Christian Diestelhorst (1), Joachim Boos (2), Jeannine S. McCune (3), James A. Russell (4), S. Bill Kangarloo (4), Georg Hempel (1,2)
(1) Department of Pharmaceutical and Medical Chemistry - Clinical Pharmacy, University of Münster, Germany; (2) Department of Paediatric Haematology and Oncology, University Children’s Hospital Münster, Germany; (3) Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA; (4) Alberta Blood and Marrow Transplant Program, Foothills Hospital, and Tom Baker Cancer Centre, Calgary, Alberta, Canada
Objectives: Busulfan (Bu), a DNA-alkylating agent, is used widely for conditioning prior to bone marrow transplantation in both children and adults for haematological malignancies and non-malignancies. Despite years of investigation there are still open questions regarding intravenous (i.v.) Bu chemotherapy, e.g. an optimal area under the curve (AUC) target to reduce toxicity and optimize efficacy, the best schedule of administration as well as the optimal dosing in children. Therefore, a Physiologically-based pharmacokinetic (PBPK) model for adults was developed with the aim to predict plasma concentration-time curves, e.g. in children and other special patient groups.
Methods: PK-Sim® (Bayer Technologies, Leverkusen, Germany) was used to build a PBPK model. We implemented several physicochemical parameters of Bu and also considered particular properties, e.g. both plasma protein binding (reversible and irreversible) and red blood cell binding [1,2]. Metabolism is implemented in the liver and the small intestine using the activity of Glutathione S-transferase (GST) A1, the predominant isoform of GST catalysing Bu [3,4,5]. A fixed combination of Km and Vmax values for GST-A1 in all simulations was applied. For model development, simulations were computed and compared to raw pharmacokinetic data from 108 adults (13 patients received i.v. Bu four times daily, 95 patients received i.v. Bu once daily). Subsequently, model appropriateness was evaluated with an external dataset consisting of 95 adults [6,7], whom had 5 pharmacokinetic samples drawn about the first once daily dose.
Results: For the evaluation dataset parameters calculated by PK-Sim® were as follows: AUC (after the first once daily dose of 2.94 ± 0.26 mg/kg) 1.16 ± 0.15 mg*min/ml, clearance 0.16 ± 0.03 l/h/kg and volume of distribution at steady state 0.65 ± 0.06 l/kg (mean ± standard deviation). Mean Percentage Error (MPE) was less than 30% for each parameter compared with data from non-compartmental analysis [6,7].
Conclusion: Our PBPK model appears to accurately characterize i.v. Bu pharmacokinetics compared to non-compartmental analysis. Further investigations, e.g. distribution processes in different organs, the influence of different comedication and clearance scaling to predict the pharmacokinetics in children, are ongoing.
References:
[1] Ehrsson H, Hassan M. Binding of busulfan to plasma proteins and blood cells. J Pharm Pharmacol. 1984 Oct; 36(10):694-6
[2] Hassan M, Oberg G, Ehrsson H, Ehrnebo M, Wallin I, Smedmyr B, Tötterman T, Eksborg S, Simonsson B. Pharmacokinetic and metabolic studies of high-dose busulphan in adults. Eur J Clin Pharmacol. 1989; 36(5):525-30
[3] Czerwinski M, Gibbs JP, Slattery JT. Busulfan conjugation by glutathione S-transferases alpha, mu, and pi. Drug Metab Dispos. 1996 Sep; 24(9):1015-9.
[4] Bredschneider M, Klein K, Mürdter TE, Marx C, Eichelbaum M, Nüssler AK, Neuhaus P, Zanger UM, Schwab M. Genetic polymorphisms of glutathione S-transferase A1, the major glutathione S-transferase in human liver: consequences for enzyme expression and busulfan conjugation. Clin Pharmacol Ther. 2002 Jun; 71(6):479-87
[5] Gibbs JP, Yang JS, Slattery JT. Comparison of human liver and small intestinal glutathione S-transferase-catalyzed busulfan conjugation in vitro. Drug Metab Dispos. 1998 Jan;26(1):52-5.
[6] Kangarloo SB, Naveed F, Ng ES, Chaudhry MA, Wu J, Bahlis NJ, Brown CB, Daly A, Duggan P, Geddes M, Quinlan D, Savoie ML, Shafey M, Stewart DA, Storek J, Yang M, Zacarias N, Yue P, Magliocco AM, Russell JA. Development and validation of a test dose strategy for once-daily i.v. busulfan: importance of fixed infusion rate dosing. Biol Blood Marrow Transplant. 2012 Feb;18(2):295-301. Epub 2011 Jul 27.
[7] Geddes M, Kangarloo SB, Naveed F, Quinlan D, Chaudhry MA, Stewart D, Savoie ML, Bahlis NJ, Brown C, Storek J, Andersson BS, Russell JA. High busulfan exposure is associated with worse outcomes in a daily i.v. busulfan and fludarabine allogeneic transplant regimen. Biol Blood Marrow Transplant. 2008 Feb; 14(2):220-8
Reference: PAGE 21 () Abstr 2378 [www.page-meeting.org/?abstract=2378]
Poster: Absorption and Physiology-Based PK