Efthtymios Neroutsos, Georgia Valsami, Aris Dokoumetzidis
Laboratory of Biopharmaceutics & Paharmacokinetics, Faculty of Pharmacy, National & Kapodistrian University of Athens, Panepistimiopolos, Zographou, 15771, Greece
Objectives: To investigate the usage of a popPK model for Bayesian individualization of oral Busulfan dosing in patients from a different hospital. This was done by simulating patients using a popPK model taken from literature and adjusting the dose by applying a different popPK model also taken from literature.
Methods: A total of 1000 children were simulated in NONMEM for three different blood sampling schemes, according to a PopPK model taken from literature (model A) [1]. Based on the posthoc estimates of clearance for these patients using the same model (model A), we calculated the AUC and individualized the dose targeting AUC=1125 μM*min (therapeutic range of Busulfan 900-1350 μM*min). The AUC of the second day of administration was recorded by simulating again using the adjusted dose. Patients that fall outside the therapeutic range were counted before and after the dose adjustment (day 1 vs day 2 of treatment). The dose of the same simulated patients was also adjusted by applying a different model from literature (model B) [2] using the same procedure.
Results: For a blood sampling scheme at 2, 4, 6 hours, the patients’ AUC that fall within the therapeutic range were 40.3%. After the individualization with model A (the same as the one used for simulation) patients within the range increased to 62% while with model B (a different model to the one used to simulate the patients) increased to 52.8%. As expected better performance is achieved with an in-house model while the overall performance even of the in-house model is moderate. Richer sampling schemes, namely at 2, 3, 4, 5, 6 h and 1.5, 3.5, 5, 6, 8, 12 h, performed similarly without offering significant improvement.
Conclusions: In the present study we observed that Bayesian individualization of oral Busulfan dosing offers some improvement while the development of an in-house model rather than the use of a literature model is deemed necessary.
References:
[1] Trame MN, Bergstrand M, Karlsson MO, Boos J, Hempel G. Population pharmacokinetics of busulfan in children: increased evidence for body surface area and allometric body weight dosing of busulfan in children. Clin Cancer Res. 2011 Nov 1;17(21):6867-77.
[2] Schiltmeyer B, Klingebiel T, Schwab M, Mürdter TE, Ritter CA, Jenke A, Ehninger G, Gruhn B, Würthwein G, Boos J, Hempel G. Population pharmacokinetics of oral busulfan in children. Cancer Chemother Pharmacol. 2003 Sep;52(3):209-16.
Reference: PAGE 22 (2013) Abstr 2791 [www.page-meeting.org/?abstract=2791]
Poster: Oncology