LOCAL IDENTIFIABILITY OF A RECEPTOR-BINDING RADIOPHARMACOKINETIC SYSTEM HAVING MEASURED PARAMETERS OF KNOWN UNCERTAINTY

Local identifiability was determined for a receptor-binding radiopharm acokinetic system that included measured parameters of known uncertain ty. Healthy subjects and patients with severe liver disease were studi ed with [Tc-99m] galactosylneoglycoalbumin (TcNGA). Measurements durin g the 30-min dynamic imaging study included the count rate over liver and heart, the quantity of TcNGA injected L(degrees), and the fraction -of-injected dose per liter of sampled plasma ($) over tilde. Typical relative standard deviations for these measurements were 1, 0.2, and 5 percent, respectively. A four-state nonlinear model describing the he patic and plasma time-activity data was then used to calculate the sta ndard error se(p(j)) for model parameters representing receptor concen tration [R](degrees), the TcNGA-receptor forward binding rate constant k(b), extrahepatic plasma volume V-e, hepatic plasma volume V-h, and hepatic plasma flow F. Accounting for the measurement uncertainties of L(degrees) and ($) over tilde f did not significantly increase the st andard errors for parameters [R](degrees), k(b), V-e, V-h and F. When the relative errors of L(degrees) and ($) over tilde f were increased to 40%, the change in se(p(j)) ranged from 10 to 100%, with parameter V-h being the most sensitive. The exception was se(k(b)), the increase of which was less than 1%. Imaging studies with reduced [R](degrees), typically associated with patients with liver disease, resulted in gr eater increases in all estimated pararmeter errors except se(k(b)) whi ch had a lower increase. Lastly, the error propagation introduced by d irect measurement of the liver observational coefficients sigma(12) an d sigma(13) was investigated by simulating changes in the relative sta ndard deviation in parameters sigma(12) and sigma(13) from 0 to 40%. I maging studies from healthy subjects showed no increase in se(p(j)). L ocal identifiability calculations using TcNGA imaging data from patien ts with liver disease resulted in parameter estimates of lower precisi on; standard errors increased by a factor of three when the relative s tandard deviation of sigma(12) and sigma(13) reached 40%.