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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Study Route Dose and Schedule Full PK PK schedule PD schedule
990146 IV (n56) NESP 2.25 µg/kg QW W1, W9 QW, W1 to W9 -
990146 SC (n84) NESP 2.25 µg/kg QW W1, W9 QW, W1 to W9 -
20010162 SC (n84) NESP 6.75 µg/kg Q3W Day 1 QW, W1 to W16 QW, W1 to W16
980290a SC (n174) NESP 0.5 to 4.5 µg/kg QW W1, W6 QW, W1 to W16 QW, W1 to W16
980290a SC (n4) rHuEPO 150 IU/kg TIW W1, W6 QW, W1 to W16 QW, W1 to W12
980290b SC (n20) NESP 3.0 to 9.0 µg/kg Q2W W1, W6 QW, W1 to W16 QW, W1 to W12
980290b SC (n9) rHuEPO 40K to 60K IU QW W1, W6 QW, W1 to W16 QW, W1 to W12
980291 SC (n25) NESP 4.5 to 15 µg/kg Q3W - - QW, W1 to W18
20010102 SC (n117) NESP 4.5 µg/kg QW until Hb 12 g/dL, then 4.5 µg/kg Q3W - - QW, W1 to W20
20010102 SC (n126) NESP 325 µg QW until Hb 12 g/dL, then 325 µg Q3W - - QW, W1 to W20
20010199 IV (n15) NESP 4.5 µg/kg QW (W1 to W6), 4.5 µg/kg Q3W (W9 to W15) - - QW, W1 to W18
20010199 SC (n12) NESP 4.5 µg/kg QW (W1 to W6), 4.5 µg/kg Q3W (W9 to W15) - - QW, W1 to W18
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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
Parameter Units Point Estimate RSE
CL mL/day 2010 6.37
V2 mL 3390 9.23
V3 mL 251 36.7
Q mL/day 2900 -
KA 1/day 0.318 8.65
F - 0.443 18.3
RBCPT day 4.68 26.9
RBCLS day 82.2 13.7
EMAX - 0.437 16.0
EC50 Ng/mL 3.68 38.6
THETA(11) - 0.9 33.3
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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
Parameter Units Point Estimate RSE
CL mL/day 64.9 4.42
V mL 45.1 0.241
Ka 1/day 0.628 0.554
F - 0.412 -
EC50 ng/mL 200 EC50 (NESP) 514 0.543
Emax - 0.688 0.182
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.