ArticleBritish journal of clinical pharmacology2017
A population pharmacokinetic model of AT9283 in adults and children to predict the maximum tolerated dose in children with leukaemia.
Article in British journal of clinical pharmacology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Article
- Aurora Kinase B Inhibition: A Potential Therapeutic Strategy for Cancer.Molecules (Basel, Switzerland) · 2021Review
- High NRF2 Levels Correlate with Poor Prognosis in Colorectal Cancer Patients and with Sensitivity to the Kinase Inhibitor AT9283 In Vitro.Biomolecules · 2020Article
- Drug Exposure to Establish Pharmacokinetic-Response Relationships in Oncology.Clinical pharmacokinetics · 2020Review
- The balance between mitotic death and mitotic slippage in acute leukemia: a new therapeutic window?Journal of hematology & oncology · 2019Review
- A population pharmacokinetic model of AT9283 in adults and children to predict the maximum tolerated dose in children with leukaemia.British journal of clinical pharmacology · 2017Article
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Authors and funding
6 authors.
Funding
Abstract
aimsAT9283 is used to treat patients with solid tumours and patients with leukaemia. However, the maximum tolerated dose (MTD) for children with leukaemia remains unknown due to early termination of the Phase I trial. The aim of this study was to develop a population model of AT9283 to describe the pharmacokinetics in adults and children and to estimate the MTD in children with leukaemia.
methodsData from Phase I dose-escalation studies in adults and children were used to build a population pharmacokinetic model (NONMEM v7.3). Potential covariates investigated included body weight, body surface area (BSA), glomerular filtration rate (GFR), age and sex. Model-derived area under the concentration-time curve was used to investigate the relationship between dose and exposure in adults and children.
resultsThe plasma concentrations of AT9283 (n = 1770) from 92 patients (53 adults, 39 children) were used to build a two-compartment model with all pharmacokinetic parameters scaled using body weight. Renal function (GFR), but not BSA, was a significant covariate for the clearance of AT9283. In children with leukaemia (median weight 16 kg), a flat dose of 500 mg 72 h
conclusionFor adults, GFR was a significant predictor of clearance, whilst body-weight based dosing was more useful than BSA in determining the drug exposure in children. The MTD was estimated to be 30 mg kg
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