USC*PACK -- Introduction

The USC*PACK consists of

1. Programs for Population Pharmacokinetic Modeling
2. Clinical Programs
3. Programs for Infectious Diseases
4. Programs for Cardiology

Product Name:

USC*PACK PC Pharmacokinetic Programs

Organization:

The Laboratory of Applied Pharmacokinetics, USC
School of Medicine (Dr. R.W. Jelliffe)

Contact:

Click here for contact information.

Computers supported:

IBM PC and compatibles (needs math coprocessor, VGA graphics, 2Mb RAM)

Operating systems/languages:

DOS 5.0 or newer.

Price:

Licensed from USC. A donation is requested to offset costs of the user manual, mailing, disks, tech support, etc..

The requested donation for this version, whether or not you are already a USC*PACK user, are:

 
                             Hospital or          Commercial
                        Academic Institution      or Industry

                               $595.00               $895.00

Please mail the signed license agreement back to us, along with a check for the appropriate amount, made out to the University of Southern California. We will send the programs back to you with the user manual and other material as soon as possible. We supply the programs on these HD 3.5 inch disks or on CD's.

1. Program for Population Pharmacokinetic Modeling

This program uses the nonparametric EM (NPEM) algorithm of Schumitzky to compute the location and probability mass of the overall joint probability density function (PDF). It is similar to the algorithm of Mallet, but runs on PC's. It is now available for a 3 compartment (7 parameter) model with oral and/or IV dosing. It can compute both volume and bioavailability from mixed oral and IV dosing when appropriate serum level data is available for each route.

The program accepts clinical data from files generated by the PASTRX programs in the USC*PACK PC clinical collection. It is designed to accept a population containing up to 999 such files. It can utilize appropriate clinical data including only a single serum level per patient.

Output consists of plots of the marginal PDF for each parameter. 3D plots can be made of the joint marginal PDF for any parameter pair. It also computes traditional mean, SD, mode, median, skewness and kurtosis, and the covariance and correlation coefficients between parameters. The means (or medians), SD's and correlation coefficients can be entered into the MB program in the USC*PACK PC clinical collection to store a population model for clinical use.

In addition, the full joint PDF can be written to a Matlab file for use in RMultiple ModelS adaptive control prototype new software for more precise stochastic design of drug dosage regimens. This program is suitable for researchers and community hospitals to make population models for patients under their care, and to couple this with the USC*PACK PC clinical software for Bayesian individualization of drug dosage regimens. The program now runs about 30 times faster than previous versions, due to implementation of various methods for accelerating the computations.

2. The USC*PACK clinical programs

The USC*PACK clinical programs, now version 11.7, and the new MM-USC*PACK programs for maximally precise multiple model (MM) design of dosage regimens to achieve desired target goals with maximal precision (minimum weighted squared error) employ a linear 3 compartment pharmacokinetic model having an absorptive, a central (serum) compartment, and a peripheral (nonserum) one. One can also enter and store parameter values for any drug having this basic structural model. There are population models available for clinical use to guide and adjust therapy with gentamicin (general medical patients, ICU patients, others, and several for newborns and premature infants). Similar models are available for Tobramycin, Netilmicin, and Amikacin. There are also models for digoxin, digoxin with quinidine, quinidine, and digitoxin. The software also permits development of dosage regimens to achieve target goals in the peripheral nonserum compartment as well as to achieve target serum concentration goals. This is especially useful for digoxin and digitoxin, where the main clinical and toxic effects are correlated much better with those peripheral (tissue) concentrations that with serum concentrations. Models are also available for lidocaine, theophylline (several different ones for smokers, etc, and for long - acting preparations), vancomycin, trimethoprim, and others.

The programs now also compute antibiotic diffusion into simulated endocardial vegetations, and calculate and plot the dynamics of bacterial growth and the killing effect of antibiotics upon the organisms.

The USC*PACK POPULATION modeling program employs a nonparametric expectation maximization (NPEM) algorithm. It reads routine patient data files and now computes the entire joint probability density for a 2 compartment model with either oral or intravenous input. It can compute both distribution volume and bioavailability from data of mixed oral and intravenous doses, and can discover unrecognized subpopulation clusters.

The USC*PACK BOXES program and package makes pharmacokinetic/dynamic models by placing boxes on the screen and connecting them with arrows. Differential equations are written for the Model portion of the ADAPT I PC programs. With a text editor it is easy to paste the equations into the ADAPT II programs as well.

3. Programs for Infectious Diseases

The USC*PACK clinical SPHERE program computes diffusion of antibiotics into spherical porous substances such as endocardial vegetations or abscesses which can be regarded as being surrounded by the serum compartment of a pharmacokinetic model of a drug. It uses the appropriate equations of Vergnaud and the software of Maire and Barbaut to plot the time course of antibiotic diffusion onto such simulated vegetations or abscesses. It is now part of the USC*PACK clinical programs. It currently uses the diffusion coefficient for Amikacin into rabbit endocardial vegetations found by Bayer and Crowell. Others may be entered by the user.

The USC*PACK clinical EFFECTS program takes literature data of the growth of organisms and their kill by various drugs, puts it together with data of a particular patient's MIC, and computes the time course of bacterial growth and kill in the central (serum) compartment, the peripheral nonserum compartment, and in various layers of an endocardial vegetation or abscess as described above. Regrowth of organisms frequently correlates with clinical relapse. These analyses are an important adjunct to planning drug dosage regimens to ensure an adequate margin of safety.

These programs are useful extensions of the USC*PACK clinical PC programs for analyzing drug behavior in patients and in individualizing drug dosage regimens to achieve and maintain specifically chosen therapeutic goals for such drug therapy.

4. Programs for Cardiology

The USC*PACK clinical digoxin program computes dosage regimens of digoxin and digitoxin to achieve specifically chosen therapeutic goals. These may be stated as desired trough serum concentrations or better yet as desired peak concentrations in the peripheral nonserum compartment. Bayesian fitting to serum level data provides individualized pharmacokinetic models. Clinical behavior may at times correlate poorly or not at all with serum levels, but usually correlates quite well with concentrations in the peripheral nonserum compartment.

The USC*PACK clinical lidocaine program computes dosage regimens of lidocaine to achieve specifically chosen therapeutic goals, stated as desired serum levels. Elimination of lidocaine is well correlated with cardiac index, which can change from dose to dose. Changing (usually tapering) infusion regimens are easily interfaced with conventional infusion apparatus to achieve and maintain the desired serum level even during the distribution phase of the drug into the nonserum compartment of the body. These regimens have been shown to result in more prompt control of arrhythmias, with less breakthrough.

Supported in part by NIH Grant LM05401 and by the Stella Slutzky Kunin Memorial Research Fund.