Evaluation of the use of accelerated infusions for the determination of pharmacokinetic linearity

Accelerated infusions are potentially useful in the investigation of pharma cokinetic linearity. However, little information exists to validate this te chnique or to demonstrate its limitations. This investigation was performed to determine whether accelerated infusion regimens reliably estimate the r ange of pharmacokinetic linearity for molecules of varying pharmacokinetic properties, to evaluate the ability of accelerated infusions to identify ph armacokinetic nonlinearity, and to validate the accelerated infusion techni que using compounds with known pharmacokinetic parameters. Simulations inco rporating accelerated infusion as the input function resulted in the antici pated concentration-time profiles that contained an initial lag phase befor e reaching a linear slope. This lag phase increased with increasing distrib utional volume and in some instances was sufficiently great to obscure or p revent the linear portion of the profile. These simulations also revealed t hat clearance estimated from the apparently linear portion of the concentra tion-time profile can be erroneous under some conditions, as for large-volu me compounds. Simulations of structured nonlinearity produced the predicted profiles for compounds with low to moderate volumes of distribution while demonstrating that modeling of data derived from compounds with large volum es of distribution may be inaccurate. Finally, experiments using accelerate d infusions with various test compounds further demonstrated the usefulness of this technique while presenting limits imposed on the interpretation of the data. The results of this investigation indicate that the accelerated infusion may be used to determine pharmacokinetic linearity for compounds w ithin certain pharmacokinetic boundaries, but that appropriate caution shou ld be exercised in the extent of interpretation that should be extracted fr om such studies.