POPULATION ANALYSIS OF THE NONLINEAR RED-BLOOD-CELL PARTITIONING OF DRAFLAZINE FOLLOWING VARIOUS INFUSION DURATIONS

Objective: The pharmacokinetics and non-linear red blood cell partitio ning of the nucleoside transport inhibitor draflazine were investigate d in 19 healthy male and female subjects (age range 22-55 years) after a 15-min i.v. infusion of 1 mg, immediately followed by infusions of variable rates (0.25, 0.5 and 1 mg . h(-1)) and variable duration (2-2 4 h). Methods: The parameters describing the capacity-limited specific binding of draflazine to the nucleoside transporters located on eryth rocytes were determined by NONMEM analysis. The red blood cell nucleos ide transporter occupancy of draflazine (RBC occupancy) was evaluated as a pharmacodynamic endpoint. Results: The population typical value f or the dissociation constant K-d (%CV) was 0.648 (12) ng . ml(-1) plas ma, expressing the very high affinity of draflazine for the erythrocyt es. The typical value of the specific maximal binding capacity B-max ( %CV) was 155 (2) ng . ml(-1) RBC. The interindividual variability (%CV ) was moderate for K-d (38.9%) and low for B-max (7.8%). As a conseque nce, the variability in RBC occupancy of draflazine was relatively low , allowing the justification of only one infusion scheme for all subje cts. The specific binding of draflazine to the red blood cells was a s ource of non-linearity in draflazine pharmacokinetics. Steady-state pl asma concentrations of draflazine virtually increased dose-proportiona lly and steady state was reached at about 18 h after the start of the continuous infusion. The t(1/2 beta) averaged 11.0-30.5 h and the mean CL from the plasma was 327 to 465 ml . min(-1). The disposition of dr aflazine in whole blood was different from that in plasma. The mean t( 1/2 beta) was 30.2 to 42.2 h and the blood CL averaged 17.4-35.6 ml . min(-1). Conclusion: Although the pharmacokinetics of draflazine were non-linear, the data of the present study demonstrate that draflazine might be administered as a continuous infusion over a longer time peri od (e.g., 24 h). During a 15-min i.v. infusion of 1 mg, followed by an infusion of 1 mg . h(-1), the RBC occupancy of draflazine was 96% or more. As the favored RBC occupancy should be almost complete, this dos e regimen could be justified in patients.