Abstract
Purpose
(1) To describe the neutropenic response of BI 2536 a polo-like kinase 1 inhibitor in patients with cancer using a semi-mechanistic model. (2) To explore by simulations (a) the neutropenic effects for the maximum tolerated dose (MTD) and the dose at which dose-limiting toxicity occurred, (b) the possibility to reduce the cycle duration without increasing neutropenia substantially, and (c) the impact of the initial absolute neutrophil count (ANC) on the degree of neutropenia for different doses.
Experimental design
BI 2536 was administered as intravenous infusion over 60 min in the dose range from 25 to 250 mg. Three different administration schedules were explored: (a) day 1, (b) days 1, 2, and 3 or (c) days 1 and 8 within a 3 week treatment cycle.
BI 2536 plasma concentrations and ANC obtained during the first treatment cycle from 104 patients were analysed using the population approach with NONMEM VI.
Results
Neutropenia was described by a semi-mechanistic model resembling proliferation at the stem cell compartment, maturation, degradation, and homeostatic regulation. BI 2536 acts decreasing proliferation rate.
Simulations showed that (1) all MTD doses showed an acceptable risk of neutropenia, (2) when BI 2536 is given as 200 mg single administration, cycle duration can be reduced from 3 to 2 weeks, and (3) baseline ANC might be considered to individualise the dose of BI 2536.
Conclusions
A semi-mechanistic population model was applied to describe the neutropenic effects of BI 2536. The model was used for simulations to support further clinical development.
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Notes
Karlsson and Holford [29].
References
Nigg EA (2001) Mitotic kinases as regulators of cell division and its checkpoints. Nat Rev Mol Cell Biol 2:21–32. doi:10.1038/35048096
Smits VA, Klompmaker R, Arnaud L, Rijksen G, Nigg EA, Medema RH (2000) Polo-like kinase-1 is a target of the DNA damage checkpoint. Nat Cell Biol 2:672–676. doi:10.1038/35023629
Steegmaier M, Hoffmann M, Baum A, Lenart P, Petronczki M, Krssak M, Gurtler U, Garin-Chesa P, Lieb S, Quant J, Grauert M, Adolf GR, Kraut N, Peters JM, Rettig WJ (2007) BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo. Curr Biol 17:316–322. doi:10.1016/j.cub.2006.12.037
Mross K, Frost A, Steinbild S, Hedbom S, Rentschler J, Kaiser R, Rouyrre N, Trommeshauser D, Hoesl CE, Munzert G (2008) Phase I dose escalation and pharmacokinetic study of BI 2536, a novel Polo-like kinase 1 inhibitor, in patients with advanced solid tumors. J Clin Oncol 26:5511–5517. doi:10.1200/JCO.2008.16.1547
Marangolo M, Bengala C, Conte PF, Danova M, Pronzato P, Rosti G, Sagrada P (2006) Dose and outcome: the hurdle of neutropenia (Review). Oncol Rep 16:233–248
Rombout F, Aarons L, Karlsson M, Man A, Mentre F, Nygren P, Racine A, Schaefer H, Steimer JL, Troconiz I, van Peer A, COST B15 Experts (2004) Modelling and simulation in the development and use of anti-cancer agents: an underused tool? J Pharmacokinet Pharmacodyn 31:419–440
Minami H, Sasaki Y, Saijo N, Ohtsu T, Fujii H, Igarashi T, Itoh K (1998) Indirect-response model for the time course of leukopenia with anticancer drugs. Clin Pharmacol Ther 64:511–521. doi:10.1016/S0009-9236(98)90134-5
Zamboni WC, D’Argenio DZ, Stewart CF, MacVittie T, Delauter BJ, Farese AM, Potter DM, Kubat NM, Tubergen D, Egorin MJ (2001) Pharmacodynamic model of topotecan-induced time course of neutropenia. Clin Cancer Res 7:2301–2308
Friberg LE, Henningsson A, Maas H, Nguyen L, Karlsson MO (2002) Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol 20:4713–4721
Panetta JC, Kirstein MN, Gajjar AJ, Nair G, Fouladi M, Stewart CF (2003) A mechanistic mathematical model of temozolomide myelosuppression in children with high-grade gliomas. Math Biosci 186:29–41
Woo S, Krzyzanski W, Jusko WJ (2008) Pharmacodynamic model for chemotherapy-induced anemia in rats. Cancer Chemother Pharmacol 62:123–133. doi:10.1007/s00280-007-0582-9
Leger F, Loos WJ, Bugat R, Mathijssen RH, Goffinet M, Verweij J, Sparreboom A, Chatelut E (2004) Mechanism-based models for topotecan-induced neutropenia. Clin Pharmacol Ther 76:567–578. doi:10.1016/j.clpt.2004.08.008
van Kesteren C, Zandvliet AS, Karlsson MO, Mathot RA, Punt CJ, Armand JP, Raymond E, Huitema AD, Dittrich C, Dumez H, Roche HH, Droz JP, Ravic M, Yule SM, Wanders J, Beijnen JH, Fumoleau P, Schellens JH (2005) Semi-physiological model describing the hematological toxicity of the anti-cancer agent indisulam. Invest New Drugs 23:225–234. doi:10.1007/s10637-005-6730-3
Troconiz IF, Garrido MJ, Segura C, Cendros JM, Principe P, Peraire C, Obach R (2006) Phase I dose-finding study and a pharmacokinetic/pharmacodynamic analysis of the neutropenic response of intravenous diflomotecan in patients with advanced malignant tumours. Cancer Chemother Pharmacol 57:727–735. doi:10.1007/s00280-005-0112-6
Sandstrom M, Lindman H, Nygren P, Lidbrink E, Bergh J, Karlsson MO (2005) Model describing the relationship between pharmacokinetics and hematologic toxicity of the epirubicin-docetaxel regimen in breast cancer patients. J Clin Oncol 23:413–421. doi:10.1200/JCO.2005.09.161
Sandstrom M, Lindman H, Nygren P, Johansson M, Bergh J, Karlsson MO (2006) Population analysis of the pharmacokinetics and the haematological toxicity of the fluorouracil-epirubicin-cyclophosphamide regimen in breast cancer patients. Cancer Chemother Pharmacol 58:143–156. doi:10.1007/s00280-005-0140-2
Latz JE, Karlsson MO, Rusthoven JJ, Ghosh A, Johnson RD (2006) A semimechanistic-physiologic population pharmacokinetic/pharmacodynamic model for neutropenia following pemetrexed therapy. Cancer Chemother Pharmacol 57:412–426. doi:10.1007/s00280-005-0077-5
Ozawa K, Minami H, Sato H (2007) Population pharmacokinetic and pharmacodynamic analysis for time courses of docetaxel-induced neutropenia in Japanese cancer patients. Cancer Sci 98:1985–1992. doi:10.1111/j.1349-7006.2007.00615.x
Hing J, Perez-Ruixo JJ, Stuyckens K, Soto-Matos A, Lopez-Lazaro L, Zannikos P (2008) Mechanism-based pharmacokinetic/pharmacodynamic meta-analysis of trabectedin (ET-743, Yondelis) induced neutropenia. Clin Pharmacol Ther 83:130–143. doi:10.1038/sj.clpt.6100259
Friberg LE, Sandstrom M, Karlsson MO (2009) Scaling the time-course of myelosuppression from rats to patients with a semi-physiological model. Invest New Drugs. doi:10.1007/s10637-009-9308-7
Beal SL, Sheiner LB (1989–2006) NONMEM users guides. Icon Development Solutions, Ellicot City
Ludden TM, Beal SL, Sheiner LB (1994) Comparison of the Akaike information criterion, the Schwarz criterion and the F test as guides to model selection. J Pharmacokinet Biopharm 22:431–445
Mandema JW, Verotta D, Sheiner LB (1992) Building population pharmacokinetic–pharmacodynamic models. I. Models for covariate effects. J Pharmacokinet Biopharm 20:511–528
Jonsson EN, Karlsson MO (1999) Xpose–an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Methods Programs Biomed 58:51–64
Karlsson MO, Savic RM (2007) Diagnosing model diagnostics. Clin Pharmacol Ther 82:17–20. doi:10.1038/sj.clpt.6100241
Latz JE, Chaudhary A, Ghosh A, Johnson RD (2006) Population pharmacokinetic analysis of ten phase II clinical trials of pemetrexed in cancer patients. Cancer Chemother Pharmacol 57:401–411. doi:10.1007/s00280-005-0036-1
Lyman GH, Lyman CH, Agboola O (2005) Risk models for predicting chemotherapy-induced neutropenia. Oncologist 10:427–437. doi:10.1634/theoncologist.10-6-427
Kloft C, Wallin J, Henningsson A, Chatelut E, Karlsson MO (2006) Population pharmacokinetic-pharmacodynamic model for neutropenia with patient subgroup identification: comparison across anticancer drugs. Clin Cancer Res 12:5481–5490. doi:12/18/5481[pii];10.1158/1078-0432.CCR-06-0815
Karlsson M, Holford NH (2008) A tutorial on visual predictive checks, p 17, Abstr 1434. www.page-meeting.org/?abstract=1434
Acknowledgments
Dr. Martina Wein, Department of Pharmacokinetics and Drug Metabolism, Boehringer Ingelheim Pharma GmbH & Co. KG
Funding
Elena Soto and Iñaki F. Trocóniz have received financial research support from Boehringer Ingelheim Pharma GmbH & Co. KG; Alexander Staab, Christiane Tillmann, Dirk Trommeshauser, Holger Fritsch, and Gerd Munzert are employees of Boehringer Ingelheim Pharma GmbH & Co. KG.
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Soto, E., Staab, A., Tillmann, C. et al. Semi-mechanistic population pharmacokinetic/pharmacodynamic model for neutropenia following therapy with the Plk-1 inhibitor BI 2536 and its application in clinical development. Cancer Chemother Pharmacol 66, 785–795 (2010). https://doi.org/10.1007/s00280-009-1223-2
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DOI: https://doi.org/10.1007/s00280-009-1223-2