Supplementary Materials s18

Supplementary Materials

1. Kagan L, Turner MR, Balu-Iyer SV, Mager DE. Subcutaneous absorption of monoclonal antibodies: role of dose, site of injection, and injection volume on rituximab pharmacokinetics in rats. Pharmaceutical Research. 2012;29(2):490-499. 2. Fischer SK, Yang J, Anand B, Cowan K, Hendricks R, Li J, Nakamura G, Song A. The assay design used for measurement of therapeutic antibody concentrations can affect pharmacokinetic parameters: Case studies. MAbs. 2012;4(5):623-631. 3. Kelley SK, Gelzleichter T, Xie D, Lee WP, Darbonne WC, Qureshi F, Kissler K, Oflazoglu E, Grewal IS. Preclinical pharmacokinetics, pharmacodynamics, and activity of a humanized anti-CD40 antibody (SGN-40) in rodents and non-human primates. British Journal of Pharmacology. 2006;148(8):1116-1123. 4. Everitt DE, Davis CB, Thompson K, DiCicco R, Ilson B, Demuth SG, Herzyk DJ, Jorkasky DK. The pharmacokinetics, antigenicity, and fusion-inhibition activity of RSHZ19, a humanized monoclonal antibody to respiratory syncytial virus, in healthy volunteers. The Journal of Infectious Diseases. 1996;174(3):463-469. 5. Fisher RG, Johnson JE, Dillon SB, Parker RA, Graham BS. Prophylaxis with respiratory syncytial virus F-specific humanized monoclonal antibody delays and moderately suppresses the native antibody response but does not impair immunity to late rechallenge. The Journal of Infectious Diseases. 1999;180(3):708-713. 6. Davis CB, Hepburn TW, Urbanski JJ, Kwok DC, Hart TK, Herzyk DJ, Demuth SG, Leland M, Rhodes GR. Preclinical pharmacokinetic evaluation of the respiratory syncytial virus-specific reshaped human monoclonal antibody RSHZ19. Drug Metabolism and Disposition. 1995;23(10):1028- 1036. 7. Wu F, Tamhane M, Morris ME. Pharmacokinetics, lymph node uptake, and mechanistic PK model of near-infrared dye-labeled bevacizumab after IV and SC administration in mice. The AAPS Journal. 2012;14(2):252-261. 8. Meyer CH, Krohne TU, Holz FG. Intraocular pharmacokinetics after a single intravitreal injection of 1.5 mg versus 3.0 mg of bevacizumab in humans. Retina. 2011;31(9):1877-1884. 9. Wu B, Johnson J, Soto M, Ponce M, Calamba D, Sun YN. Investigation of the mechanism of clearance of AMG 386, a selective angiopoietin-1/2 neutralizing peptibody, in splenectomized, nephrectomized, and FcRn knockout rodent models. Pharmaceutical Research. 2012;29(4):1057- 1065. 10. Herbst RS, Hong D, Chap L, Kurzrock R, Jackson E, Silverman JM, Rasmussen E, Sun YN, Zhong D, Hwang YC, Evelhoch JL, Oliner JD, Le N, Rosen LS. Safety, pharmacokinetics, and antitumor activity of AMG 386, a selective angiopoietin inhibitor, in adult patients with advanced solid tumors. Journal of Clinical Oncology. 2009;27(21):3557-3565. 11. Furie R, Stohl W, Ginzler EM, Becker M, Mishra N, Chatham W, Merrill JT, Weinstein A, McCune WJ, Zhong J, Cai W, Freimuth W. Biologic activity and safety of belimumab, a neutralizing anti-B- lymphocyte stimulator (BLyS) monoclonal antibody: a phase I trial in patients with systemic lupus erythematosus. Arthritis Research & Therapy. 2008;10(5):R109. 12. Halpern WG, Lappin P, Zanardi T, Cai W, Corcoran M, Zhong J, Baker KP. Chronic administration of belimumab, a BLyS antagonist, decreases tissue and peripheral blood B-lymphocyte populations in cynomolgus monkeys: pharmacokinetic, pharmacodynamic, and toxicologic effects. Toxicological Sciences. 2006;91(2):586-599. 13. Vugmeyster Y, Allen S, Szklut P, Bree A, Ryan M, Ma M, Spaulding V, Young D, Guay H, Bloom L, Leach MW, O'Toole M, Adkins K. Correlation of pharmacodynamic activity, pharmacokinetics, and anti-product antibody responses to anti-IL-21R antibody therapeutics following IV administration to cynomolgus monkeys. Journal of Translational Medicine. 2010;8:41. 14. Vugmeyster Y, Guay H, Szklut P, Qian MD, Jin M, Widom A, Spaulding V, Bennett F, Lowe L, Andreyeva T, Lowe D, Lane S, Thom G, Valge-Archer V, Gill D, Young D, Bloom L. In vitro potency, pharmacokinetic profiles, and pharmacological activity of optimized anti-IL-21R antibodies in a mouse model of lupus. MAbs. 2010;2(3):335-346. 15. Lin YS, Nguyen C, Mendoza JL, Escandon E, Fei D, Meng YG, Modi NB. Preclinical pharmacokinetics, interspecies scaling, and tissue distribution of a humanized monoclonal antibody against vascular endothelial growth factor. The Journal of Pharmacology and Experimental Therapeutics. 1999;288(1):371-378. 16. Gordon MS, Margolin K, Talpaz M, Sledge GW, Jr., Holmgren E, Benjamin R, Stalter S, Shak S, Adelman D. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. Journal of Clinical Oncology. 2001;19(3):843-850. 17. Chakraborty A, Tannenbaum S, Rordorf C, Lowe PJ, Floch D, Gram H, Roy S. Pharmacokinetic and pharmacodynamic properties of canakinumab, a human anti-interleukin-1beta monoclonal antibody. Clinical Pharmacokinetics. 2012;51(6):e1-18. 18. Benincosa LJ, Chow FS, Tobia LP, Kwok DC, Davis CB, Jusko WJ. Pharmacokinetics and pharmacodynamics of a humanized monoclonal antibody to factor IX in cynomolgus monkeys. The Journal of Pharmacology and Experimental Therapeutics. 2000;292(2):810-816. 19. Chow FS, Benincosa LJ, Sheth SB, Wilson D, Davis CB, Minthorn EA, Jusko WJ. Pharmacokinetic and pharmacodynamic modeling of humanized anti-factor IX antibody (SB 249417) in humans. Clinical Pharmacology and Therapeutics. 2002;71(4):235-245. 20. Kakkar T, Ma M, Zhuang Y, Patton A, Hu Z, Mounho B. Pharmacokinetics and safety of a fully human hepatocyte growth factor antibody, AMG 102, in cynomolgus monkeys. Pharmaceutical Research. 2007;24(10):1910-1918. 21. Ryan CJ, Rosenthal M, Ng S, Alumkal J, Picus J, Gravis G, Fizazi K, Forget F, Machiels JP, Srinivas S, Zhu M, Tang R, Oliner KS, Jiang Y, Loh E, Dubey S, Gerritsen WR. Targeted MET inhibition in castration-resistant prostate cancer: a randomized phase II study and biomarker analysis with rilotumumab plus mitoxantrone and prednisone. Clinical Cancer Research. 2013;19(1):215-224. 22. Vugmeyster Y, Szklut P, Tchistiakova L, Abraham W, Kasaian M, Xu X. Preclinical pharmacokinetics, interspecies scaling, and tissue distribution of humanized monoclonal anti-IL- 13 antibodies with different IL-13 neutralization mechanisms. International Immunopharmacology. 2008;8(3):477-483. ADAPT-5 code for mPBPK model (human prediction):

********************************************************************** C ADAPT * C Version 5 * C********************************************************************** C * C MODEL * C * C This file contains Fortran subroutines into which the user * C must enter the relevant model equations and constants. * C Consult the User's Guide for details concerning the format for * C entered equations and definition of symbols. * C * C 1. Symbol- Parameter symbols and model constants * C 2. DiffEq- System differential equations * C 3. Output- System output equations * C 4. Varmod- Error variance model equations * C 5. Covmod- Covariate model equations (ITS,MLEM) * C 6. Popinit- Population parameter initial values (ITS,MLEM) * C 7. Prior - Parameter mean and covariance values (ID,NPD,STS) * C 8. Sparam- Secondary parameters * C 9. Amat - System state matrix * C * C**********************************************************************

C######################################################################C

Subroutine SYMBOL Implicit None

Include 'globals.inc' Include 'model.inc'

CC C------C C Enter as Indicated C C----c------C

NDEqs = 4 ! Enter # of Diff. Eqs. NSParam = 5 ! Enter # of System Parameters. NVparam = 2 ! Enter # of Variance Parameters. NSecPar = 0 ! Enter # of Secondary Parameters. NSecOut = 0 ! Enter # of Secondary Outputs (not used). Ieqsol = 1 ! Model type: 1 - DIFFEQ, 2 - AMAT, 3 - OUTPUT only. Descr = ' mPBPK Model human PK prediction'

CC C------C C Enter Symbol for Each System Parameter (eg. Psym(1)='Kel') C C----c------C Psym(1)='sigma_1' Psym(2)='sigma_2' Psym(3)='Kp' Psym(4)='a1' Psym(5)='m1'

CC C------C C Enter Symbol for Each Variance Parameter {eg: PVsym(1)='Sigma'} C C----c------C PVsym(1)='intercept' PVsym(2)='Slope'

CC C------C C Enter Symbol for Each Secondary Parameter {eg: PSsym(1)='CLt'} C C----c------C

C------C C------C C Return End

C######################################################################C

Subroutine DIFFEQ(T,X,XP) Implicit None

Real*8 T,X(MaxNDE),XP(MaxNDE),sigma_1,Kp,CLp,ISF,Vp,L Real*8 sigma_2,VL,sigmaL,a1,m1

CC C------C C Enter Differential Equations Below {e.g. XP(1) = -P(1)*X(1) } C C----c------C

ISF = 18.2-2.6 Vp = 2.6 L = 2.9/24 VL = 5.2 sigmaL = 0.2

sigma_1 = P(1) sigma_2 = P(2) Kp = P(3) a1 = P(4) m1 = P(5)

CLp=a1*70**m1 if (P(1) .GT. 1 .OR. P(2) .GT. 1) Then XP(1)=0 Else XP(1)= R(1)-X(1)/Vp*(CLp+0.33*L*(1-sigma_1)+ 0.67*L*(1-sigma_2)) c + X(4)*(L/VL) Endif

XP(2)= X(1)/Vp*(0.33*L)*(1-sigma_1) c - X(2)/(0.65*ISF*Kp)*(0.33*L)*(1-sigmaL)

XP(3)= X(1)/Vp*(0.67*L)*(1-sigma_2) c - X(3)/(0.35*ISF*Kp)*(0.67*L)*(1-sigmaL) XP(4)=X(2)/(0.65*ISF*Kp)*(0.33*L)*(1-sigmaL) + X(3)/(0.35*ISF*Kp) C *(0.67*L)*(1-sigmaL) - X(4)*(L/VL)

C######################################################################C

Subroutine OUTPUT(Y,T,X) Implicit None

Real*8 Y(MaxNOE),T,X(MaxNDE),Vp

CC C------C C Enter Output Equations Below {e.g. Y(1) = X(1)/P(2) } C C----c------C Vp = 2.6 Y(1) = X(1)/Vp

C######################################################################C

Subroutine VARMOD(V,T,X,Y) Implicit None

Real*8 V(MaxNOE),T,X(MaxNDE),Y(MaxNOE)

CC C------C C Enter Variance Model Equations Below C C {e.g. V(1) = (PV(1) + PV(2)*Y(1))**2 } C C----c------C V(1) = (PV(1) + PV(2)*Y(1))**2

C######################################################################C

Subroutine COVMOD(Pmean, ICmean, PC) C Defines any covariate model equations (MLEM, ITS) Implicit None

Real*8 PC(MaxNCP) Real*8 Pmean(MaxNSP+MaxNDE), ICmean(MaxNDE)

CC C------C C Enter # of Covariate Parameters C C----c------C

NCparam = 0 ! Enter # of Covariate Parameters.

CC C------C C Enter Symbol for Covariate Params {eg: PCsym(1)='CLRenal'} C C----c------C CC C------C C For the Model Params. that Depend on Covariates Enter the Equation C C {e.g. Pmean(1) = PC(1)*R(2) } C C----c------C

C######################################################################C

Subroutine POPINIT(PmeanI,ICmeanI,PcovI,ICcovI, PCI) C Initial parameter values for population program parameters (ITS, MLEM)

Implicit None

Integer I,J Real*8 PmeanI(MaxNSP+MaxNDE), ICmeanI(MaxNDE) Real*8 PcovI(MaxNSP+MaxNDE,MaxNSP+MaxNDE), ICcovI(MaxNDE,MaxNDE) Real*8 PCI(MaxNCP)

CC C------C C Enter Initial Values for Population Means C C { e.g. PmeanI(1) = 10.0 } C C----c------C

CC C------C C Enter Initial Values for Pop. Covariance Matrix (Lower Triang.) C C { e.g. PcovI(2,1) = 0.25 } C C----c------C

CC C------C C Enter Values for Covariate Model Parameters C C { e.g. PCI(1) = 2.0 } C C----c------C

C------C C------C C Return End C######################################################################C

Subroutine PRIOR(Pmean,Pcov,ICmean,ICcov) C Parameter mean and covariance values for MAP estimation (ID,NPD,STS) Implicit None

Integer I,J Real*8 Pmean(MaxNSP+MaxNDE), ICmean(MaxNDE) Real*8 Pcov(MaxNSP+MaxNDE,MaxNSP+MaxNDE), ICcov(MaxNDE,MaxNDE)

CC C------C C Enter Nonzero Elements of Prior Mean Vector C C { e.g. Pmean(1) = 10.0 } C C----c------C

CC C------C C Enter Nonzero Elements of Covariance Matrix (Lower Triang.) C C { e.g. Pcov(2,1) = 0.25 } C C----c------C

C######################################################################C

Subroutine SPARAM(PS,P,IC) Implicit None

Include 'globals.inc'

Real*8 PS(MaxNSECP), P(MaxNSP+MaxNDE), IC(MaxNDE)

CC C------C C Enter Equations Defining Secondary Paramters C C { e.g. PS(1) = P(1)*P(2) } C C----c------C

C######################################################################C

Subroutine AMAT(A) Implicit None

Integer I,J Real*8 A(MaxNDE,MaxNDE)

DO I=1,Ndeqs Do J=1,Ndeqs A(I,J)=0.0D0 End Do End Do

CC C------C C Enter non zero elements of state matrix {e.g. A(1,1) = -P(1) } C C----c------C

C######################################################################C

Phoenix code for mPBPK model (human):

MODEL remark ****************************************************** remark This code is for mPBPK with allometric scaling remark ******************************************************

COMMANDS

NFUNCTIONS 1 NDERIVATIVES 4

NPARAMETERS 4

PNAMES 'sigma1','sigma2','a', 'm'

NCONS 1

NSECO 0

TEMPORARY

Dose = CON(1)

ISF = 18.2 - 2.6

Vp = 2.6

L = 2.9/24

VL = 5.2

Kp = 0.8

CLp= a1*70**m1

Duration = 1

IF T>Duration THEN

Rinf = 0

Rinf = Dose/Duration

Z(1)=0

Z(2)=0

Z(3)=0 Z(4)=0

DIFFERENTIAL

IF sigma1 > 1 THEN

DZ(1) = 0

DZ(1)= Rinf -Z(1)/Vp*(CLp+0.33*L*(1-sigma1)+ 0.67*L*(1-sigma2))+ Z(4)*(L/VL)

IF sigma2 >1 THEN

DZ(1) = 0

DZ(1)= Rinf -Z(1)/Vp*(CLp+0.33*L*(1-sigma1)+ 0.67*L*(1-sigma2))+ Z(4)*(L/VL)

DZ(2)= Z(1)/Vp*(0.33*L)*(1-sigma1) - Z(2)/(0.65*ISF*Kp)*(0.33*L)*0.8

DZ(3)= Z(1)/Vp*(0.67*L)*(1-sigma2) - Z(3)/(0.35*ISF*Kp)*(0.67*L)*0.8

DZ(4)= Z(2)/(0.65*ISF*Kp)*(0.33*L)*0.8 + Z(3)/(0.35*ISF*Kp)*(0.67*L)*0.8 - Z(4)*(L/VL)

FUNCTION 1

F=Z(1)/2.6