library(deSolve)
library(ggplot2)
library(grid)
library(gridExtra)
library(extrafont)
library(cowplot)
devtools::document()
#or devtools:install()
#library(pbpkr)
# Model Based on: Takeuchi et al (2014). DMD 45:726-734, with added biliary excretion into the gut and delay compartment for Tlag
# Clinical data: Prueksaritanont et al. (2014). Br.J.Clin.Pharmacol 78(3): 587-598
Prueksaritanont <- read.csv('Pruesksaritanont_2014_Pita.csv',head=TRUE)
# y1-y4 = pita
# assuming that 100% of the dose is available to be absorbed (Fa=1)
# CfPP = fu.plasma/BL:PL
####################Function##########################################
PitaODE <- function(t, In_Cond, parameters)
{with(as.list(c(In_Cond, parameters)),{
# pita lag compartment
dy1dt <- -ktransP*y1
# Pita gut compartment (y2)
dy2dt <- - kaP*y2 + BiTrans*(CL_BiPi*y4/VGaBl) + ktransP*y1
# Pita liver extracellular space (y3)
dy3dt <- (kaP*y2 -
Cfpp*y3*(VmP/(KmP+y3) + PdPi) -
Qh*(y3 - y5) + y4*PdePi
)/Vext
# Pita liver (y4)
dy4dt <- (Cfpp*y3*(VmP/(KmP+y3) + PdPi) -
(CL_BiPi + CL_MePi + PdePi)*y4
)/VH
# Pita plasma (y5)
dy5dt <- (Qh*(y3 - y5) - Cfpp*CL_ur*y5)/VcP
list(c(dy1dt,dy2dt,dy3dt,dy4dt,dy5dt)) }) }
times <- c(seq(0,600,1)) # min
######################################################################
parameters_Norm <- c(
1000000 , # Dose, ng, Prueksaritanont et al. (2014). Br.J.Clin.Pharmacol 78(3): 587-598
ktransP = 0.1 , #/min, min gastric emptying time = 10min. Hirano et al (2006)
kaP = 0.07 , # FDA doc, ka=1/(MRT_PO - MRT_IV)=1/(4.55-2.18)=0.42h^-1= 0.007min^-1/ktransp
BiTrans = 0.0618 , # /min. Gallbladder emptying rate. Guiastrennec et al (2016). CPT Pmetric 5(12):692-700
CL_BiPi = 169.63 , # Biliary CL, Total CL = 394.5mL/min (FDA)*0.43(fraction in faeces) = 169.63ml/min
#fTP = 0.026 , # fu, tissue from RED expt #2
Qh = 1450 , # Hepatic blood flow (ml/min)
VGaBl = 30 , # Gallbladder volume (mL), Guiastrennec et al (2016)
VmP = 10755828 , # ng/min/liver. Model C. 0.171*421.46*139*1800*0.6(fraction hepatocytes) = 10755828
Cfpp = 0.009 , # fu.pl/BL:PL = 0.004 (Aus TGA, 2013) / 0.425 (Izumi et al (2017). J.Pharm.Sci 106: 2678-2687 )
KmP = 139.17 , # ng. Model C (12.7*421.46*ftp) = 5352*0.026 = 139.17
PdPi = 683 , # P.diff into heps. ml/min. Model C, Pdiff =0.68 of trans up, therefore 2009(scaled*0.68)=1366ml/min /2
PdePi = 464 , # P.diff out of heps. ml/min. Model C 0.34 of Pdif, therefore 1366*0.34 = 464
Vext = 469 , # ml. Watanabe et al (2009). JPET 328:652-662
CL_MePi = 181.44 , # ml/min. Fujino et al (2003) 2.52ul/min/mg prot * 40(MPPGL) * 1800 = 181.44
VH = 1690 , # ml. vol of liver. Davies and Morris (1993)
CL_ur = 11.84 , # ml/min.Urine. FDA = 3% of parent in urine
VcP = 16890 # Vz for pita. ml.Vz/F=226*0.51*1000 (Prueksaritanont et al (2014). )
)
In_Cond <- c(y1=parameters_Norm[1],y2=0,y3=0,y4=0,y5=0)
#In_Cond <- c(y2=parameters_Norm[1],y3=0,y4=0,y5=0)
#Vz for pita. FDA = 133.2L. Gives very low plasma values. Total Body Water = 42L
#HPGL:139, Sohlenius-Sternbeck (2006). ToxInVit 20: 1582-1583. wt of liver,1800: Davies and Morris (1993). Pharm Res 10(7): 1093-1095
#MPPGL: Zhang et al (2015). Sci Rep 5:17671
out <- ode(y = In_Cond, times = times, func = PitaODE, parms = parameters_Norm)
##### HERE STARTS THE BIT , LOOK IN FOLDER R TO FIND THE FUNCTION odes
rangeVmP = seq(from = 8e6, to = 11e6, by = .1e6)
test <- odes(y = In_Cond, times = times,
func = PitaODE, parms = parameters_Norm,
var = "VmP", range_var = rangeVmP )
p <- odes.plot(test)
p + ggtitle("S-C Plot")
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