Erythropoietin Modeling and Simulation

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Erythropoietin Modeling and Simulation

• Immanuel Freedman, Ph.D., SMIEEE

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O2 sensor
A
??
HIF-1
enhancer
P
EPO
apoptosis
neocytolysis
EPO
C
D
B
Self renewal
Default suicide pathway
selective hemolysis of early erythroblasts
Bone-marrow sinusoidal endothelium
Hematopoietic stem cells
erythroid precursor cells BFU-e/CFU-e
reticulocytes
erythrocytes
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Hemoglobin
RBC Production
RBC Lifespan
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CL
Dose efficiency
Ceff
Ferrokinetics?
Prior Radio/Chemo Therapy
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Clinical Trial Simulation
Dose withholding
If ?Hgblt1 g/dL _at_ Week 6 Dose 5/3Dose
If Hgblt14 15 g/dL
If Hgb?14 15 g/dL
Dose 0.75xDose
Dose increase
TEST ARM Dose 200 ?g Q2W
If Hgblt8.0
Transfusion
Treatment
Treat Monitor
Censor for 4 weeks
Patient Dropout
CONTROL ARM Dose 3.0 ?g/kg Q2W
Baseline Characteristics
Random pt censoring 3.1/week cf study
Hgbo9.8 0.6 (8-11) g/dL 74.7 18.5 (27-156)
kg Male 32, Female 68 n254/cohort x 1000
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Simulator Customer Groups

• Corporate
• Clinical
• Marketing
• Research

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Simulator Goals

• The simulator must be
• Accurate
• Responsive
• Portable
• Easy to Use

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Amgen Clinical Data
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Inclusion Criteria (1 of 2)

• Subjects must be
• at least 18 years of age,
• receiving cyclic chemotherapy,
• diagnosed with non-myeloid malignancies,
• diagnosed with Anemia of Cancer or Chemotherapy
  Induced Anemia,
• anemic (Hb 9.0 g/dL and Hb 11.0 g/dL), except
  in Amgen Study 990146 (Hb 13.0 g/dL),
• capable of self-care (ECOG 0 to 2), and
• diagnosed with adequate renal and hepatic
  function.

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Inclusion Criteria (2 of 2)

• Subjects must have
• no history of seizures, cardiac or hematologic
  disorders that could cause anemia,
• no rHuEPO treatment before study begins,
• less than 2 RBC transfusions within 4 weeks
  before study drug, and
• no RBC transfusions during current chemotherapy
  cycle before randomization.

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Population PK/PD Model Features

• eight compartments,
• an indirect Emax link model,
• non-Gaussian residuals,
• censored transfusion data,
• allometric parameter scaling,
• step-down covariate analysis,
• validation on data not used in estimation, and
• estimation with NONMEM V and MATLAB software.

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Population PK/PD Model Discussion

• fitted Emax scales with body weight according to
  (BWT/70.9)-0.90.3

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Population PK/PD Simulation Features

• a dose adjustment model,
• a transfusion censoring model,
• a patient dropout model, and
• a multilognormal cohort.

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NESP PK/PD Model (1 of 7)

• PROB TEMPLATE FOR POP PKPD MODEL FOR DARBEPOETIN
  ALFA
• Run 1011 based on Run 501 and Run 701 for
  simulation
• Run 501 PD fit Hb data from 290, 162, and 291
  studies. No transfusion points.
• Run 701 PK fit Aranesp 162 SC, 146 SC and IV.
• INPUT C ID TIME AMT DV HB0 CMT CHEM TYPE ROUT
  STUD BWT
• DATA 20010102PD.csv IGNOREC
• SUBROUTINE ADVAN6 TRANS1 TOL3
• MODEL COM(SC) COM(CONC) COMP(PERI)
• COMP(PR1) COMP(LS1) COMP(LS2) COMP(LS3)
  COMP(LS4)

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NESP PK/PD Model (2 of 7)

• PK
• CLTHETA(1)EXP(ETA(1)) Clearance from central
  compartment (mL/day)
• V2THETA(2)EXP(ETA(2)) Volume of
  distribution (mL)
• V3THETA(3)EXP(ETA(3))
• QTHETA(4)EXP(ETA(4))
• KATHETA(5)EXP(ETA(5)) Absorption rate
  constant (/day)
• LT1THETA(6)EXP(ETA(6))
• F1LT1/(1LT1) Bioavailability of SC dose
• KCL/V2 Elimination rate constant (/day)
• K23Q/V2
• K32Q/V3
• S2V2

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NESP PK/PD Model (3 of 7)

• PD MODEL PARAMETERS
• RBCPTTHETA(7)EXP(ETA(7)) Maturation time
  (day)
• RBCLSTHETA(8)EXP(ETA(8)) Transit time (day)
• EMAXTHETA(9)EXP(ETA(9)) Maximum stimulation
  effect
• EC50THETA(10)EXP(ETA(10)) Concentration at
  half maximal effect (ng/mL)
• KPT1/RBCPT Production rate constant (/day)
• KLS4/RBCLS Loss rate constant (/day)
• KCPQ/V2
• KPCQ/V3
• ALLOMETRIC SCALING
• CLCL(BWT/70.9)0.75
• V2V2(BWT/70.9)
• V3V3(BWT/70.9)
• QQ(BWT/70.9)
• EMAXEMAX(BWT/70.9)THETA(11)

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NESP PK/PD Model (4 of 7)

• DES
• PK
• C2A(2)/V2
• EEMAXC2/(EC50C2)
• DADT(1) -KAA(1) SC injection site
  compartment
• DADT(2)KAA(1)-(KKCP)A(2) Central
  compartment
• DADT(3)KCPA(2)-KPCA(3) Peripheral
  compartment
• PD
• DADT(4)KPT(1E)-KPTA(4) Progenitor
  stimulation
• DADT(5)KLS(A(4)-A(5)) Erythrocyte maturation
• DADT(6)KLS(A(5)-A(6))
• DADT(7)KLS(A(6)-A(7))
• DADT(8)KLS(A(7)-A(8))

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NESP PK/PD Model (5 of 7)

• ERROR
• EFF(A(5)A(6)A(7)A(8))HB0/4.0
• WEFF
• IPREDEFF
• IRESDV-IPRED
• IF(W.GT.0) THEN
• IWRESIRES/W
• ELSE
• IWRES0
• ENDIF
• YEFFERR(1)

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NESP PK/PD Model (6 of 7)

• THETA
• (2010 FIX) CL
• (3390 FIX) V2
• (251 FIX) V3
• (2900 FIX) Q
• (0.318 FIX) KA
• (0.795 FIX) LT1 (F10.443)
• (4.68 FIX) RBCPT
• (0, 120) RBCLS
• (0, 10) EMAX
• (0, 10) EC50
• (0, 5) THETA(11)
• OMEGA 0.296 FIX 3.22 FIX 1.29 FIX 0.483 FIX
  0.004 0.216 FIX 20 0.004 0.004 0.004
• SIGMA 10.0

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NESP Covariate PK/PD Model (7 of 7)
function yresampleResiduals(residual,
numberOfSamples, numberOfPatients) sizeVarsize(re
sidual) maxIndexsizeVar(1)-1
resplusresidual(2end) resminusresidual(1end-
1) correlationMatrixcorrcoef(resplus,
resminus) correlationcorrelationMatrix(1,2)
off diagonal innovation resplus-correlationre
sminus for subject1numberOfPatients
y(1, subject)0 initial for
sample2numberOfSamples
index1round(abs(maxIndexrand))
while(index0 index gt maxIndex)
index1round(abs(maxIndexrand)) end
if y(sample, subject)correlationy(samp
le-1, subject) innovation(index) end for
sample end for subject return
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NESP Covariate PK/PD Model Parameters
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ACF of IRES before non-Gaussian process
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ACF of IRES after non-Gaussian process
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IRES v. SEX
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IRES v. AGE
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IRES v. Chemo Cycle Count (CCNT)
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IRES v. Platinum-containing Chemo Cycle Count
(PCNT)
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rHuEPO Baseline PK/PD Model Parameters
EC50 scaled from NESP EC50 using peptide mass
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Relative Efficacy of rHuEPO and Aranesp
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AMG114 First-in-Human Portal
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Darbepoietin Alfa Regimens
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Endogenous EPO
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NESP Endogenous EPO PK/PD Model
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Future Exploration

• model non-linear clearance on receptors,
• model transfusions explicitly,
• explore effects of endogenous EPO,
• explore effects of chemotherapy,
• explore impact of angiogenesis on model,
• develop first order titration scheme, and
• distribute simulator to more customers.