Use of the NONMEM computer program to predict an oral cyclosporin dose when changing over from intravenous therapy

Abstract

The introduction of cyclosporin has brought about a new era in drug therapy for transplantation and other immune-related diseases. However, cyclosporin therapy has been associated with large interindividual differences in drug absorption, distribution, metabolism and elimination making it impossible to establish fixed dose regimens based on body weight. Recently, a new oral formulation called Sandimmune Neoral, also known as Neoral, was introduced showing a more consistent absorption profile, improved dose linearity and enhanced relevance of cyclosporin blood levels. This is a retrospective pilot study conducted at the Garden City Clinic on 13 de novo renal transplant patients and the aims were: ® to establish the relative bioavailability between the IV and the oral dose of cyclosporin, » to calculate population pharmacokinetic parameters from routinely taken trough levels using the NONMEM program, » to investigate the influence of factors such as weight and gender on pharmacokinetic parameters. This information could then be applied to arrive at a formula for the smooth changeover from IV to oral therapy. For the IV cyclosporin doses population mean values of total body clearance (Cl) and volume of distribution (Vd) were estimated to be 22.4 L/h and 167 L respectively, with an inter-individual variation (n) of 48% and 44% respectively. The residual error was 10%. For the oral cyclosporin, they were 52.6 L/h (q = 10%) and 339 L (q = 48%) respectively with a fixed absorption constant (ka) of 0.7 h'1. The residual error was 10%. Consequently, the relative bioavailability was estimated to be around 43%. More data is needed to confirm this result Although this study included only a small number of patients a significant correlation was found between total body clearance of cyclosporin and creatinine clearance. This should be investigated further in a more indepth study. Due to the power of NONMEM, we were able to show that it is possible to calculate pharmacokinetic parameters from only cyclosporin trough levels without the need for the extra expense and morbidity of multiple blood level monitoring. This study showed us that it is possible to arrive at a formula to calculate what oral dose is needed for the smooth changeover from IV cyclosporin therapy using NONMEM if more data is available.