An open-label crossover study to evaluate potential pharmacokinetic interactions between oral oseltamivir and intravenous zanamivir in healthy Thai adults

Abstract

There is no parenteral formulation of the neuraminidase inhibitor oseltamivir, the most widely used anti-influenza virus drug. Oseltamivir resistance is an increasing problem. Zanamivir is effective against the most prevalent oseltamivir-resistant influenza viruses. A parenteral formulation of zanamivir is in development for the treatment of severe influenza. It is not known if there is any pharmacokinetic interaction between the two drugs. Sixteen healthy Thai adult volunteers were studied in an open-label, four-period, randomized two-sequence crossover pharmacokinetic study in which zanamivir was given by constant-rate infusion or slow intravenous injection either alone or together with oral oseltamivir. Plasma concentration profiles of oseltamivir, the active metabolite oseltamivir carboxylate, and zanamivir were measured by liquid chromatography-mass spectrometry-mass spectrometry. Both drugs were well tolerated alone and in combination. The maximum plasma concentrations and the areas under the plasma concentration-time curves (AUC) of oseltamivir and oseltamivir carboxylate were not significantly different when oseltamivir was given separately or together with zanamivir. Maximum plasma concentrations of zanamivir were 10% (95% confidence interval, 7 to 12%) higher when zanamivir was infused concurrently with oral oseltamivir than with infusions before or after oral oseltamivir. The plasma zanamivir total AUC was positively correlated with the total oseltamivir carboxylate AUC (Pearson's correlation coefficient [r(P)] = 0.720, P = 0.002, n = 16) but not with the oseltamivir AUC (r(p) = 0.121, n = 16). There is no clinically significant pharmacokinetic interaction between oseltamivir and zanamivir.

Fig. 1.

Plasma concentrations of oseltamivir (OS) after three oral regimens: B, oseltamivir administered alone; C, oseltamivir administered with zanamivir as an i.v. infusion during 72 h; D, oseltamivir administered with a 30-min rapid zanamivir i.v. infusion.

Fig. 2.

Plasma concentrations of oseltamivir carboxylate (OC) after three oral regimens: B, oseltamivir administered alone; C, oseltamivir administered with zanamivir as an i.v. infusion during 72 h; D, oseltamivir administered with a 30-min rapid zanamivir i.v. infusion.

Fig. 3.

Plasma zanamivir concentrations after three dosage regimens: A, zanamivir administered alone as a slow (800 mg during 16 h) i.v. infusion; C, i.v. infusion of 3,600 mg during 72 h administered concurrently with oral oseltamivir; D, 30-min rapid i.v. infusion of zanamivir (600 mg) administered with oral oseltamivir.

Fig. 4.

Comparison of predicted plasma zanamivir concentrations from one-compartment (light gray circles) and two-compartment (dark gray circles) models. (A) Results for regimen A, i.e., 16-h i.v. zanamivir infusion (800 mg) administered alone; (B) results for regimen D, i.e., 0.5-h i.v. infusion (600 mg) administered with oral oseltamivir.

Fig. 5.

Correlation between plasma AUC values for zanamivir and oseltamivir carboxylate in regimen D, i.e., 0.5-h i.v. zanamivir (600 mg) infusion administered concurrently with oral oseltamivir.