Abstract
Interindividual variability (IIV) is considered a crucial factor for the general use of mathematical modelling in physiology. However, mechanistic models of physiological systems are commonly built for an average patient, raising the question of their applicability at the population level. Using our previously developed physiological model of neutrophil regulation, which accounts for the detailed hematopoietic mechanisms as well as the pharmacokinetics (PKs) of a chemotherapeutic agent (PM00104) and a granulostimulant (filgrastim), we incorporated the reported population pharmacokinetic (PopPK) models of each drug to investigate the impact of PK variability on fully mechanistic models. A variety of scenarios, including multiple doses of PM00104, were simulated for cohorts of 500 in silico patients to analyse the model’s predictability in terms of several pharmacological indicators, such as the time to neutrophil nadir, the value of the nadir, and the area under the effect curve. Our results indicate the robustness of our model’s predictions in all considered scenarios. Based on our findings, we conclude that for drugs with short-lived PKs in comparison with their pharmacodynamics (PDs), models that “sufficiently” account for physiological mechanisms inherently assimilate PK deviations, making the further inclusion of PK variability unnecessary.
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References
Bai, J.P.F., Abernathy, D.R.: Systems pharmacology to predict drug toxicity: integration across levels of biological organization. Annu. Rev. Pharmacol. Toxicol. 53, 451–473 (2013)
Brooks, G., Langlois, G., Lei, J., Mackey, M.C.: Neutrophil dynamics after chemotherapy and G-CSF: the role of pharmacokinetics in shaping the response. J. Theor. Biol. 315, 97–109 (2012)
Brown, R., Delp, M., Lindstedt, S., Rhomberg, L., Beliles, R.: Physiological parameter values for physiologically based pharmacokinetic models. Toxicol. Ind. Health 13, 407–484 (1997)
Center for Drug Evaluation and Research (CDER): U.S. Department of Health and Human Services Food and Drug Administration. Guidance for industry. Bioavailability and bioequivalence studies submitted in NDAs or INDs—general considerations. Tech. rep. (2014)
Colijn, C., Mackey, M.C.: A mathematical model of hematopoiesis: II. Cyclical neutropenia. J. Theor. Biol. 237, 133–146 (2005)
Craig, M., Humphries, A., Bélair, J., Li, J., Nekka, F., Mackey, M.C.: Neutrophil dynamics during concurrent chemotherapy and g-csf administration: mathematical modelling guides dose optimisation to minimise neutropenia. J. Theor. Biol. 385, 77–89 (2015)
Dancey, J., Deubelbeiss, K., Harker, L., Finch, C.: Neutrophil kinetics in man. J. Clin. Invest. 58, 705–715 (1976)
Danhof, M., DeLange, E., Della Pasqua, O., Ploeger, B., Voskuyl, R.: Mechanism-based pharmacokinetic-pharmacodynamic (pkpd) modeling in translational drug research. Trends Pharmacol. Sci. 29, 186–191 (2008)
Foley, C., Mackey, M.C.: Mathematical model for G-CSF administration after chemotherapy. J. Theor. Biol. 257, 27–44 (2009)
Foley, C., Bernard, S., Mackey, M.C.: Cost-effective G-CSF therapy strategies for cyclical neutropenia: mathematical modelling based hypotheses. J. Theor. Biol. 238, 756–763 (2006)
Furze, R.C., Rankin, S.M.: Neutrophil mobilization and clearance in the bone marrow. Immunology 125, 281–288 (2008)
Gobburu, J., Agersø, H., Jusko, W., Ynddal, L.: Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers. Pharm. Res. 16, 1412–1416 (1999)
González-Sales, M., Valenzuela, B., Pérez-Ruixo, C., Fernández Teruel, C., Miguel-Lillo, B., Matos, A.S., et al.: Population pharmacokinetic-pharmacodynamic analysis of neutropenia in cancer patients receiving PM00104 (Zalypsis). Clin. Pharmacokinet. 51, 751–764 (2012)
Krzyzanski, W., Wiczling, P., Lowe, P., Pigeolet, E., Fink, M., Berghout, A., et al.: Population modeling of filgrastim PK-PD in healthy adults following intravenous and subcutaneous administrations. J. Clin. Pharmacol. 9 (Suppl.), 101S–112S (2010)
Kuwabara, T., Kato, Y., Kobayashi, S., Suzuki, H., Sugiyama, Y.: Nonlinear pharmacokinetics of a recombinant human granulocyte colony-stimulating factor derivative (Nartograstim): species differences among rats, monkeys and humans. J. Pharmacol. Exp. Ther. 271, 1535–1543 (1994)
Layton, J.E., Hall, N.E.: The interaction of G-CSF with its receptor. Front. Biosci. 31, 177–199 (2006)
Mathworks: MATLAB 2013a. Mathworks, Natick (2013)
Pérez-Ruixo, C., Valenzuela, B., Fernández Teruel, C., González-Sales, M., Miguel-Lillo, B., Soto-Matos, A., et al.: Population pharmacokinetics of PM00104 (Zalypsis) in cancer patients. Cancer Chemother. Pharmacol. 69, 15–24 (2012)
Petek, B., Jones, R.: PM00104 (Zalypsis®;): a marine derived alkylating agent. Molecules 19, 12328–12335 (2014). doi:10.3390/molecules190812328
Price, T.H., Chatta, G.S., Dale, D.C.: Effect of recombinant granulocyte colony-stimulating factor on neutrophil kinetics in normal young and elderly humans. Blood 88, 335–340 (1996)
Rankin, S.M.: The bone marrow: a site of neutrophil clearance. J. Leukoc. Biol. 88, 241–251 (2010)
Scholz, M., Schirm, S., Wetzler, M., Engel, C., Loeffler, M.: Pharmacokinetic and -dynamic modelling of G-CSF derivatives in humans. Theor. Biol. Med. Model. 9, 1497–1502 (2012)
Sorger, D.R., Allerheiligen, S.R.B., Abernethy, R.B., Altman, K.L.R., Brouwer, A.C., Califano, A., D’Argenio, D.Z., Iyengar, R., Jusko, W.J., Lalonde, R., Lauffenburger, D.A., Shoichet, B., Stevens, J.L., Subramaniam, S., van der Graaf, P., Vincini, P.: Quantitative and systems pharmacology in the post-genomic era: new approaches to discovering drugs and understanding therapeutic mechanisms. An NIH white paper by the QSP Workshop Group – October 2011, pp. 1–47. National Institutes of Health of the United States of America, Bethesda (2011)
Vainas, O., Ariad, S., Amir, O., Mermershtain, W., Vainstein, V., Kleiman, M., Inbar, O., Ben-Av, R., Mukherjee, A., Chan, S., Agur, Z.: Personalising docetaxel and G-CSF schedules in cancer patients by a clinically validated computational model. Br. J. Cancer 107, 814–822 (2012)
Wang, B., Ludden, T.M., Cheung, E.N., Schwab, G.G., Roskos, L.K.: Population pharmacokinetic-pharmacodynamic modeling of filgrastim (r-metHuG-CSF) in healthy volunteers. J. Pharmacokinet. Pharmacodyn. 28, 321–342 (2001)
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Craig, M., González-Sales, M., Li, J., Nekka, F. (2016). Impact of Pharmacokinetic Variability on a Mechanistic Physiological Pharmacokinetic/Pharmacodynamic Model: A Case Study of Neutrophil Development, PM00104, and Filgrastim. In: Toni, B. (eds) Mathematical Sciences with Multidisciplinary Applications. Springer Proceedings in Mathematics & Statistics, vol 157. Springer, Cham. https://doi.org/10.1007/978-3-319-31323-8_6
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