Specifying A Pediatric Simulation Model
Here we have a simple one-compartment PK model with first-order absorption where clearance and volume are allometrically scaled. The reference subject is a 4 year old female with a weight of 15.9 kg.
* First we plot a typical PK profile with between subject variability (BSV).
pedpkmodelcov <- '
$PARAM @annotated
KA : 0.5 : Absorption rate constant Ka (1/h)
CL : 4 : Clearance CL (L/h)
V : 10 : Central volume Vc (L)
CLWT : 0.75 : Weight on CL (ref. 22.5 kg)
VWT : 1 : Weight on V (ref. 22.5 kg)
$PARAM @annotated // reference values for covariate
WT : 15.8 : Weight (kg)
SEX : 0 : Sex (0=Female, 1=Male)
AGE : 4 : Age (years)
$CMT GUT CENT
$MAIN
double CLi = CL *
pow((WT/15.8), CLWT)*exp(ETA(1));
double Vi = V *
pow((WT/15.8), VWT)*exp(ETA(2));
double KAi = KA;
double Keli = CLi/Vi;
$OMEGA
0.09
0.01 0.09
$ODE
dxdt_GUT = -KAi*GUT;
dxdt_CENT = KAi*GUT-Keli*CENT;
$TABLE
double CP = CENT/ Vi;
$CAPTURE CP KAi CLi Vi WT SEX AGE
'
pedmodsim <- mcode("pedpkmodelcov", pedpkmodelcov)
partab <- setDT(pedmodsim@annot$data)[block=="PARAM", .(name, descr, unit)]
partab <- merge(partab, melt(setDT(pedmodsim@param@data), meas=patterns("*"), var="name"))
knitr::kable(partab)| name | descr | unit | value |
|---|---|---|---|
| AGE | Age | years | 4.00 |
| CL | Clearance CL | L/h | 4.00 |
| CLWT | Weight on CL | ref. 22.5 kg | 0.75 |
| KA | Absorption rate constant Ka | 1/h | 0.50 |
| SEX | Sex | 0=Female, 1=Male | 0.00 |
| V | Central volume Vc | L | 10.00 |
| VWT | Weight on V | ref. 22.5 kg | 1.00 |
| WT | Weight | kg | 15.80 |
idata <- data.table(
ID = 1:nsubj,
WT = c(rep(15.8,nsubj/2),
rep(16.2,nsubj/2)),#from Nhanes at 4 years female and male
AGE = 4,
SEX = c(rep(0,nsubj/2),rep(1,nsubj/2))
)
ev1 <- ev(time = 0, amt = 100, cmt = 1)
data.dose <- ev(ev1)
data.dose <- setDT(as.data.frame(data.dose))
data.all <- data.table(idata, data.dose)
set.seed(678549)
outputsim <- pedmodsim %>%
data_set(data.all) %>%
mrgsim(end = 24, delta = 0.25)%>%
as.data.frame %>%
as.data.table
outputsim$SEX <- as.factor(outputsim$SEX)
outputsim$SEX <- factor(outputsim$SEX, labels=c("Girls","Boys"))
p1 <- ggplot(data = outputsim[outputsim$SEX=="Girls",],
aes(time, CP, group = ID)) +
geom_line(alpha = 0.2, size = 0.1) +
facet_grid(AGE ~ WT+SEX,
labeller = label_both) +
scale_y_log10() +
labs(y = expression(Log[10]~~Plasma~~Concentrations), color = "Sex", x = "Time (h)")
p1
