Physiologically based pharmacokinetic modelling of Busulfan: a new approach to describe and predict the pharmacokinetics in adults

• DOI: 10.1007/s00280-013-2275-x
• Publication Date: 2013-09-05T14:28:51Z
• Authors: Christian Diestel...; Joachim Boos; Jeannine S. McCune; James Russell; S. Bill Kangarloo; Georg Hempel
• Keywords: Adult; Male; Adolescent; Chemical Phenomena; Dose-Response Relationship, Drug; Middle Aged; Models, Biological; Metabolic Detoxication, Phase II; 3. Good health; 03 medical and health sciences; 0302 clinical medicine; Liver; Artificial Intelligence; Intestine, Small; Humans; Computer Simulation; Female; Drug Monitoring; Infusions, Intravenous; Antineoplastic Agents, Alkylating; Busulfan; Aged; Glutathione Transferase

A physiologically based pharmacokinetic (PBPK) model was established and evaluated describing the pharmacokinetics (PK) of the DNA-alkylating agent Busulfan in adults in order to predict the systemic Busulfan drug exposure in both plasma and toxicity-related organs.A generic PBPK model was tailored to describe Busulfan PK by implementing compound-specific physicochemical and metabolism data. With regard to possible influences of glutathione S transferase (GST) variations on Busulfan PK, two different PBPK model parameterizations were investigated: a first parameterization with individual GST activity (expressed as different estimated V(max) values) for each patient, and a resulting second model parameterization with a mean GST activity for all patients. Simulations were computed and compared to concentration-time data after intravenous Busulfan administration to 108 adults serving as development dataset. Subsequently, appropriateness of the PBPK model was evaluated with an external dataset not used for model development, consisting of 95 adults.Both PBPK model parameterizations of Busulfan successfully described the observed plasma concentrations. For the validation dataset, calculated PK parameters were as follows: clearance 0.16 ± 0.03 L/h/kg and volume of distribution 0.65 ± 0.06 L/kg (mean ± standard deviation). Mean absolute percentage error was less than 30 % for each PK parameter. Mass balances for distribution and excretion were in good agreement with the literature data.Both PBPK model parameterizations sufficiently described the observed concentration-time data while showing an adequate predictive performance. The model should be further evaluated for its ability to explain the between-subject variability in intravenous Busulfan PK parameters.