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Warfarin is often used with etravirine (ETV) to prevent HIV-related thromboembolic events. As both warfarin and ETV bind to plasma proteins and are metabolized by hepatic cytochrome P450s, they are likely to interact. Hence, we evaluated the effect of ETV on the pharmacokinetics and blood clotting time of racemic warfarin in rats. EXPERIMENTAL APPROACHTwo groups of male Sprague-Dawley rats, in which the jugular vein had been cannulated, were studied. The control group (n = 10) received 1 mg·kg -1 racemic warfarin i.v., and the test group (n = 13) 1 mg·kg -1 of racemic warfarin followed by 25 mg·kg -1 ETV i.v. Serial blood samples were collected for up to 144 h and the blood clotting time (calculated as international normalized ratio [INR]) measured in blood plasma at each sample point. Plasma concentrations of R-warfarin, S-warfarin, R-7-hydroxywarfarin and S-7-hydroxywarfarin were measured by a LC/MS/MS method using a chiral lux cellulose-1 column. Pharmacokinetic parameters were analysed using non-compartmental methods. KEY RESULTSETV significantly increased, by threefold, the systemic clearance and volume of distribution of S-warfarin, but not those of R-warfarin. ETV decreased the total AUC of warfarin, but had no effect on its elimination half-life. ETV also increased the systemic clearance of both R-7-hydroxywarfarin and S-7-hydroxywarfarin but only increased the volume of distribution of R-7-hydroxywarfarin. Interestingly, the effect of warfarin on blood clotting time (INR) was significantly increased in the presence of etravirine. CONCLUSION AND IMPLICATIONSOur data suggest that etravirine may potentiate the anticoagulant effect of warfarin and this could have clinical significance. Abbreviations

Etravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that is active against NNRT-resistant HIV-1. A simple, sensitive, and specific LC-MS/MS method was developed and validated for the analysis of etravirine in rat plasma using itraconazole as the internal standard. The analytes were extracted with ethyl acetate and chromatographed on a reverse-phase XTerra MS C18 column. Elution was achieved with a mobile phase gradient varying the proportion of a 2 mM ammonium acetate aqueous solution containing 0.1% formic acid (solvent A) and a 0.1% formic acid in methanol solution (solvent B) at a flow rate of 300 μL/min. The analytes were monitored by tandem-mass spectrometry with positive electrospray ionization. The precursor/product transitions (m/z) in the positive ion mode were 435.9→163.6 and 706.7→392.6 for etravirine and the internal standard, respectively. Calibration curves were linear over the etravirine rat plasma concentration range of 1 ng/mL to 100 ng/mL. The inter- and intra-day accuracy and precision were within ±10%. The assay has been successfully used for pharmacokinetic evaluation of etravirine using the rat as an animal model.

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An extemporaneously prepared simple-syrup suspension of zonisamide was stable for at least 28 days when stored at room temperature or under refrigeration. An extemporaneously prepared methylcellulose suspension of zonisamide was stable for 28 days when stored under refrigeration and for 7 days when stored at room temperature.