ACCURACY OF NUMERICAL INVERSION OF LAPLACE TRANSFORMS FOR PHARMACOKINETIC PARAMETER-ESTIMATION

Numerical inversion of the Laplace transform is a useful technique for pharmacokinetic modeling and parameter estimation when the model equations can be solved in the Laplace domain but the solutions cannot be inverted back to the time domain. The accuracy of numerical inversion of the Laplace transform using an infinite series approximation due to Hosono was systematically studied by reference to 17 widely differing functions having known inverse transforms. The error of inversion was found to be very sensitive to the details of the computer implementation of the method; for example, double-precision arithmetic is essential. The method used to sum the series in the least-squares program MULTI(FILT) was often unable to achieve a relative error of less than 10(-4), and a Monte Carlo simulation showed that this method is insufficiently accurate for reliable least-squares parameter estimation. Improvements to the algorithm are described whereby a better method of applying Euler's transformation is used and the number of terms summed is determined automatically by the rate of convergence of the series. The improved algorithm is more efficient in inverting easy functions and more reliable in inverting difficult functions, especially those involving a time lag. With its use, pharmacokinetic parameter estimation can be performed with essentially the same accuracy as when the function is defined in the time domain.