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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Pharmaceutical and Medical Chemistry, Clinical Pharmacy, University of Münster, Corrensstr. 48, 48149, Münster, Germany.
Christian
C
Diestelhorst
Joachim
J
Boos
Jeannine S
JS
McCune
James
J
Russell
S Bill
SB
Kangarloo
Georg
G
Hempel
D000293:Adolescent; D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D001185:Artificial Intelligence; D002066:Busulfan / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D055598:Chemical Phenomena; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007262:Infusions, Intravenous; D007421:Intestine, Small / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D050217:Metabolic Detoxication, Phase II; D008875:Middle Aged; D008954:Models, Biological; D055815:Young Adult
D018906:Antineoplastic Agents, Alkylating; D005982:Glutathione Transferase; D002066:Busulfan