title: Permeability enhancers dramatically increase zanamivir absolute bioavailability in rats: implications for an orally bioavailable influenza treatment.
abstract: We have demonstrated that simple formulations composed of the parent drug in combination with generally regarded as safe (GRAS) permeability enhancers are capable of dramatically increasing the absolute bioavailability of zanamivir. This has the advantage of not requiring modification of the drug structure to promote absorption, thus reducing the regulatory challenges involved in conversion of an inhaled to oral route of administration of an approved drug. Absolute bioavailability increases of up to 24-fold were observed when Capmul MCM L8 (composed of mono- and diglycerides of caprylic/capric acids in glycerol) was mixed with 1.5 mg of zanamivir and administered intraduodenally to rats. Rapid uptake (t(max) of 5 min) and a C(max) of over 7200 ng/mL was achieved. Variation of the drug load or amount of enhancer demonstrated a generally linear variation in absorption, indicating an ability to optimize a formulation for a desired outcome such as a targeted C(max) for enzyme saturation. No absorption enhancement was observed when the enhancer was given 2 hr prior to drug administration, indicating, in combination with the observed tmax, that absorption enhancement is temporary. This property is significant and aligns well with therapeutic applications to limit undesirable drug-drug interactions, potentially due to the presence of other poorly absorbed polar drugs. These results suggest that optimal human oral dosage forms of zanamivir should be enteric-coated gelcaps or softgels for intraduodenal release. There continues to be a strong need and market for multiple neuraminidase inhibitors for influenza treatment. Creation of orally available formulations of inhibitor drugs that are currently administered intravenously or by inhalation would provide a significant improvement in treatment of influenza. The very simple GRAS formulation components and anticipated dosage forms would require low manufacturing costs and yield enhanced convenience. These results are being utilized to design prototype dosage forms for initial human pharmacokinetic studies.
authors.affiliation: Department of Cell and Molecular Biology, John A. Burns School of Medicine, Honolulu, Hawaii, United States of America. eholmes3@hawaii.edu
authors.forename: Eric H
authors.initials: EH
authors.lastname: Holmes
authors.forename: Harikrishna
authors.initials: H
authors.lastname: Devalapally
authors.forename: Libin
authors.initials: L
authors.lastname: Li
authors.forename: Michael L
authors.initials: ML
authors.lastname: Perdue
authors.forename: Gary K
authors.initials: GK
authors.lastname: Ostrander
mesh_terms: D000042:Absorption / Q000187:drug effects; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007251:Influenza, Human / Q000188:drug therapy* / Q000473:pathology* / Q000821:virology; D008297:Male; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000473:pathology* / Q000821:virology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D053243:Zanamivir / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D004791:Enzyme Inhibitors; D009439:Neuraminidase; D053243:Zanamivir