The PKPDsim software package

The software covers a broad range of topics related to pharmacokinetics and
pharmacodynamics (PK/PD) of antibiotics in particular; from estimation of drug
concentrations from zone diameters in a bio assay to simulation assisted design
of experimental studies, e.g. optimum selection of dosage regimens for in vivo
effect studies.

The PKPDsim package consists of a number of programs:

• AssayDeterm estimates drug concentrations from measured zone
  diameters in bio assays. The program also finds the assay error pattern,
  i.e. the estimate's standard deviation as a function of the concentration.
  The results can be used as input for the initESTIM program.
  See examples

• BinKin fits various mathematical expressions to experimental data for
  protein binding as a fuction of drug concentration in plasma. The estimated
  parameter values (e.g. the specific binding capacity and the product of
  binding affinity and mean time in bound state) are used in the other
  PKPDsim programs for calculation of the free fraction of drug.
  See examples

• initESTIM processes and formats PK data (concentration-time points)
  and generates the necessary input files for use in an external population
  PK parameter estimation program such as NPAG¹. initESTIM also performs
  noncompartmental modelling and estimates entities such as C_max, AUC,
  T_>MIC and T_1/2. See examples

• postESTIM extracts and processes information from an external data file
  (from the external program used for population PK parameter estimation,
  e.g. NPAG) for subsequent use in the program SIM. The quality of the
  parameter estimates is studied and presented in a number of graphs, and
  various parameter distributions (including nonparametic) can be obtained
  from the support points. See examples

• SIM is the core program of the PKPDsim package and built for Monte
  Carlo simulation with compartment models. The drug concentration (free
  or total) including lower and upper confidence bounds as a function of
  time, as well as the resulting microbial net growth and density, can be
  found for an arbitrary dosage regimen. SIM also estimates T_>MIC, AUC,
  C_max, probability of target attainment, MIC breakpoints, etc. SIM has a
  built-in library of predefined compartment models and support for
  user-specified models using the Pascal programming language. Some of
  the other programs in the PKPDsim package also call SIM silently as a
  simulation engine during their execution. See examples

• studyDESIGN is a tool mainly for optimum selection of dosage regimens
  for experimental effect studies (in vivo). The program displays the inter-
  relationship between T_>MIC, AUC, C_max, for a series of specified dosage
  regimens in tables and scatter plots. The corresponding concentration-
  time curves are also shown. Modelling of the various dosage regimens
  is based on a number of single bolus PK studies (up to five) with
  different dose size. These PK data can come from either initESTIM
  (noncompartmental description) or postESTIM (fitted compartment model).
  See examples

• studyEFFECT fits a sigmoid curve to the chosen measure of effect, e.g.
  Δlog(CFU₂₄), as function of T_>MIC, AUC, C_max , or total dose, respectively.
  The CFU effect data can be specified explicitly (experimental data) or
  generated internally (studyEFFECT will call TimKil and SIM). studyEFFECT
  gets the information on T_>MIC, AUC, C_max , etc. from the studyDESIGN
  output file. See examples

• TimKil is used for processing of CFU data from in vitro time-kill experiments
  and for time-kill curve modelling with a variety of advanced semimechanistic
  models including phenomena such as pre-existing resistant subpopulations,
  persisters, adaptive resistance mechanisms, etc. Various in silico studies,
  including combination therapy schemes, are facilitated by the automated
  exchange of files between TimKil, studyEFFECT, SIM, and the external
  parameter estimation program. See examples

The package runs on computers using Windows 7 or 10 and requires Microsoft
Office Excel (2010 or newer) and Free Pascal Compiler (Ver 3.0.4 or newer).

PKPDsim uses Knuth's portable subtractive generator² for production of pseudo-
random numbers.

Originally, the software package was developed exclusively for in-house research
use. Therefore only little time has been spent on developing a standard Windows
graphical interface for operating the software.

The various subprograms have been extensively tested on synthetic (simulation
generated) data where the "correct answer" is known as well as collaborators
genuine experimental data and - when available - also experimental data and
simulation results from the literature.

References

1. Pmetrics package for R, Laboratory of Applied Pharmacokinetics and
   Bioinformatics, Children's Hospital Los Angeles, University of Southern
   California.
    
2. Knuth, DE, The art of Computer Programming: Seminumerical Algorithms,
   Vol 2, 3rd Ed, 1997, Addison-Wesley.