SAAM II

University of Washington working through its Resource Center for Kinetic Analysis in the Center for Bioengineering, rewrote code for a software package called SAAM (I or 1.0), which had been developed in the late 1950s and early 1960s at the National Institutes of Health and at other research sites in the United States. The original SAAM was a powerful research tool to aid in the design of experiments and the analysis of data. Its dictionary permitted compartmental models to be developed without formally specifying the differential equations. However, SAAM was developed before the era of modem computer software design and implementation techniques, and as a result, it was not user-friendly. In addition, the computational kernel was not well documented, which made validation, maintenance, and further enhancements difficult.[1] In 1995 Prof David Foster led the re-writing of the SAAM code, including a strategic user interface, which generated SAAM II. It was then licensed for-profit concern. The SAAM Institute held the license until it was terminated in 2005. A particular boost to SAAM II was then given by both Prof Foster and Dr. Vicini's labs furthering the development and support, plus the creation of a Population pharmacokinetics plug-in, called PopKinetics. From 2011 to 2021 the distribution was licensed to a software company in Virginia, the Epsilon Group. They have updated SAAM to the current version 2.3, with bugs fixing, graphic improvements, and the creation of the Mac version.

Now, SAAM II is distributed by Nanomath LLC, a Washington company held by Dr. Simone Perazzolo a modeler and scientist at University of Washington Pharmaceutics.

It has a user-friendly graphical user interface wherein compartmental models are constructed by creating a visual representation of the model. From this model, the program automatically creates systems of ordinary differential equations (ODEs). The program can both simulate and fit models to data, returning optimal parameter estimates and associated statistics. It is composed of a compartmental and numerical module.

The Compartmental Module

In the compartmental module, the user can choose from a set of drag and drop model-building icons representing compartments, transfers (0th-order, linear, Michaelis–Menten kinetics, etc.), and delays to build a visual representation of a system on a drawing canvas. For each icon, attributes can be defined using dialogue boxes. For example, reference names can be assigned to compartments. To simulate the behavior of the model, an experiment must be created (model conditions). Using the drag and drop experiment-building icons, the user directly specifies exogenous inputs and sample sites. Each has an attribute box where, for example, measurement equations are written and associations with data elements are made. The example of a two compartmental model for the oral absorption of a candidate drug (#1) and the plasma elimination (#2) is depicted in Figure 1. Note that the input (dose) is in the digestive compartment 1, while the output (observations) is made in the plasma compartment 2. The Compartmental Module is the most used feature of SAAM II.

Example of SAAM II graphic of a 2 compartment model describing the pharmacokinetics of an oral drug (image taken from the Mac version). The left compartment 1 is the input pool for the oral drug (GI tract) as a bolus, infusion, or custom; the right compartment 2 is the output pool where observations are collected in the plasma. Parameters connecting compartments (usually rate constants 1/time) can be either fixed or fitted to the available data. k21 denotes the absorption from the digestive system to the blood; k01 is the non-available dose elimination in the feces; k02 denotes the drug elimination from the blood.

popKinetics is an add-on to SAAM II and a powerful simulator to simulate the PK of a drug in populations with variability in data and model parameters. It was funded by the NIH for the population analysis of the compartmental models built in SAAM II. It has a user interface that is easy to use (no programming or pseudo-code is needed). It computes the Standard Two-Stage and Iterated Two-Stage approaches for population parameters with their confidence intervals. Few if any assumptions about the population are necessary prior to analysis. For example, clinical trials can be simulated to determine the effect of varying dosing regimens.

The Type 1 Diabetes Simulator (AKA, Padua-Virginia Simulator) allows the simulation of the glucose and insulin profile of a type 1 diabetic.[4] In 2008 the US Food and Drug Administration accepted the T1D simulator developed by University of Virginia and University of Padova as a substitute for preclinical trials for certain insulin treatments, including closed-loop algorithms for artificial pancreas. Cobelli and Kovatchev labs prototyped the simulator in SAAM II. A SAAM II version of the simulator is avialble for charge.

Classic pharmacokinetic studies using SAAM II are by Foster and Vicini labs, while more complex lipid dynamics studies are by Barrett lab in Australia.[5] SAAM II is currently employed for prototyping PBPK models. When complex mechanisms participate in the PK of new drugs or formulations, SAAM II can be used for rapid in vivo testing. Perazzolo and colleagues in Seattle use SAAM II jointly with experimental data to inform nanoparticle PBPK and the clinical transition of long-acting or extended-release therapies.[6][7]

SAAM II was present in several curricula in Universities in the US and around the world, especially in the early 2000. The University of Washington is still teaching SAAM II in the PK module at the School of Pharmacy. At the University of Padova, SAAM II is introduced to biomedical engineers in their graduate modeling modules.