Oseltamivir Population Pharmacokinetics in the Ferret: Model Application for Pharmacokinetic/Pharmacodynamic Study Design

Abstract

The ferret is a suitable small animal model for preclinical evaluation of efficacy of antiviral drugs against various influenza strains, including highly pathogenic H5N1 viruses. Rigorous pharmacokinetics/pharmacodynamics (PK/PD) assessment of ferret data has not been conducted, perhaps due to insufficient information on oseltamivir PK. Here, based on PK data from several studies on both uninfected and influenza-infected groups (i.e., with influenza A viruses of H5N1 and H3N2 subtypes and an influenza B virus) and several types of anesthesia we developed a population PK model for the active compound oseltamivir carboxylate (OC) in the ferret. The ferret OC population PK model incorporated delayed first-order input, two-compartment distribution, and first-order elimination to successfully describe OC PK. Influenza infection did not affect model parameters, but anesthesia did. The conclusion that OC PK was not influenced by influenza infection must be viewed with caution because the influenza infections in the studies included here resulted in mild clinical symptoms in terms of temperature, body weight, and activity scores. Monte Carlo simulations were used to determine that administration of a 5.08 mg/kg dose of oseltamivir phosphate to ferret every 12 h for 5 days results in the same median OC area under the plasma concentration-time curve 0-12 h (i.e., 3220 mg h/mL) as that observed in humans during steady state at the approved dose of 75 mg twice daily for 5 days. Modeling indicated that PK variability for OC in the ferret model is high, and can be affected by anesthesia. Therefore, for proper interpretation of PK/PD data, sparse PK sampling to allow the OC PK determination in individual animals is important. Another consideration in appropriate design of PK/PD studies is achieving an influenza infection with pronounced clinical symptoms and efficient virus replication, which will allow adequate evaluation of drug effects.

Fig 1. Schematic diagram of the oseltamivir PK model.

Fig 2. Flowchart of method used in model fitting.

Fig 3. Diagnostic plots for the PK model from influenza-inoculated ferret data from studies 1 and 2.

Closed squares and open circles are for animals inoculated with influenza A and influenza B, respectively. Diagnostic plots include (A) predicted versus observed, (B) weighted residuals versus predicted, and (C) weighted residuals versus time since the last dose. The dashed lines are loess curves.

Fig 4. Diagnostic plots for the PK model from uninfected ferret data from studies 1 to 3.

Diagnostic plots include (A) predicted versus observed, (B) weighted residuals versus predicted, and (C) weighted residuals versus time since the last dose. The dashed lines are loess curves.

Fig 5. Post-hoc fits in representative ferrets.

Observed and simulated OC PK in representative ferrets from studies 1 and 2: (A) rich PK in an H5N1-inoculated ferret administered a 12.5 mg/kg OP dose; (B) rich PK in an uninfected ferret administered a 5.0 mg/kg OP dose; (C) sparse PK in an H5N1-infected ferret administered 25.0 mg/kg OP q12h; (D) sparse PK in an H3N2-infected ferret administered 12.5 mg/kg OP every twelve h (q12h); (E) PK for an uninfected ferret in the PK control group administered 0.76, 3.8, and 19.0 mg/kg OP on days 1, 3, and 5, respectively; and (F) sparse PK in a ferret inoculated with influenza B/Yamagata/16/1988 influenza virus administered 3.8 mg/kg OP q12h.

Fig 6. Monte Carlo simulation of steady-state OC PK at a 5.08 mg/kg OP dose.

The thin solid curves are simulated PK for 100 individual ferrets, the open curves are the 10th–90th percentile, and the thick solid curve is the median OC concentration-time profile.