The Low Potential for Drug Interactions with Zanamivir
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The objective of this study was to assess the potential of zanamivir, a specific inhibitor of influenza A and B virus neuraminidase, to interact with other coadministered therapies in the clinical setting.
Potential interactions with zanamivir were examined in a series of in vitro and in vivo model systems.
The expression of microsomal cytochrome P450 (CYP) isoenzymes was examined after daily treatment of rats with intravenous zanamivir. The ability of zanamivir to inhibit the metabolism of CYP probe substrates was studied in human liver microsomes. The binding of zanamivir to human and animal red blood cell fractions and plasma proteins was measured. Finally, the effect of commonly coadministered drugs on the ability of zanamivir to inhibit viral replication in vitro was tested.
Zanamivir had no effect on the expression of microsomal CYP isoenzymes after daily intravenous treatment of rats with zanamivir 1, 9 or 90 mg/kg for 5 weeks. Zanamivir at concentrations up to 500 μmol/L (150 mg/L) had no effect on the metabolism of the CYP probe substrates bufuralol, chlorzoxazone, coumarin, ethoxyresorufin, mephenytoin, midazolam, phenacetin and tolbuta-mide by human liver microsomes. The binding of zanamivir 0.05 to 10 mg/L to human, dog and rat red blood cells and plasma proteins was low. The in vitro potency of zanamivir against influenza virus in Madin Darby canine kidney cells was not adversely affected by aspirin (acetylsalicylic acid) 1.2 mmol/L, paracetamol (acetaminophen) 6.6 mmol/L, ibuprofen 243 μmol/L, phenylephrine 6 mmol/L, oxymetazoline 380 μmol/L, promethazine 35 μmol/L and co-amoxiclav (amoxicillin-clavulanic acid) 1.66 mmol/L.
These data suggest the following: (i) there is no theoretical basis for expecting metabolic interactions between zanamivir and other coadministered compounds; (ii) zanamivir is unlikely to interact with coadministered compounds that are protein bound; and (iii) commonly coadministered drugs will not interfere with the antiviral activity of zanamivir in vivo. Although none of these in vitro or in vivo studies were exhaustive, and although none were performed in humans, all the data are consistent with zanamivir having a very low potential for interactions with coadministered drugs in the clinical setting.
KeywordsAdis International Limited Zanamivir Human Liver Microsome Phenacetin Madin Darby Canine Kidney Cell
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- 2.Herriott D, Fenton DNM, Bayliss MK. The validation of Western blot analysis of rat microsomes. Ware: Glaxo Wellcome, WBP/94/043.Google Scholar
- 3.Woods JM, Bethell RC, Coates JAV, et al. 4-Guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid is a highly effective inhibitor both of the sialidase (neuraminidase) and of the growth of a wide range of influenza A and B viruses in vitro. Antimicrob Agents Chemother 1993; 37(7): 1473–9.PubMedCrossRefGoogle Scholar
- 8.American Hospital Formulary Drug Information 90. In: McEvoy GK, editor. American Society of Hospital Pharmacists. Bethesda, MD: 1990.Google Scholar
- 10.Hsyu P, Hussey BK. Renal disposition and drug screening of GR121167X (GG167) in the isolated perfused rat kidney. Research Triangle Park: Glaxo Wellcome report RM1996/ 00072/00.Google Scholar
- 11.Peng A, Hussey B. Population pharmacokinetics of zanamivir (protocols NAIA 2005 and NAIA 2006) including combined phase I and II study analysis. Research Triangle Park, NC, USA: Glaxo Wellcome, RM 1996/0060/00.Google Scholar