Comparative study of four different pharmacokinetic computer programs: Case study of a factor VIII preparation

Objective: To compare the pharmacokinetic parameters after a single dose of a monoclonally purified factor VIII concentrate in four different computer programs for pharmacokinetic analysis. Setting: Haemophilia unit of a tertiary care university hospital. Methods: Ten patients with severe haemophilia A were administered a single dose of 30-50 IU kg(-1) body weight. Blood samples were drawn at different times during the first 48 h after infusion of factor VIII. Plasma factor VIII activity was measured by standard one-stage clotting assay and experimental data were analysed using four computer programs: JANA, PKCALC, F8SD and PCNONLIN. The pharmacokinetic models of analysis employed in the study were both compartmental and non-compartmental. The parameters compared were half-lives (t(1/2)) and mean residence time (MRT), volumes of distribution (V) and clearance (CL). Values obtained for each pharmacokinetic parameter in each program for the same model were tested for differences with a multiple analysis of variance (MANOVA). Linear correlation with the equivalent parameters for each program was also performed. Results: Pharmacokinetic parameters differed depending on the computer program used to analyse the same data set. There were differences of statistical significance in t(1/2) and V for one-compartment and two-compartment models derived by some of the programs, but none with the non-compartmental one. CL, considered model independent, showed differences between the programs evaluated. Correlations for each parameter generated were in general good (P < 0.05). Conclusion: Pharmacokinetic parameters differed depending on the computer program used to analyse the same data set. The same patient data used in different computer programs will result in significantly different parameter estimations, although the non-compartmental approach is less affected by variation, and this should be taken into consideration for comparative purposes, for the development of new preparations and for the implications in patient care and therapy monitoring.