (56%), all of whom died, while no patients with non-refractory infection died (p = 0.001) All deaths that occurred before curative treatment and three of the five after the treatment were attributed to cytomegalovirus. Patients with refractory cytomegalovirus disease had the highest pre-HSCT mortality rate (64.3%), compared with the non-infected children and those with non-refractory cytomegalovirus disease (10.1%) (p < 0.0001).ConclusionPrevention and prompt control of cytomegalovirus infection, together with early HSCT/gene therapy, are crucial for improving the prognosis in children with IEI.What is known• Cytomegalovirus is the most frequent viral infection in children with inborn errors of immunity who are candidates to hematopoietic stem cell transplantation (HSCT). • Active viral infections at the time of HSCT lead to worse prognosis.What is new• In children with inborn errors of immunity and indication of HSCT, refractory cytomegalovirus disease is associated with a very high mortality rate, compared with non-infected children and those with non-refractory cytomegalovirus disease. • In patients with novel transplantation indications, the presence and treatment response of CMV infection should be considered to decide the best possible moment for HSCT.

Dataset Information

Population pharmacokinetics of treosulfan and development of a limited sampling strategy in children prior to hematopoietic stem cell transplantation.

Publications

Population pharmacokinetics of treosulfan and development of a limited sampling strategy in children prior to hematopoietic stem cell transplantation.

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