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.

Baloxavir treatment of ferrets infected with influenza A(H1N1)pdm09 virus reduces onward transmission

“…(8h interval) for up to five days to non-sedated ferrets by providing it orally dropwise into the mouth of the ferret using a pipette (total dose 10 mg/kg/day). The OST dose was based on a previous pharmacokinetic analysis that showed a 5 mg/kg dose of oseltamivir every 12 hours for 5 days results in the PLOS PATHOGENS same median area under the plasma concentration-time curve drug concentration as observed in humans following the approved dose of 75 mg twice daily for 5 days [14].…”

“…Ferrets are considered the gold standard animal model for evaluating influenza infection and transmission as they are susceptible to human influenza strains, shed virus in the nasal cavity with similar kinetics to that seen in humans, show similar clinical signs to humans, and can readily transmit the virus to exposed contacts [12,13]. A detailed pharmacokinetic (PK) analysis of OST in ferrets has been previously completed and a dose established that aligns to the typical PK profile of OST observed in humans following standard dosing [14]. However this has not previously been completed for BXM/BXA in ferrets.…”

A comparison of RSV and influenza in vitro kinetic parameters reveals differences in infecting time

“…While more complex, some attempts have been made to extend these models to reflect in vivo infections through the inclusion of an immune response [ 27 – 29 ] or consideration of associated symptoms [ 25 , 30 ]. In addition, mathematical models can be used to describe the pharmacodynamic effects of new compounds in a strict quantitative manner [ 31 , 32 ]. Thus, the combination of viral kinetics and pharmacodynamic models can help us assess the influence of different mechanisms of actions [ 26 , 33 ], or the effect of combination therapies [ 34 ].…”

Utilising animal models to evaluate oseltamivir efficacy against influenza A and B viruses with reduced in vitro susceptibility

“…An outline for the experimental model used in this study is illustrated in S1 Fig. Ferrets were dosed orally with 5 mg/kg dose of oseltamivir phosphate (kindly provided by F. Hoffmann-La Roche AG, Basel, Switzerland) twice a day, which is considered equivalent to the standard treatment human adult dose of 75 mg/kg delivered twice daily [49]. Oseltamivir phosphate solution was prepared at a concentration of 10 mg/mL in a sterile 0.5% sugar/phosphate buffered saline (PBS) solution, while a placebo solution was prepared containing only sterile 0.5% sugar/PBS solution.…”