Zanamivir Pharmacokinetics and Pulmonary Penetration into Epithelial Lining Fluid following Intravenous or Oral Inhaled Administration to Healthy Adult Subjects

Abstract

Zanamivir serum and pulmonary pharmacokinetics were characterized following intravenous (i.v.) or oral inhaled administration. I.v. zanamivir was given as intermittent doses of 100 mg, 200 mg, and 600 mg every 12 h (q12h) for two doses or as a continuous infusion (6-mg loading dose followed by 3 mg/h for 12 h). Oral inhaled zanamivir (two 5-mg inhalations q12h for two doses) was evaluated as well. Each zanamivir regimen was administered to six healthy subjects with serial pharmacokinetic sampling. In addition, a single bronchoalveolar lavage (BAL) fluid sample was collected at various time points and used to calculate epithelial lining fluid (ELF) drug concentrations for each subject. For intermittent i.v. administration of 100 mg, 200 mg, and 600 mg zanamivir, the median zanamivir concentrations in ELF collected 12 h after dosing were 74, 146, and 419 ng/ml, respectively, each higher than the historic mean 50% inhibitory concentrations for the neuraminidases of wild-type strains of influenza A and B viruses. Median ELF/serum zanamivir concentration ratios ranged from 55 to 79% for intermittent i.v. administration (when sampled 12 h after the last dose) and 43 to 45% for continuous infusion (when sampled 6 to 12 h after the start of the infusion). For oral inhaled zanamivir, the median zanamivir concentrations in ELF were 891 ng/ml for the first BAL fluid collection and 326 ng/ml for subsequent BAL fluid collections (when sampled 12 h after the last dose); corresponding serum drug concentrations were undetectable. This study demonstrates zanamivir's penetration into the human pulmonary compartment and supports the doses selected for the continuing development of i.v. zanamivir in clinical studies of influenza.

Intrapulmonary Distribution and Pharmacokinetics of Laninamivir, a Neuraminidase Inhibitor, after a Single Inhaled Administration of Its Prodrug, Laninamivir Octanoate, in Healthy Volunteers

“…Similarly, the concentration of zanamivir in ELF following i.v. and twice-daily oral inhalation was evaluated, and it was found that the zanamivir concentration in ELF also achieved remarkably higher values than the IC 50 s for influenza virus neuraminidases of various influenza virus subtypes, including the subtype A/H1N1, A/H3N2, and B neuraminidases (19). These data support the doses used in a phase III study to evaluate the efficacy and safety of i.v.…”

“…In this study, the distribution of LO and laninamivir in the lung was explored by comparison of the concentrations in the first BAL fluid and those in the remaining aliquots recovered, as performed in a study of zanamivir (19). The C max and AUC last of LO in ELF from BAL1 were 14-and 8.2-fold higher, respectively, than those for BAL2 (Table 2).…”

“…administration was evaluated to demonstrate drug distribution from the systemic circulation to the pulmonary compartment to support the i.v. dose regimens used in clinical studies (19). The distribution of zanamivir after multiple oral inhaled administrations was also evaluated by analyzing the concentration of zanamivir in both the first BAL fluid and subsequent BAL fluid aliquots, since the contents of BAL fluid may vary according to the segment of the washed lung.…”

Impact of Mutations at Residue I223 of the Neuraminidase Protein on the Resistance Profile, Replication Level, and Virulence of the 2009 Pandemic Influenza Virus

“…In that regard, following oral administration with the standard 75 mg twice-daily treatment, the average minimum plasma concentration of oseltamivir carboxylate is approximately 330 nM, which is significantly higher than the 50% inhibitory concentration for viral NA (10). Furthermore, a trial by Shelton et al (30) reported median pulmonary zanamivir concentrations of 326 ng/ml in healthy adults treated with the regular 10-mg inhaled dose. Altogether, these clinical data suggest that only important increases in IC 50 s (at least 100-fold or higher) would be associated with resistance to NAIs in the clinical setting.…”

Penetration of GSK1322322 into Epithelial Lining Fluid and Alveolar Macrophages as Determined by Bronchoalveolar Lavage

“…Standardized bronchoscopy and BAL procedures have been previously described (13). In brief, subjects received the following medications prior to the bronchoscopy procedure: nebulized 0.5 mg atropine with 4% lidocaine, 1 to 2 mg of midazolam, and 25 to 75 g of fentanyl.…”