US2021093696A1PendingUtilityA1
Methods for the prediction of a personalized esa-dose in the treatment of anemia
Assignee: DEUTSCHES KREBSFORSCHUNGSZENTRUM STIFTUNG DES OFFENTLICHEN RECHTSPriority: Jun 18, 2014Filed: Aug 28, 2020Published: Apr 1, 2021
Est. expiryJun 18, 2034(~7.9 yrs left)· nominal 20-yr term from priority
Inventors:Agustin Rodriguez GonzalezMarcel SchillingUrsula KlingmuellerAndreas RaueMax SchelkerJens TimmerMichael JarschBernhard Steiert
G01N 33/5044A61K 38/1816G16B 5/00G01N 2800/222G16H 50/50G01N 33/6893G01N 33/80G16H 50/20G16H 20/17G01N 33/721A61K 9/0019
47
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Claims
Abstract
An integrative pharmacokinetic/pharmacodynamics (PK/PD) ESA-EpoR mathematical model calculates the binding behavior of erythropoiesis stimulating agents (ESA). The invention provides methods for the determining of ESA binding sites in cells or patients suffering from anemia. Knowing the amount of ESA binding sites enables the clinical practitioner to optimize the dosage regimen during a treatment of anemia, in particular in patients suffering from a cancerous disease. Further provided are methods for screening ESAs which have a higher specificity for cells strongly expressing the EPO receptor such as colony forming units-erythroid (CFU-E) cells, and not to cells with a low level of EPO receptor cell surface expression, which is the case in cancer cells. Also provided is a computer implemented method, comprising the use of the mathematical model of the invention.
Claims
exact text as granted — not AI-modified1 . A method for determining a dosage of an Erythropoiesis Stimulating Agent (ESA) that is sufficient for treating anemia in a patient, the method comprising the steps of:
a) Calculating a degradation of hemoglobin per time for the patient from a hemoglobin concentration of the patient from at least two separate time points, b) Determining a present hemoglobin concentration of the patient from a concentration of hemoglobin from a recent blood sample obtained from the patient, c) Calculating an ESA dosage based on the degradation of hemoglobin per time and the present hemoglobin concentration to treat anemia in the patient; and d) Administering the ESA dosage to the patient to thereby treat anemia in the patient.
2 . (canceled)
3 . The method according to claim 1 , wherein the hemoglobin concentration of the patient from at least two separate time points is determined by measuring the hemoglobin concentrations in blood samples obtained from the patient from at least two different time points, or from a past anemia treatment history of the patient.
4 . The method of claim 1 , further including the step of:
Monitoring the hemoglobin concentration of the patient over time after the administration of the ESA dosage.
5 . The method of claim 1 , wherein the administration is a subcutaneous or intravenous injection.
6 . The method of to claim 4 , wherein the hemoglobin concentration of the patient is monitored by obtaining a blood sample from the patient.
7 . The method of claim 1 , further including the steps of:
a) Monitoring the clearance of said ESA dosage from a serum in said patient, b) Calculating from the clearance of said ESA dosage in said patient the number of initial ESA binding sites present in said patient using a non-linear dynamic pharmacokinetic (PK) ESA-EPO-R pathway model, and c) Adjusting the ESA dosage administered to the patient in accordance with the number of ESA binding sites.
8 . (canceled)
9 . (canceled)
10 . The method of claim 7 , wherein the ESA dosage is administered subcutaneously, and wherein the non-linear dynamic pharmacokinetic (PK) ESA-EPO-R pathway model considers clearance of the administered ESA in a blood compartment, transport of the administered ESA from an interstitial compartment into the blood compartment, and clearance of the ESA in the interstitial compartment.
11 . The method of claim 1 , wherein the ESA dosage is selected from the group of an Epoetin alfa dosage, an Epoetin beta dosage, an erythropoiesis stimulating protein dosage and a Continuous erythropoietin receptor activator dosage.
12 . The method of claim 7 , wherein said non-linear dynamic pharmacokinetic (PK) ESA-EPO-R pathway model is based on a system of the ordinary differential equations (ODE):
d
[
ESASC
]
dt
=
-
ksc
clear
·
[
ESASC
]
/
(
k
sc_clear
_sat
+
[
ESASC
]
)
-
ksc_out
·
[
ESASC
]
(
2.1
.
)
d
[
ESA
]
dt
=
k
sc
out
·
[
ESASC
]
-
k
clear
·
[
ESA
]
-
k
on
·
[
ESA
]
·
[
EpoR
]
+
k
off
·
[
ESAEpoR
]
+
k
ex
·
[
ESAEpoRi
]
(
2.2
.
)
d
[
EpoR
]
dt
=
-
k
on
·
[
ESA
]
·
[
EpoR
]
+
k
off
·
[
ESAEpoR
]
+
k
t
·
B
max
-
k
t
·
[
EpoR
]
+
k
ex
·
[
ESAEpoRi
]
(
2.3
.
)
d
[
ESAEpoR
]
dt
=
k
on
·
[
ESA
]
·
[
EpoR
]
-
k
off
·
[
ESAEpoR
]
-
k
e
·
[
ESAEpoR
]
(
2.4
.
)
d
[
ESAEpoRi
]
dt
=
k
e
·
[
ESAEpoR
]
-
k
ex
·
[
ESAEpoRi
]
-
k
di
·
[
ESAEpoRi
]
-
k
de
·
[
ESAEpoRi
]
(
2.5
.
)
d
[
dESAi
]
dt
=
k
di
·
[
ESAEpoRi
]
(
2.6
.
)
d
[
dESAe
]
dt
=
k
de
·
[
ESAEpoRi
]
,
(
2.7
.
)
where,
ESA is Erythropoiesis-stimulating agent in medium/blood,
EpoR is Erythropoietin receptor,
ESA EpoR is a complex of ESA bound to EpoR on the cell surface,
ESAEpoR i is an internalized complex of ESA bound to EpoR,
dESA i is intracellular degraded ESA,
dESA e is extracellular degraded ESA,
ESA SC is ESA in the subcutaneous compartment,
k sc_clear is ESA clearance in the subcutaneous compartment,
k sc_clear_sat is saturation of ESA clearance in the subcutaneous compartment,
K sc_out is an ESA transportation constant to the blood compartment,
k clear is an ESA clearance constant in the blood compartment,
k on is an ESA-EpoR association rate/on-rate,
k off is an ESA-EpoR dissociation rate/off-rate,
k t is a ligand-independent receptor turnover rate,
k e is an ESA-EpoR complex internalization constant,
k ex is an ESA and EpoR recycling constant,
k di is an intracellular ESA degradation constant,
k de is an extracellular ESA degradation constant,
and wherein B max is the number of initial ESA binding sites per cell/per patient.
13 . A method for identifying an Erythropoiesis Stimulating Agent (ESA) having a specific activity for cells with a high cell surface expression of Erythropoietin-receptor (EPO-R), comprising the steps of:
a) Obtaining the half maximal effective concentrations (EC50) of a candidate ESA and a reference ESA for EPO-R activation in a first cell, b) Obtaining the EPO-R activation induced by the candidate ESA and the reference ESA at their respective EC50 as obtained in (a) in a second cell, wherein said second cell is characterized by a significantly lower cell surface expression of EPO-R compared to the first cell,
wherein a decreased activation of EPO-R in said second cell by the candidate ESA compared to the activation of EPO-R in said second cell by the reference ESA, is indicative for the specificity of said candidate ESA for cells with a strong cell surface expression of EPO-R.
14 . The method according to claim 13 , wherein said reference ESA is Epoetin beta.
15 . The method according to claim 13 , wherein the method is an in-vitro or an in-silico method.
16 . The method according to claim 15 , wherein the method is the in-silico method and wherein said EPO-R activation is calculated with a non-linear dynamic ESA-EPO-R pathway model.
17 . The method according to claim 16 , wherein said non-linear dynamic ESAEPO-R pathway model is based on the following ODE:
d
[
ESA
]
dt
=
-
k
on
·
[
ESA
]
·
[
EpoR
]
+
k
off
·
[
ESAEpoR
]
+
k
ex
·
[
ESAEpoRi
]
(
1.1
.
)
d
[
EpoR
]
dt
=
-
k
on
·
[
ESA
]
·
[
EpoR
]
+
k
off
·
[
ESAEpoR
]
+
k
t
·
B
max
-
k
t
·
[
EpoR
]
+
k
ex
·
[
ESAEpoRi
]
(
1.2
.
)
d
[
ESAEpoR
]
dt
=
k
on
·
[
ESA
]
·
[
EpoR
]
-
k
off
·
[
ESAEpoR
]
-
k
e
·
[
ESAEpoR
]
(
1.3
.
)
d
[
ESAEpoRi
]
dt
=
k
e
·
[
ESAEpoR
]
-
k
ex
·
[
ESAEpoRi
]
-
k
di
·
[
ESAEpoRi
]
-
k
de
·
[
ESAEpoRi
]
(
1.4
.
)
d
[
dESAi
]
dt
=
k
di
·
[
ESAEpoRi
]
(
1.5
.
)
d
[
dESAe
]
dt
=
k
de
·
[
ESAEpoRi
]
,
wherin
B
max
is
the
number
of
initial
ESA
binding
sites
(
1.6
.
)
where,
ESA is Erythropoiesis-stimulating agent in medium/blood,
EpoR is Erythropoietin receptor,
ESA EpoR is a complex of ESA bound to EpoR on the cell surface,
ESAEpoR i is an internalized complex of ESA bound to EpoR,
dESA i is intracellular degraded ESA,
dESA e is extracellular degraded ESA,
ESA SC is ESA in the subcutaneous compartment,
k sc_clear is ESA clearance in the subcutaneous compartment,
k sc_clear sat is saturation of ESA clearance in the subcutaneous compartment,
K sc_out is an ESA transportation constant to the blood compartment,
k clear is an ESA clearance constant in the blood compartment,
k on is an ESA-EpoR association rate/on-rate,
k off is an ESA-EpoR dissociation rate/off-rate,
k t is a ligand-independent receptor turnover rate,
k e is an ESA-EpoR complex internalization constant,
k ex is an ESA and EpoR recycling constant,
k di is an intracellular ESA degradation constant,
k de is an extracellular ESA degradation constant.
18 . The method according to claim 15 , wherein the method is the in-vitro method, and wherein said first cell is a cell ectopically expressing EPO-R, such as H838-EpoR, and/or wherein said second cell is not ectopically expressing EPO-R, such as H838.
19 . A computer implemented method for assessing the number of ESA binding sites in a cell, or a an organism, the method comprising
(a) Obtaining the depletion rate of an ESA in said cell or the organism, (b) Calculating the amount of ESA binding sites in said cell or organism based on the depletion rate of the ESA using a non-linear dynamic EPO-R pathway model.
20 . The method according to claim 19 , wherein said organism is a patient or wherein said cell is a cell endogenously expressing the EPO-R receptor, and wherein the cell is a red blood cell precursor cell, or a tumor cell, or a cell ectopically expressing EPO-R.
21 . The method according to claim 19 , wherein the patient is a human patient, and wherein step (a) constitutes the obtaining the depletion rate of an ESA as acquired in a serum sample of a patient at a time point subsequent to the administration of an initial ESA dose to said patient, and step (b) constitutes calculating the amount of ESA binding sites based on the depletion rate of the ESA using a non-linear dynamic pharmacokinetic (PK) ESA-EPO-R pathway model.
22 - 24 . (canceled)
25 . A method for estimating the biological activity of an ESA, comprising the steps of:
Calculating the occupancy of the EPO receptor on human CFU-E cells in response to a range of ESA concentrations using the non-linear dynamic pharmacokinetic (PK) ESA-EPO-R pathway model, a) Calculating the area under the curve for the ESA from the resultant of step (a) as a measure for EPO receptor occupancy of the ESA, b) Calculating the concentration of the ESA for which the half maximum occupancy of the EPO receptor is reached to obtain an EC50 ESA , c) Compare the EC50 ESA with a predetermined EC50 EPOalfa or EC50 EPObeta , Wherein the difference between the EC50 ES A compared to the predetermined EC50 EPOalfa or EC50 EPObeta correlates with the difference of the biological activity of the ESA compared with the biological activity of EPO alfa or EPO beta.
26 . The method according to claim 25 , wherein the EC50 EPOalfa or EC50 EPObeta are predetermined by performing in addition steps (a) to (c) with EPO alfa or EPO beta as the ESA to obtain in step (c) the EC50 EPOalfa or EC50 EPObeta .
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