Oseltamivir Distributes to Influenza Virus Replication Sites in the Middle Ear and Sinuses

Oseltamivir Distributes to Influenza Virus Replication Sites in the Middle Ear and Sinuses

Medscape,

Michael Kurowski, Charles Oo, Hugh Wiltshire, Joanne Barrett

Clin Drug Invest. 2004;24(1)

Oseltamivir is the ethyl ester prodrug of oseltamivir carboxylate, a potent (concentration that produces 95% inhibition [IC95] 1-40 µg/L) and selective inhibitor of influenza A and influenza B virus neuraminidase.[1]Oseltamivir is indicated for the treatment and prophylaxis of influenza A and influenza B virus infection in adolescents and adults, and for the treatment of children aged ≥1 year.

Influenza virus replicates throughout the upper and lower respiratory tracts[2,3]and has been implicated in the development of complications, including otitis media (OM).[2]A recent population-based study reported that 9.5% of patients with influenza-like illness experience clinical complications, including pneumonia and OM.[4]These contribute to the economic burden associated with influenza epidemics, and raise the frequency of doctor-attended illness, antibiotic use and hospitalisation.[4-7]

Concentrations of influenza virus in the middle ear of infected patients are much higher than can be explained by passive diffusion,[8]and it has been shown that the virus can replicate in human middle ear cellsin vitro.[9]Thus, to prevent the development of secondary complications, it is important that anti-influenza agents reach extrapulmonary sites at concentrations high enough to inhibit influenza viral replication. Previous animal studies have indicated that the middle ear is penetrated by oseltamivir carboxylate at such concentrations.[10-14]

This study investigated the distribution of oseltamivir carboxylate in the middle-ear and sinus fluid of patients undergoing surgical drainage for serous OM or chronic maxillary sinusitis, following single- or multiple-dose oral administration of oseltamivir.

his was a single-centre parallel-group study conducted at the Institute of Oto-Rhino-Laryngology, University of Poznan, Poznan, Poland. The study was conducted in accordance with the principles of the amended Declaration of Helsinki and the guidelines for Good Clinical Practice. Written informed consent was obtained from each patient before enrolment.

Twenty-seven subjects undergoing surgical drainage for chronic serous OM (n = 13) or chronic maxillary sinusitis (n = 14) received either a single dose of oseltamivir 75mg before the surgical procedure (n = 8) or oseltamivir 75mg twice daily starting 2 days prior to surgery (n = 19). The last dose (dose 5) preceded surgery, which was carried out on day 3. To ensure compliance, all study drugs were administered with water under qualified surveillance at the study centre and a mouth check was done to ensure that the drug had been taken.

In the single-dose group, a blood sample (3mL) was taken before dosing on day 1. Additional single blood and fluid samples (from sinus or middle ear) were taken during the elective surgery 2-6h after dosing.

For the multiple-dose group, serial blood samples were collected for the determination of oseltamivir carboxylate concentrations immediately before dosing (15-20 min) and 1, 2, 4, 6 and 12h after the third dose on day 2; serial samples could not be taken following the fifth dose (surgery) as this would have compromised the patient's welfare and pharmacokinetic sampling. A single trough blood sample was taken before the dosing and additional single blood and fluid samples (from sinus or middle ear) were collected during the elective surgery 2-6 hours after dose 5 on day 3. Fluid sample volumes were determined by collection with a Hamilton syringe and blank plasma was added up to a total volume of 200µL. Careful examination of samples confirmed that they were not contaminated with blood. Plasma and fluid specimens were stored at -70°C until analysed.

Concentrations of oseltamivir carboxylate were measured in all samples by liquid chromatography (LC)-tandem mass spectrometry (MS) following solid-phase extraction using deuterated analogues of both compounds.[15]The limit of quantification for oseltamivir carboxylate was 10 µg/L. To ensure quality control, a series of spiked plasma samples containing 10, 50, 100, 250 and 1000ng of oseltamivir carboxylate were analysed before the study samples. The accuracy and precision of the assay were 96% and ±3.8%, respectively.

Eight subjects (four with OM and four with sinusitis) treated with single doses and 16 subjects (eight with OM and eight with sinusitis) treated with multiple doses of oseltamivir completed the study. Three patients did not complete the study for the following reasons: failed to appear at day 1; failed to appear at follow-up; and sinusoidal fluid sampling failed. The demographics of all subjects are shown inTable I.

Middle-ear and sinus fluid concentrations of oseltamivir carboxylate exceeded the IC95required for both influenza A and influenza B virus neuraminidase inhibition (1-40 µg/L) following single dosing (figure 1).

Figure 1: Individual concentrations of oseltamivir carboxylate in plasma, middle ear and sinuses following a single dose of oseltamivir 75mg. Plasma samples were taken at the same time as the surgical samples

In the multiple-dose group, mean trough plasma concentrations of oseltamivir carboxylate before dose 3 (132 µg/L) and dose 4 (124 µg/L) were 92% of the mean plasma concentrations before the fifth dose (139 µg/L), demonstrating that steady-state plasma exposure was achieved within 2 days of starting therapy. The concentrations of oseltamivir carboxylate in middle-ear and sinus fluid were generally higher than plasma concentrations following both single and multiple doses (Table II), with concentrations following multiple dosing being significantly different (p < 0.05).

During multiple dosing, oseltamivir carboxylate concentrations in the middle ear and sinus fluid were also above the IC95for neuraminidase inhibition (figure 2).

Figure 2: Concentration-time curves for oseltamivir carboxylate. Individual concentrations of oseltamivir carboxylate in the middle ear and sinuses following the fifth dose of oseltamivir 75mg twice daily were compared with mean plasma concentrations observed after the third dose.

This study demonstrated that adequate concentrations of oseltamivir carboxylate were rapidly achieved in the middle ear and sinus fluid following the first dose of the prodrug oseltamivir. Previous pharmacokinetic studies have demonstrated that oseltamivir carboxylate is detectable in plasma within 30 min and reaches maximal concentrations after 3-4h.[12]Concentrations of oseltamivir carboxylate in the middle-ear and sinus fluids were two to three times higher than plasma concentrations. The reason for this is unclear; it is possible that it may involve an active transport process similar to renal tubular secretion.[12]Our study also confirmed that steady-state plasma concentrations are achieved within 2 days of starting twice-daily administration. Middle-ear and sinus fluid concentrations of oseltamivir carboxylate exceeded the IC95for influenza A and influenza B virus neuraminidase (1-40 µg/L) after single and multiple dosing.

The distribution of oseltamivir carboxylate in the upper respiratory tract is supported by data previously obtained from studies performed in animal models.[11,13]Quantitative whole body autoradio-graphy showed that ferrets given oseltamivir twice daily had similar exposure to oseltamivir carboxylate compared with humans receiving a 75mg twice-daily regimen.[13]Oseltamivir carboxylate penetrated the trachea lining, nasal mucosa and middle ear at concentrations shown to provide antiviral efficacy. In a number of double-blind, randomised, multicentre clinical trials in adults,[7,16,17]oseltamivir treatment not only reduced the duration of influenza illness but also reduced the risk of secondary complications compared with placebo. Furthermore, in a study of young children, oseltamivir treatment reduced the incidence of OM by 44% (p < 0.05), with reductions in frequency of ≤60% in children <5 years of age.[17,18]The distribution of oseltamivir carboxylate to extravascular sites, as demonstrated in the present study, should inhibit viral replication and reduce the incidence of extrapulmonary complications associated with influenza.

One limitation of the present study was that the patients did not have influenza. Acute systemic infection may influence drug distribution by lowering the pH in various compartments and by altering drug pharmacokinetics.[19-22]The effect of such changes on the distribution of oseltamivir carboxylate is unknown. Patients in the current study had chronic local infections, which would not be expected to alter pharmacokinetics on a systemic level. While these infections could alter pharmacokinetics in the middle ear and sinuses, it is clear that sufficient antiviral levels of oseltamivir carboxylate were still able to reach these compartments under such circumstances.

In conclusion, we have shown that the active metabolite of oseltamivir reaches the middle-ear and sinus fluids rapidly and at concentrations required for anti-influenza activity. These data suggest that the observed reductions in complications may be due to specific inhibition of influenza virus replication at these sites.

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