Time- and dose-dependent digoxin redistribution by digoxin-specific antigen binding fragments in a rat model

To study the influence of the interval between digoxin intake and digoxin-specific antigen binding fragment (DSFab) administration, we developed a rat kinetic model. 3H-digoxin (0.77 nmol/kg) was injected by intravenous route and DSFab was injected at different times (12, 30 or 60 min) corresponding to different levels of 3H-digoxin distribution (50, 83 and 100%). The effect of increasing the molar DSFab/3H-digoxin ratio from 1 to 5 was also investigated. To evaluate DSFab effect on the 3H-digoxin pharmacokinetics, we also investigated the pharmacokinetics of the 125I-DSFab and DSFab-3H-digoxin complex. 3H-digoxin and DSFab-3H-digoxin complex pharmacokinetics showed that DSFab altered immunoreactive 3H-digoxin pharmacokinetics. In redistribution studies performed 12, 30 or 60 min after 3H-digoxin injection, DSFab bound immunoreactive 3H-digoxin including native 3H-digoxin and active metabolites of 3H-digoxin. This binding induced a redistribution process of immunoreactive 3H-digoxin in the DSFab distribution compartment and was evaluated by the redistribution fraction (F(R)). F(R) was 23% lower at 60 min than at 12 and 30 min, and by increasing the DSFab/3H-digoxin ratio from 1 to 5, F(R) increased by 60%. In conclusion, the longer the time interval between digoxin intake and DSFab administration, the lower the efficacy of the redistribution process. This effect could be reduced by increasing the DSFab dose.