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Objectives:
Oseltamivir phosphate is an orally available prodrug, and is metabolized to its active species, oseltamivir carboxylate. It is an inhibitor of influenza A and B neuraminidase. Ferrets are useful animal models frequently used in studying influenza. We sought to develop a simple PK model to describe the active metabolite PK in the ferret without explicitly including prodrug in the model.
Methods:
In the extensively sampled PK ferret group, animals were infected with low inoculation doses of A/SZ/406H/06 H5N1 and dosed with 5 or 12.5 mg/kg of oseltamivir free base, while uninfected ferrets were dosed at 5 mg/kg. PK samples were collected at 0, 0.5, 1, 1.5, 2, 4, 6, 8 and 12 hrs after dosing. In the sparse PK ferret groups, animals were infected with H5N1 and were dosed either at 0, 12.5, or 25.0 mg/kg twice daily for 5 days. PK samples were collected at 1, 4, 49, and 52 hours after the first dose. The candidate PK model was fitted to the data using iterative 2-stage analysis (ADAPT 5); weighting was by the inverse of the error variance; model discrimination was by Akaike's information criterion.
Results:
The final PK model had a drug administration compartment and two transit compartments (transit rate constant Kt) leading to the appearance (Ka) of active metabolite in the plasma (Vc) and the tissue (Vp) compartments. Distribution (CLd) and elimination (CLt) clearances were linear.
Kt (h-1) | Ka (h-1) | CLd (L/h) | CLt (L/h) | Vc (L) | Vp (L) | |
Mean | 1.0 | 0.52 | 0.15 | 3.0 | 0.23 | 1.8 |
CV | 0.54 | 0.53 | 0.15 | 0.63 | 0.15 | 0.17 |
The overall mean R2 was 0.84.
Conclusion:
The PK model proposed fits both rich and sparse PK data well. This simplified model can be used to perform PK/PD analysis and design optimal sampling strategies.