Modeling of busulfan pharmacokinetics and relapses in adult patients with acute myeloid leukemia
Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
Introduction: Busulfan is used as a conditioning drug prior to bone marrow transplants in patients with acute myeloid leukemia. To achieve busulfan target exposure, therapeutic drug monitoring is common clinical practice where rich pharmacokinetic (PK) sampling is utilized. Despite of doing so, the clinical outcome still greatly varies. Cytogenetics are one of the main factors for predicting disease outcome.
Aim: The objective of this project was to characterize busulfan population PK. Secondary aims were to (i) optimize the number of samples needed to estimate busulfan exposure and (ii) to develop a model characterizing relapse/death incidence incorporating different predictors.
Methods: Data were compiled from a UCSF patient database. Standard non-linear mixed effects methodology was utilized for the model building. A proportional odds model was applied to characterize probability of a relapse/death. Busulfan exposure as well as 50 genes identified as top hits by GWAS were tested as potential predictors of relapses.Results: Population estimates of clearance and volume of distribution (typical patient 75 kg), were 0.156 L/h/kg and 0.604 L/kg with between-subject variability of 19.6% and 17.5%, respectively. One sample in combination with the developed model is sufficient to dose adjust and reach target exposure (relative predictive error < 2% compared to current clinical practice). Probability of relapse/death was associated with cytogenetic factors (rs555513, rs10122691), showing modified risk of relapse/death depending on genotype.
Conclusions: Current clinical practices used to achieve target busulfan exposure can be simplified by utilizing the developed model. The number of PK samples can be reduced from four to one, thereby lowering costs and improving overall quality of life for the patient. The identified cytogenetic predictors of relapse/death are in line with results obtained from the GWAS study, which was carried out in parallel.
Place, publisher, year, edition, pages
2012. , 24 p.
IdentifiersURN: urn:nbn:se:uu:diva-185687OAI: oai:DiVA.org:uu-185687DiVA: diva2:572365
Rada Savic, Univeristy of California, San Francisco
Subject / course
Master of Science Programme in Pharmacy
Savic, Rada, PhD