mapbayr

CRAN status

mapbayr is a free and open source package for maximum a posteriori bayesian estimation of PK parameters in R. Thanks to a single function, mapbayest(), you can estimate individual PK parameters from:

It was designed to be easily wrapped in shiny apps in order to ease model-based Therapeutic Drug Monitoring, also referred to as Model-Informed Prediction Dosing (MIPD).

Installation

mapbayr is available on CRAN. You can install the development version from github by executing the following code in R console.

install.packages("devtools")
devtools::install_github("FelicienLL/mapbayr")

mapbayr relies on mrgsolve for model implementation and ordinary differential equation solving which requires C++ compilers. If you are a Windows user, you would probably need to install Rtools. Please refer to the installation guide of mrgsolve for additional information.

Example

library(mapbayr)
library(mrgsolve)

1) Properly code you model

code <- "
$PARAM @annotated
TVCL:  0.9 : Clearance
TVV1: 10.0 : Central volume
V2  : 10.0 : Peripheral volume of distribution
Q   :  1.0 : Intercompartmental clearance

ETA1: 0 : Clearance (L/h)
ETA2: 0 : Central volume (L)

$PARAM @annotated @covariates
BW : 70 : Body weight (kg)

$OMEGA 0.3 0.3
$SIGMA
0.05 // proportional
0.1 // additive

$CMT @annotated
CENT  : Central compartment (mg/L)[ADM, OBS]
PERIPH: Peripheral compartment ()

$TABLE
double DV = (CENT/V1) *(1 + EPS(1)) + EPS(2);

$MAIN
double CL = TVCL * exp(ETA1 + ETA(1)) * pow(BW / 70, 1.2) ;
double V1 = TVV1 * exp(ETA2 + ETA(2)) ;
double K12 = Q / V1  ;
double K21 = Q / V2  ;
double K10 = CL / V1 ;

$ODE
dxdt_CENT   =  K21 * PERIPH - (K10 + K12) * CENT ;
dxdt_PERIPH =  K12 * CENT - K21 * PERIPH ;

$CAPTURE DV CL
"

my_model <- mcode("Example_model", code)

2) Bring your dataset

my_data <- data.frame(ID = 1, time = c(0,6,15,24), evid = c(1, rep(0,3)), cmt = 1, amt = c(100, rep(0,3)), 
                      rate = c(20, rep(0,3)), DV = c(NA, 3.9, 1.1, 2), mdv = c(1,0,0,1), BW = 90)
my_data
#>   ID time evid cmt amt rate  DV mdv BW
#> 1  1    0    1   1 100   20  NA   1 90
#> 2  1    6    0   1   0    0 3.9   0 90
#> 3  1   15    0   1   0    0 1.1   0 90
#> 4  1   24    0   1   0    0 2.0   1 90

3) And estimate !

my_est <- mapbayest(my_model, data = my_data)

As building dataset into a NM-TRAN format can be painful, you can use pipe-friendly obs_lines(), adm_lines() and add_covariates() functions in order to pass administration and observation information, and perform the estimation subsequently.

my_est <- my_model %>% 
  adm_lines(time = 0, amt = 100, rate = 20) %>% 
  obs_lines(time = 6, DV = 3.9) %>% 
  obs_lines(time = 20, DV = 1.1) %>% 
  obs_lines(time = 24, DV = 2, mdv = 1) %>% 
  add_covariates(list(BW = 90)) %>% 
  mapbayest()

4) Then, use the estimations

The results are returned in a single object (“mapbayests” S3 class) which includes input (model and data), output (etas and tables) and internal arguments passed to the internal algorithm (useful for debugging). Additional methods are provided to ease visualization and computation of a posteriori outcomes of interest.

print(my_est)
#> Model:  Example_model 
#> ID : 1  individual(s).
#> OBS: 2  observation(s).
#> ETA: 2  parameter(s) to estimate.
#> 
#> Estimates: 
#>   ID      ETA1      ETA2
#> 1  1 0.3872104 0.1569604
#> 
#> Output (4 lines): 
#>   ID time evid cmt amt rate mdv  DV     IPRED      PRED      CL BW      ETA1
#> 1  1    0    1   1 100   20   1  NA 0.0000000 0.0000000 1.79217 90 0.3872104
#> 2  1    6    0   1   0    0   0 3.9 4.1621701 5.1739186 1.79217 90 0.3872104
#> 3  1   15    0   1   0    0   0 1.1 1.0867408 1.6468556 1.79217 90 0.3872104
#> 4  1   24    0   1   0    0   1 2.0 0.5559693 0.9594398 1.79217 90 0.3872104
#>        ETA2
#> 1 0.1569604
#> 2 0.1569604
#> 3 0.1569604
#> 4 0.1569604
plot(my_est)

hist(my_est)  

# Easily extract a posteriori parameter values to compute outcomes of interest
get_eta(my_est)
#>      ETA1      ETA2 
#> 0.3872104 0.1569604
get_param(my_est, "CL")
#> [1] 1.79217

# The `use_posterior()` functions updates the model object with posterior values and covariates to simulate like with a regular mrgsolve model
my_est %>% 
  use_posterior() %>% 
  data_set(expand.ev(amt = c(50, 100, 200, 500), dur = c(5, 24)) %>% mutate(rate = amt/dur)) %>% 
  carry_out(dur) %>% 
  mrgsim() %>% 
  plot(DV~time|factor(dur), scales = "same")

Development

mapbayr is under development. Your feedback for additional feature requests or bug reporting is welcome. Contact us through the issue tracker.

Features

mapbayr is a generalization of the “MAP Bayes estimation” tutorial available on the mrgsolve blog. Additional features are:

Performance

Reliability of parameter estimation against NONMEM was assessed for a wide variety of models and data. The results of this validation study were published in CPT:Pharmacometrics & System Pharmacology, and materials are available in a dedicated repository. If you observe some discrepancies between mapbayr and NONMEM on your own model and data, feel free to contact us through the issue tracker.

mrgsolve model specification

mapbayr contains a library of example model files (.cpp), accessible with exmodel(). You are invited to perform MAP-Bayesian estimation with your own models. These model files should be slightly modified in order to be “read” by mapbayr with the subsequent specifications:

1. $PARAM block

1.1 ETA specifications

$PARAM @annotated
ETA1 : 0 : CL (L/h)
ETA2 : 0 : VC (L)
ETA3 : 0 : F ()
//do not write ETA(1)
//do not write iETA

1.2 Covariates

$PARAM @annotated @covariates
BW : 70 : Body weight (kg)
SEX : 0 : Sex (0=Male, 1=Female)

2. $CMT block

//example: model with dual zero and first order absorption in compartment 1 & 2, respectively, and observation of parent drug + metabolite 
$CMT @annotated
DEPOT: Depot [ADM]
CENT_PAR: examplinib central [ADM, OBS]
PERIPH : examplinib peripheral
CENT_MET : methylexamplinib central [OBS] 

3. $OMEGA block

$OMEGA
0.123 0.456 0.789
$OMEGA @block
0.111 
0.222 0.333
// reminder: omega values can be recorded in multiple $OMEGA blocks

4. $SIGMA block

The definition of the $SIGMA block may not be as straightforward as other blocks, but we tried to keep it as simple as possible. Keep in mind that mapbayr always expect a pair of sigma values for each type of dependent variable: the first value for proportional error, the second for additive.

Two situations can be distinguished:

  1. You only have one type of concentration to fit, and you did not use the [OBS] assignment in $CMT.

Simply write one pair of sigma values to describe proportional and additive error on your concentrations. This error model will be automatically applied to the compartment where observations were recorded in your dataset (i.e. value of CMT when MDV = 0).

$SIGMA 0.111 0 // proportional error 
$SIGMA 0 0.222 // (log) additive error
$SIGMA 0.333 0.444 // mixed error
  1. You have multiple types of DV (parent and metabolite), and/or you used the [OBS] assignment in $CMT.

Write as many pairs of sigma values as there are compartments assigned with [OBS] in $CMT. The order of the pair must respect the order in which compartments were assigned. To put it more clearly, the sigma matrix will be interpreted as such whatever the model :

N° in the SIGMA matrix diagonal Associated error
1 Proportional on concentrations in the 1st cmt with [OBS]
2 Additive on concentrations in the 1st cmt with [OBS]
3 Proportional on concentrations in the 2nd cmt with [OBS]
4 Additive on concentrations in the 2nd cmt with [OBS]
//example: correlated proportional error between parent and metabolite
$SIGMA @block
0.050 // proportional error on parent drug
0.000 0.000 // additive error on parent drug
0.100 0.000 0.200 // proportional error on metabolite
0.000 0.000 0.000 0.000 // additive error on metabolite
// reminder: sigma values can be recorded in multiple $SIGMA blocks

6. $TABLE block or $ERROR block

$TABLE
double DV  = (CENTRAL / VC) * exp(EPS(2)) ;
$TABLE
double PAR = (CENT_PAR / V) * (1 + EPS(1)) ;
double MET = (CENT_MET / V) * (1 + EPS(3)) ;
double DV = PAR ;
if(self.cmt == 4) DV = MET ; 
// reminder: use "self.cmt" to internaly refer to a compartment in a mrgsolve model code. 

Note that mapbayr does not strictly rely on this $ERROR block to define the residual error internally and compute the objective function value, but on information passed in the $SIGMA block. However, we strongly advise you to properly code your $ERROR block with EPS(1), EPS(2) etc…, if only to use your code as a regular mrgsolve model code and simulate random effects.

7. $MAIN block

$PK
double CL = TVCL * exp(ETA1 + ETA(1))

8. $CAPTURE block

$CAPTURE DV PAR MET CL