Route of administration • posologyr

library(posologyr)

Introduction

The Caldès 2009 ganciclovir model (https://doi.org/10.1128/aac.00085-09) is capable of describing the pharmacokinetics of either injectable ganciclovir or oral valganciclovir.

mod_ganciclovir_Caldes_2009 <- function() {
  ini({
    THETA_cl  <- 7.49
    THETA_v1  <- 31.90
    THETA_cld <- 10.20
    THETA_v2  <- 32.0
    THETA_ka  <- 0.895
    THETA_baf <- 0.825
    ETA_cl ~ 0.107
    ETA_v1 ~ 0.227
    ETA_ka ~ 0.464
    ETA_baf ~ 0.049
    add.sd <- 0.465
    prop.sd <- 0.143
  })
  model({
    TVcl  = THETA_cl*(ClCr/57);
    TVv1  = THETA_v1;
    TVcld = THETA_cld;
    TVv2  = THETA_v2;
    TVka  = THETA_ka;
    TVbaf = THETA_baf;

    cl  = TVcl*exp(ETA_cl);
    v1  = TVv1*exp(ETA_v1);
    cld = TVcld;
    v2  = TVv2;
    ka  = TVka*exp(ETA_ka);
    baf = TVbaf*exp(ETA_baf);

    k10 = cl/v1;
    k12 = cld / v1;
    k21 = cld / v2;
    Cc = centr/v1;

    d/dt(depot)  = -ka*depot
    d/dt(centr)  =  ka*depot - k10*centr - k12*centr + k21*periph;
    d/dt(periph) =                         k12*centr - k21*periph;
    d/dt(AUC)    = Cc;

    f(depot)=baf;
    alag(depot)=0.382;

    Cc ~ add(add.sd) + prop(prop.sd) + combined1()
  })
}

mod_ganciclovir_Caldes_2009 <- mod_ganciclovir_Caldes_2009()

Intravenous ganciclovir

Patient record with TDM data

To describe intravenous administration, a CMT column has been added to the TDM data table to indicate administrations directly into the central compartment.

Note: to compute the AUC between the last dose and the time of the last dose + 24 hours, a dummy dose of 0 mg is added to the time of the last observation of interest (i.e. H144).

patient <- data.frame(ID=1,TIME=c(0,121,122,126,144),
                      DV=c(NA,10.8,5.8,3.3,NA),
                      ADDL=c(5,0,0,0,0),
                      II=c(24,0,0,0,0),
                      EVID=c(1,0,0,0,1),
                      CMT=c("centr",NA,NA,NA,"centr"),
                      AMT=c(250,0,0,0,0),
                      DUR=c(0.5,NA,NA,NA,NA),
                      ClCr=25)
patient
#>   ID TIME   DV ADDL II EVID   CMT AMT DUR ClCr
#> 1  1    0   NA    5 24    1 centr 250 0.5   25
#> 2  1  121 10.8    0  0    0  <NA>   0  NA   25
#> 3  1  122  5.8    0  0    0  <NA>   0  NA   25
#> 4  1  126  3.3    0  0    0  <NA>   0  NA   25
#> 5  1  144   NA    0  0    1 centr   0  NA   25

Individual PK profile and AUC 0-24

The individual PK profile can be estimated, and plotted.

map_patient <- poso_estim_map(patient,mod_ganciclovir_Caldes_2009)
#> using C compiler: ‘gcc (Ubuntu 13.3.0-6ubuntu2~24.04) 13.3.0’

plot(map_patient$model,Cc)

Plot of the individual PK profile

The difference between the cumulative AUC at H144 and that at H120 gives the AUC 0-24 after the last dose. Using data.table is optional, but the syntax is more convenient.

library(data.table)
data.table(map_patient$model)[time==144,AUC] - 
  data.table(map_patient$model)[time==120,AUC]
#> [1] 72.19084

Optimal dose for an intravenous ganciclovir injection

The optimal dose to achieve an AUC of 50 mg.h/L can be determined for a new injection of IV ganciclovir by setting cmt_dose = "centr".

poso_dose_auc(patient,mod_ganciclovir_Caldes_2009,tdm=TRUE,
              time_dose = 145,
              duration = 1,
              time_auc = 24,
              target_auc = 50,
              cmt_dose = "centr")
#> using C compiler: ‘gcc (Ubuntu 13.3.0-6ubuntu2~24.04) 13.3.0’
#> $dose
#> [1] 156.533
#> 
#> $type_of_estimate
#> [1] "point estimate"
#> 
#> $auc_estimate
#> [1] 50
#> 
#> $indiv_param
#>   THETA_cl THETA_v1 THETA_cld THETA_v2 THETA_ka THETA_baf add.sd prop.sd
#> 1     7.49     31.9      10.2       32    0.895     0.825  0.465   0.143
#>       ETA_cl     ETA_v1        ETA_ka      ETA_baf covar
#> 1 0.05256373 -0.4773317 -3.099019e-06 2.772041e-07    25

Optimal dose for an oral valganciclovir administration

The optimal dose to achieve an AUC of 50 mg.h/L can be determined for an administration of oral valganciclovir by setting cmt_dose = "depot".

poso_dose_auc(patient,mod_ganciclovir_Caldes_2009,tdm=TRUE,
              time_dose = 145,
              time_auc = 24,
              target_auc = 50,
              cmt_dose = "depot")
#> $dose
#> [1] 193.1298
#> 
#> $type_of_estimate
#> [1] "point estimate"
#> 
#> $auc_estimate
#> [1] 50
#> 
#> $indiv_param
#>   THETA_cl THETA_v1 THETA_cld THETA_v2 THETA_ka THETA_baf add.sd prop.sd
#> 1     7.49     31.9      10.2       32    0.895     0.825  0.465   0.143
#>       ETA_cl     ETA_v1        ETA_ka       ETA_baf covar
#> 1 0.05256457 -0.4773339 -9.298227e-07 -1.072357e-07    25

Keeping the default value of cmt_dose, which is the first compartment declared in the PK model, would also work here.

Note in this case the estimated dose should be corrected by a factor of 1/0.72 as the Caldès 2009 paper states:

“As NONMEM estimated the pharmacokinetic parameters of ganciclovir, valganciclovir doses were converted to their equivalent ganciclovir content by multiplying the valganciclovir dose by 0.720 (corresponding to the ratio between the molecular weights of ganciclovir and valganciclovir).”