PROB NIVOLUMAB Population PK Analysis ; DESCRIPTION: Linear 2-cmpt PK model, with time-varying CL (sigmoid-Emax) - Final PPK model ; NOTES: Method: FOCEI; proportional residual error model ; Definitions of Variables in PPK dataset ; TIME: Actual time after first dose ; BBWT: Baseline body weight ; BALB: Baseline Albumin ; BLDH: Baseline lactate dehydrogenase ; TTYPEN: Tumor type (1=MEL; 2=NSCLC; 3=OTHERS; 4=RCC) ; HEPAN: Hepatic function (1=normal) ; RACEN: Race (1=White; 2=African American; 3=Asian, 4=Others) ; PS: Performance Status (0, 1) ; SEXN: 1=Male; 2=Female ; FLAGN: Exclusion variable (1=excluded records) $INPUT ID TIME EVID AMT RATE DV AGE SEXN BBWT BGFR PS RACEN FLAGN MDV $DATA ../pkdata1.csv IGNORE=@ IGNORE=(FLAGN=1) $SUBROUTINE ADVAN3 TRANS4 $SIM (NEW 123456) ONLY SIM SUBPROBLEMS=1 $COVARIANCE PRINT=ER $THETA (0, 0.010) ; CL [L/h] ; theta1 (0, 4) ; VC [L] ; theta2 (0, 0.04) ; Q [L/h] ; theta3 (0, 4) ; VP [L] ; theta4 ; 0 FIX ; AERR [ug/mL] ; theta5 (0, 0.5) ; PERR [-] ; theta6 ; (0.05) ; CL_BBWT ; theta7 (0.1) ; CL_GFR ; theta8 (0.1) ; CL_SEX ; theta9 (0.05) ; CL_PS ; theta10 (-0.05) ; CL_RAAS; theta11 (0.05) ; VC_BBWT ; theta12 (0.1) ; VC_SEX ; theta13 ; 0.01 ; CL_EMAX ; theta14 1800 ; CL_T50 ; theta15 1 ; CL_HILL; theta16 $OMEGA BLOCK(2) 0.5 ; ZCL [-] 0.1 0.3 ; ZVC [-] ; $OMEGA 0.3 ; ZVP [-] 0.1 ; ZEMAX [h] $SIGMA 1 FIX ; RESERR $PK ; Define fixed effects parameters ACL = THETA(1) AV1 = THETA(2) AQ = THETA(3) AV2 = THETA(4) ; Define parameters of time-varying CL (sigmoid Emax) AEMAX = THETA(14) T50 = THETA(15) HILL = THETA(16) ; Define parameters of residual error model AERR = THETA(5) ; Additive PERR = THETA(6) ; proportional ; Define parameters of between-subject variability ZCL = ETA(1) ZV1 = ETA(2) ZV2 = ETA(3) ZEMAX = ETA(4) ; Impute covariate values and define effects ; Missing continuous covariates are imputed as median ; Missing categorical covariates are imputed as mode MVAL = -99 ; missing value in dataset ; Baseline Body Weight BBWT_R = 80 ; refernce value, kg BBWT_I = BBWT IF (BBWT_I .EQ. MVAL) BBWT_I = BBWT_R ; imputation to reference (~median) ; CL_BBWT = (BBWT_I/BBWT_R)**THETA(7) ;Baseline GFR BGFR_R = 90 ; reference value, mL/min BGFR_I = BGFR IF (BGFR_I .EQ. MVAL) BGFR_I = BGFR_R; GFR imputation to median CL_BGFR = (BGFR_I/BGFR_R)**THETA(9) ; SEX SEX_I = SEXN IF (SEX_I .EQ. MVAL) SEX_I = 1; male CL_MALE = THETA(9) ; effect of female:male ; Performance Status (PS) PS_I = PS IF (PS .EQ. MVAL) PS_I = 1 ; impute missing PS to 1 CL_PS_1 = THETA(10); effect of PS 1+:0 ; Race RACE_I = RACEN IF (RACE_I .EQ. MVAL) RACE_I = 1; White CL_RAAS = THETA(11) ; effect of Asian:White/Other ; VC V1_BBWT = (BBWT_I/BBWT_R)**THETA(12) V1_SEX = THETA(13) ; Time-varying CL (Sigmoid Emax Function) EMAX = AEMAX + ZEMAX CL_TIME = EXP(EMAX*TIME**HILL/(T50**HILL+TIME**HILL)) ; Define model parameters: add covariate effect TVCL = ACL * CL_BBWT * CL_BGFR * CL_TIME IF (SEX_I .EQ. 1) TVCL = TVCL * EXP(CL_MALE) ; reference is SEX=2 (Female) IF (PS_I .GE. 1) TVCL = TVCL * EXP(CL_PS_1) ; reference is PS=0 IF (RACE_I .EQ. 3) TVCL = TVCL * EXP(CL_RAAS) ; reference is White/Others ; TVV1 = AV1 * V1_BBWT IF (SEX_I .EQ. 1) TVV1 = TVV1 * EXP(V1_SEX) ; reference is SEX=2 (Female) ; Calculate PK parameters CL = TVCL*EXP(ZCL) V1 = TVV1*EXP(ZV1) Q = AQ V2 = AV2*EXP(ZV2) S1 = V1 ; Calculate alpha and beta half-life KE = CL/V1 K23 = Q/V1 K32 = Q/V2 AA = KE+K23+K32 ALPH = (AA+SQRT(AA*AA-4*KE*K32))/2 BETA = (AA-SQRT(AA*AA-4*KE*K32))/2 ALPHHL = LOG(2)/ALPH BETAHL = LOG(2)/BETA $ERROR ; Define Residual Error Weight REWT = F*PERR + AERR ; proportional error model (additive error fixed to 0) IPRED = F IRES = DV - IPRED IWRES = IRES/REWT Y = IPRED + REWT*EPS(1) $TABLE ID TIME EVID AMT RATE DV PRED CIPRED RES CIRES CWRES CIWRES CL V1 Q V2 ALPHHL BETAHL EMAX T50 HILL FLAGN NOPRINT ONEHEADER FILE=nm.tab