Chapter 2 Methods

2.1 R packages (NonCompart and ncar)

Two R packages (NonCompart and ncar) for NCA were developed in the open-source R programming language in order to allow free public use. R packages can be installed and loaded using the following scripts.

install.packages(c('NonCompart', 'ncar'))
library(NonCompart)
library(ncar)

Detailed documentation and examples for each package can be found on the online user manual in the CRAN repository (http://cran.r-project.org/web/packages/NonCompart/index.html, http://cran.r-project.org/web/packages/ncar/index.html) or directly within the R console by entering ?function (e.g.?NonCompart,?ncar ). These two packages are implemented in R and can accept a set of input arguments that allow for generation of NCA output. The names of most NCA metrics estimated by the function of these packages are consistent with those used in WinNonlin®. (Table 2.1)

Table 2.1: Description of PK parameters of WinNonlin and the R packages

Parameter	WinNonlin	Description
b0	b0	Intercept
CMAX	Cmax	Max Concentration (Conc)
CMAXD	Cmax_D	Max Conc Norm by Dose
TMAX	Tmax_D	Time of Cmax
TLAG	Tlag	Time Until First Nonzero Conc
CLST	Clast	Last Nonzero Conc
CLSTP	Clast_pred	Last Nonzero Conc Pred
TLST	Tlast	Time of Last Nonzero Conc
LAMZHL	HL_Lambda_z	Half-Life Lambda z
LAMZ	Lambda_z	Lambda z
LAMZLL	Lambda_z	lower Lambda z Lower Limit
LAMZUL	Lambda_z	upper Lambda z Upper Limit
LAMZNPT	No_points_Lambda_z	Number of Points for Lambda z
CORRXY	Corr_XY	Correlation Between Time X and Log Conc Y
R2	Rsq	R Squared
R2ADJ	Rsq_adjusted	R Squared Adjusted
AUCLST	AUClast	AUC to Last Nonzero Conc
AUCALL	AUCall	AUC All
AUCIFO	AUCINF_obs	AUC Infinity Obs
AUCIFOD	AUCINF_D_obs	AUC Infinity Obs Norm by Dose
AUCIFP	AUCINF_Pred	AUC Infinity Pred
AUCIFPD	AUCINF_D_pred	AUC Infinity Pred Norm by Dose
AUCPEO	AUC_Extrap_obs	AUC %Extrapolation Obs
AUCPEP	AUC_Extrap_pred	AUC %Extrapolation Pred
AUMCLST	AUMClast	AUMC to Last Nonzero Conc
AUMCIFO	AUMCINF_obs	AUMC Infinity Obs
AUMCIFP	AUMCINF_pred	AUMC Infinity Pred
AUMCPEO	AUMC_Extrap_obs	AUMC %Extrapolation Obs
AUMCPEP	AUMC_Extrap_pred	AUMC % Extrapolation Pred
VZFO	Vz_F_obs	Vz Obs by F
VZFP	Vz_F_p	Vz Pred by F
CLFO	Cl_F_obs	Total CL Obs by F
CLFP	Cl_F_pred	Total CL Pred by F
MRTEVLST	MRTlast	MRT Extravasc to Last Nonzero Conc
MRTEVIFO	MRTINF_obs	MRT Extravasc Infinity Obs
MRTEVIFP	MRTINF_pred	MRT Extravasc Infinity Pred

2.2 Software

WinNonlin® (Pharsight, Mountain View, CA, USA)[4] in Microsoft-Windows 7 (64 bit) was used for the computation. R 3.4.2 in Microsoft-Windows 7 (64 bit) was used for the comparison of calculated values.

2.3 Dataset

To compare the outputs generated by R packages and WinNonlin®, we used Theoph dataset obtained from the R software. The Theoph dataset has 132 observations from 12 subjects. A portion of the Theoph dataset (subject ID = 8) is shown in Table 2.2.

Table 2.2: Part of Theoph dataset with information on key (subject), time, and concentration

Subject	Weight (kg)	Dose (mg)	Time (h)	Concentration (mg/ml)
8	70.5	4.53	0.00	0.00
8	70.5	4.53	0.25	3.05
8	70.5	4.53	0.52	3.05
8	70.5	4.53	0.98	7.31
8	70.5	4.53	2.02	7.56
8	70.5	4.53	3.53	6.59
8	70.5	4.53	5.05	5.88
8	70.5	4.53	7.15	4.73
8	70.5	4.53	9.05	4.57
8	70.5	4.53	12.10	3.00
8	70.5	4.53	24.12	1.25