Limits...
A biomathematical model of human erythropoiesis under erythropoietin and chemotherapy administration.

Schirm S, Engel C, Loeffler M, Scholz M - PLoS ONE (2013)

Bottom Line: We added a model of EPO absorption after injection at different sites and a pharmacokinetic model of EPO derivatives to account for the effects of external EPO applications.Parameter fittings resulted in a good agreement of model and data.Prospective clinical studies are needed to validate model predictions and to explore the feasibility and effectiveness of the proposed schedules.

View Article: PubMed Central - PubMed

Affiliation: Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany. sibylle.schirm@imise.uni-leipzig.de

ABSTRACT
Anaemia is a common haematologic side effect of dose-dense multi-cycle cytotoxic polychemotherapy requiring erythrocyte transfusions or erythropoietin (EPO) administration. To simulate the effectiveness of different EPO application schedules, we performed both modelling of erythropoiesis under chemotherapy and pharmacokinetic and dynamic modelling of EPO applications in the framework of a single comprehensive biomathematical model. For this purpose, a cell kinetic model of bone marrow erythropoiesis was developed that is based on a set of differential compartment equations describing proliferation and maturation of erythropoietic cell stages. The system is regulated by several feedback loops comprising those mediated by EPO. We added a model of EPO absorption after injection at different sites and a pharmacokinetic model of EPO derivatives to account for the effects of external EPO applications. Chemotherapy is modelled by a transient depletion of bone marrow cell stages. Unknown model parameters were determined by fitting the predictions of the model to data sets of circulating erythrocytes, haemoglobin, haematocrit, percentage of reticulocytes or EPO serum concentrations derived from the literature or cooperating clinical study groups. Parameter fittings resulted in a good agreement of model and data. Depending on site of injection and derivative (Alfa, Beta, Delta, Darbepoetin), nine groups of EPO applications were distinguished differing in either absorption kinetics or pharmacokinetics. Finally, eight different chemotherapy protocols were modelled. The model was validated on the basis of scenarios not used for parameter fitting. Simulations were performed to analyze the impact of EPO applications on the risk of anaemia during chemotherapy. We conclude that we established a model of erythropoiesis under chemotherapy that explains a large set of time series data under EPO and chemotherapy applications. It allows predictions regarding yet untested EPO schedules. Prospective clinical studies are needed to validate model predictions and to explore the feasibility and effectiveness of the proposed schedules.

Show MeSH

Related in: MedlinePlus

Comparison of toxic effects between different chemotherapies.We present the relations between stem cell toxicities and resulting AOC of reticulocytes and erythrocytes for a single therapy cycle.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3675041&req=5

pone-0065630-g009: Comparison of toxic effects between different chemotherapies.We present the relations between stem cell toxicities and resulting AOC of reticulocytes and erythrocytes for a single therapy cycle.

Mentions: After establishing parameter sets of our injection, PK and cell kinetic model, we aim to apply our model to different chemotherapy scenarios. This requires estimation of toxicity parameters which were determined by fitting the predictions of the model to data of patients treated with either BEACOPP-21, BEACOPP-21 escalated, CHOEP-14,21, CHOP-14,21, the sequential chemotherapy schemes EC-T (Epirubicin plus Cyclophosphamide, Paclitaxel), E-T-C (Epirubicin, Cyclophosphamide, Paclitaxel), E-T-C plus EPO, highCHOEP-21, Platinum plus Etoposide or Platinum plus Etoposide with Darbepoetin. For most of these scenarios, only haemoglobin dynamics are available. Toxicity parameter estimates resulted in a good agreement of model predictions and data in the sense that for almost all scenarios and time points, the model curve is in between the 25th and 75th percentile of patients data [5]. Examples are shown in figure 8. All others scenarios can be found in the file S1. A complete list of toxicity parameter estimates can also be found in the file S1. We like to emphasize here, that the parameters of stem cell toxicity, which are most sensitive, were not fitted but retrieved from our granulopoiesis model [5]. To illustrate the overall toxicity of different chemotherapeutic drugs we calculated the area over curve (AOC) for erythrocyte and reticulocyte counts below normal, i.e.for days and a single chemotherapy injection at . Since in general the stem cell toxicity of a drug or drug combination is the most significant parameter influencing the haematotoxic outcome, we plot the stem cell toxicities against ERY-AOC in figure 9. We also plot RET-AOC against ERY-AOC. As expected, there is a strong correlation of RET-AOC and ERY-AOC. There is also a clear correlation of the estimates of the stem cell toxicities and ERY-AOC. But this correlation is less perfect since damage at later cell stages cannot be neglected in general. For example etoposide (E) is known to be stem cell saving but toxic to later cell stages [30]. The results fit well to our clinical understanding of the chemotherapies: BEACOPP-21 escalated and highCHOEP-21 are the therapies with highest toxicity. CHOP, CHOEP and C2500 have moderate toxicity and application of single drugs except for highly dosed cyclophosphamide (C2500) have relatively low toxicity.


A biomathematical model of human erythropoiesis under erythropoietin and chemotherapy administration.

Schirm S, Engel C, Loeffler M, Scholz M - PLoS ONE (2013)

Comparison of toxic effects between different chemotherapies.We present the relations between stem cell toxicities and resulting AOC of reticulocytes and erythrocytes for a single therapy cycle.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3675041&req=5

pone-0065630-g009: Comparison of toxic effects between different chemotherapies.We present the relations between stem cell toxicities and resulting AOC of reticulocytes and erythrocytes for a single therapy cycle.
Mentions: After establishing parameter sets of our injection, PK and cell kinetic model, we aim to apply our model to different chemotherapy scenarios. This requires estimation of toxicity parameters which were determined by fitting the predictions of the model to data of patients treated with either BEACOPP-21, BEACOPP-21 escalated, CHOEP-14,21, CHOP-14,21, the sequential chemotherapy schemes EC-T (Epirubicin plus Cyclophosphamide, Paclitaxel), E-T-C (Epirubicin, Cyclophosphamide, Paclitaxel), E-T-C plus EPO, highCHOEP-21, Platinum plus Etoposide or Platinum plus Etoposide with Darbepoetin. For most of these scenarios, only haemoglobin dynamics are available. Toxicity parameter estimates resulted in a good agreement of model predictions and data in the sense that for almost all scenarios and time points, the model curve is in between the 25th and 75th percentile of patients data [5]. Examples are shown in figure 8. All others scenarios can be found in the file S1. A complete list of toxicity parameter estimates can also be found in the file S1. We like to emphasize here, that the parameters of stem cell toxicity, which are most sensitive, were not fitted but retrieved from our granulopoiesis model [5]. To illustrate the overall toxicity of different chemotherapeutic drugs we calculated the area over curve (AOC) for erythrocyte and reticulocyte counts below normal, i.e.for days and a single chemotherapy injection at . Since in general the stem cell toxicity of a drug or drug combination is the most significant parameter influencing the haematotoxic outcome, we plot the stem cell toxicities against ERY-AOC in figure 9. We also plot RET-AOC against ERY-AOC. As expected, there is a strong correlation of RET-AOC and ERY-AOC. There is also a clear correlation of the estimates of the stem cell toxicities and ERY-AOC. But this correlation is less perfect since damage at later cell stages cannot be neglected in general. For example etoposide (E) is known to be stem cell saving but toxic to later cell stages [30]. The results fit well to our clinical understanding of the chemotherapies: BEACOPP-21 escalated and highCHOEP-21 are the therapies with highest toxicity. CHOP, CHOEP and C2500 have moderate toxicity and application of single drugs except for highly dosed cyclophosphamide (C2500) have relatively low toxicity.

Bottom Line: We added a model of EPO absorption after injection at different sites and a pharmacokinetic model of EPO derivatives to account for the effects of external EPO applications.Parameter fittings resulted in a good agreement of model and data.Prospective clinical studies are needed to validate model predictions and to explore the feasibility and effectiveness of the proposed schedules.

View Article: PubMed Central - PubMed

Affiliation: Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany. sibylle.schirm@imise.uni-leipzig.de

ABSTRACT
Anaemia is a common haematologic side effect of dose-dense multi-cycle cytotoxic polychemotherapy requiring erythrocyte transfusions or erythropoietin (EPO) administration. To simulate the effectiveness of different EPO application schedules, we performed both modelling of erythropoiesis under chemotherapy and pharmacokinetic and dynamic modelling of EPO applications in the framework of a single comprehensive biomathematical model. For this purpose, a cell kinetic model of bone marrow erythropoiesis was developed that is based on a set of differential compartment equations describing proliferation and maturation of erythropoietic cell stages. The system is regulated by several feedback loops comprising those mediated by EPO. We added a model of EPO absorption after injection at different sites and a pharmacokinetic model of EPO derivatives to account for the effects of external EPO applications. Chemotherapy is modelled by a transient depletion of bone marrow cell stages. Unknown model parameters were determined by fitting the predictions of the model to data sets of circulating erythrocytes, haemoglobin, haematocrit, percentage of reticulocytes or EPO serum concentrations derived from the literature or cooperating clinical study groups. Parameter fittings resulted in a good agreement of model and data. Depending on site of injection and derivative (Alfa, Beta, Delta, Darbepoetin), nine groups of EPO applications were distinguished differing in either absorption kinetics or pharmacokinetics. Finally, eight different chemotherapy protocols were modelled. The model was validated on the basis of scenarios not used for parameter fitting. Simulations were performed to analyze the impact of EPO applications on the risk of anaemia during chemotherapy. We conclude that we established a model of erythropoiesis under chemotherapy that explains a large set of time series data under EPO and chemotherapy applications. It allows predictions regarding yet untested EPO schedules. Prospective clinical studies are needed to validate model predictions and to explore the feasibility and effectiveness of the proposed schedules.

Show MeSH
Related in: MedlinePlus