The low potential for drug interactions with zanamivir.
OBJECTIVE
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.


METHODS
Potential interactions with zanamivir were examined in a series of in vitro and in vivo model systems.


METHODS
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.


RESULTS
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 mumol/L (150 mg/L) had no effect on the metabolism of the CYP probe substrates bufuralol, chlorzoxazone, coumarin, ethoxyresorufin, mephenytoin, midazolam, phenacetin and tolbutamide 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 mumol/L, phenylephrine 6 mmol/L, oxymetazoline 380 mumol/L, promethazine 35 mumol/L and co-amoxiclav (amoxicillin-clavulanic acid) 1.66 mmol/L.


CONCLUSIONS
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.
Daniel
M J
MJ
Glaxo Wellcome Research and Development, Ware, England.
Barnett
J M
JM
Pearson
B A
BA
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015153:Blotting, Western; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000276:immunology; D004285:Dogs; D004338:Drug Combinations; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006146:Guanidines; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000821:virology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D014663:Nasal Decongestants / Q000494:pharmacology*; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D009975:Orthomyxoviridae / Q000187:drug effects / Q000201:enzymology; D011714:Pyrans; D051381:Rats; D012794:Sialic Acids / Q000494:pharmacology*; D053243:Zanamivir
D000700:Analgesics; D000900:Anti-Bacterial Agents; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D006146:Guanidines; D006634:Histamine H1 Antagonists; D014663:Nasal Decongestants; D011714:Pyrans; D012794:Sialic Acids; D003577:Cytochrome P-450 Enzyme System; D009439:Neuraminidase; D053243:Zanamivir