Mechanism-based models for topotecan-induced neutropenia

Leger, Frédéric; Loos, Walter J.; Bugat, R.; Mathijssen, Ron H.J.; Goffinet, Marine; Verweij, Jaap; Sparreboom, Alex; Chatelut, Étienne

doi:10.1016/j.clpt.2004.08.008

Cited by 35 publications

(35 citation statements)

References 11 publications

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“…The time course of the neutrophil counts after the administration of BI 2536 was adequately described by the semi-mechanistic model previously proposed by Friberg et al [9]. The estimates of the system related parameters (Circ 0 = 4.96 cells 9 10 9 /L, MTT = 4.45 days, and c = 0.161) and their IPV estimates were very similar to those reported during the last 7 years for a variety of different anticancer drugs on the market or in development: 4.46-5.81 9 10 9 cells/L for Circ 0 , 3.65-5.62 days for MTT and 0.119-0.23 for c [9,[12][13][14][17][18][19]. The model selected in the current analysis is well established and has shown consistency in the system related parameter across several studies involving different anti-cancer drugs [14][15][16][17].…”

Section: Discussionsupporting

confidence: 65%

“…The inter-patient variability of the slope parameter was high (65%) for BI 2536, however, the value was within the range reported for other anticancer drugs: 40-82% [9,12,14,[16][17][18].…”

Section: Absolute Neutrophil Count-time Profile Vpcmentioning

confidence: 92%

“…Over the last years, the time course of neutropenia or other drug related haematological toxicities have been modelled linking the pharmacokinetic (PK) model with a model that describes the haematological toxicity [7][8][9][10][11]. Among these approaches, the model developed by Friberg et al [9] has been applied repeatedly to describe the time course of myelosuppression after administration of several cytotoxic anticancer drugs [12][13][14][15][16][17][18][19]. In addition, this model has successfully been applied in the scaling of the time course of myelosuppression from rat data to patients showing its usefulness in the drug development process [20].…”

Section: Introductionmentioning

confidence: 99%

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Semi-mechanistic population pharmacokinetic/pharmacodynamic model for neutropenia following therapy with the Plk-1 inhibitor BI 2536 and its application in clinical development

Soto

Staab

Tillmann

et al. 2010

Cancer Chemother Pharmacol

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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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Section: Discussionsupporting

confidence: 65%

“…The inter-patient variability of the slope parameter was high (65%) for BI 2536, however, the value was within the range reported for other anticancer drugs: 40-82% [9,12,14,[16][17][18].…”

Section: Absolute Neutrophil Count-time Profile Vpcmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Semi-mechanistic population pharmacokinetic/pharmacodynamic model for neutropenia following therapy with the Plk-1 inhibitor BI 2536 and its application in clinical development

Soto

Staab

Tillmann

et al. 2010

Cancer Chemother Pharmacol

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show abstract

“…With respect to the system related parameters, the estimated of Circ 0 was consistent with ANC normal values. The MTT could not be estimated correctly with the available data and, therefore, was fixed to 118 h as previously reported in the literature (30,(44)(45)(46)(47)(48). The estimated γ value, 0.135, was also similar to those obtained previously for other anticancer drugs, such as irinotecan (0.132) or topotecan (0.120) (30,49).…”

Section: Discussionsupporting

confidence: 52%

Pharmacokinetic and Pharmacodynamic Analysis of Hyperthermic Intraperitoneal Oxaliplatin-Induced Neutropenia in Subjects with Peritoneal Carcinomatosis

Valenzuela

Nalda-Molina

Bretcha-Boix

et al. 2011

AAPS J

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Abstract. The objective of this study was to characterize the pharmacokinetics and the time course of the neutropenia-induced by hyperthermic intraperitoneal oxaliplatin (HIO) after cytoreductive surgery in cancer patients with peritoneal carcinomatosis. Data from 30 patients who received 360 mg/m 2 of HIO following cytoreductive surgery were used for pharmacokinetic-pharmacodynamic (PK/PD) analysis. The oxaliplatin plasma concentrations were characterized by an open two-compartment pharmacokinetic model after first-order absorption from peritoneum to plasma. An oxaliplatin-sensitive progenitor cell compartment was used to describe the absolute neutrophil counts in blood. The reduction of the proliferation rate of the progenitor cells was modeled by a linear function of the oxaliplatin plasma concentrations. The typical values of oxaliplatin absorption and terminal half-lives were estimated to be 2.2 and 40 h, with moderate interindividual variability. Oxaliplatin reduced the proliferation rate of the progenitor cells by 18.2% per mg/L. No patient's covariates were related to oxaliplatin PK/PD parameters. Bootstrap and visual predictive check evidenced the model was deemed appropriate to describe oxaliplatin pharmacokinetics and the incidence and severity of neutropenia. A peritoneum oxaliplatin exposure of 65 and 120 mg·L/h was associated with a 20% and 33% incidence of neutropenia grade 4. The time course of neutropenia following HIO administration was well described by the semiphysiological PK/PD model. The maximum tolerated peritoneum oxaliplatin exposure is 120 mg L/h and higher exposures should be avoided in future studies. We suggest the prophylactic use of granulocyte colony stimulating factor for patients treated with HIO exposure higher than 65 mg L/h.

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“…This approach has been widely applied to various anticancer agents [10,[37][38][39] since it is simple in nature to operate with minimum number of parameters while accounting for the time delay for onset of responses and rebound phase typically observed in myelosuppression profiles. A similar approach has been also applied to chemotherapy-related thrombocytopenia [40].…”

Section: Discussionmentioning

confidence: 99%

Pharmacodynamic model for chemotherapy-induced anemia in rats

Woo

Krzyzanski

Jusko

2007

Cancer Chemother Pharmacol

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Anticancer agents often cause bone marrow toxicity resulting in progressive anemia which may influence the therapeutic effects of erythropoietic-stimulating agents. The objective of this study was to develop a pharmacodynamic (PD) model to describe chemotherapy-induced anemia in rats. Anemia was induced in male Wistar rats with a single intravenous (i.v.) injection of 60 mg/kg carboplatin. Hematological responses including reticulocytes, red blood cells (RBC), hemoglobin, and endogenous rat erythropoietin (EPO) were measured for up to 4 weeks. A catenary, lifespanbased, indirect response model served as a basic PD model to represent erythroid cellular populations in the bone marrow and blood involved in erythropoiesis. The model assumed that actively proliferating progenitor cells in the bone marrow are sensitive to anti-cancer agents and subject to an irreversible removal process. The removal rate of the target cells is proportional to drug activity concentrations and the cell numbers. An additional RBC loss from the circulation resulting from thrombocytopenia was described by a first-order process. The turnover process of rat EPO and EPOmediated feedback inhibition mechanism regulated by hemoglobin changes were incorporated. Reticulocyte counts decreased rapidly and reached a nadir by day 3 after administration of carboplatin and returned to the baseline by day 13. This was followed by a gradual increase and the rebound peak occurred at about day 15. The hemoglobin nadir was approximately 9 g/dl observed at about 11-13 days compared to its normal value of 13 g/dl and hemoglobin returned to the baseline by day 30. The increase in endogenous rat EPO mirrored inversely hemoglobin changes and the maximum increase was observed soon after the hemoglobin nadir. The carboplatin-treated rats exhibited progressive anemia. The proposed model adequately described the time course of hematological changes after carboplatin in rats and can be a useful tool to explore potential strategies for the management of anemia caused by chemotherapy.

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Mechanism-based models for topotecan-induced neutropenia

Cited by 35 publications

References 11 publications

Semi-mechanistic population pharmacokinetic/pharmacodynamic model for neutropenia following therapy with the Plk-1 inhibitor BI 2536 and its application in clinical development

Semi-mechanistic population pharmacokinetic/pharmacodynamic model for neutropenia following therapy with the Plk-1 inhibitor BI 2536 and its application in clinical development

Pharmacokinetic and Pharmacodynamic Analysis of Hyperthermic Intraperitoneal Oxaliplatin-Induced Neutropenia in Subjects with Peritoneal Carcinomatosis

Pharmacodynamic model for chemotherapy-induced anemia in rats

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