Pharmacokinetics, biotransformation, and mass balance of edoxaban, a selective, direct factor Xa inhibitor, in humans.

This study determined the mass balance and pharmacokinetics of edoxaban in humans after oral administration of [¹4C]edoxaban. After oral administration of 60 mg (as active moiety) of [¹4C]edoxaban to six healthy male subjects, serial blood/plasma and urinary and fecal samples were collected for up to 168 h postdose. All samples were analyzed for total radioactivity by liquid scintillation counting and for concentrations of edoxaban and four metabolites in plasma, urine, and fecal samples by either high-performance liquid chromatography/tandem mass spectrometry method using multiple reaction modes, or a liquid chromatography radiometric method. The mean recovery of radioactivity was >97% of the administered radioactive dose, with 62.2% eliminated in feces and 35.4% in urine. Unchanged edoxaban accounted for the majority of radioactivity, with 49.1 and 23.8% of the dose as parent observed in feces and urine, respectively. Unchanged edoxaban was the most abundant species in plasma, with a mean area under the curve (AUC)(0-∞) of 1596 ng · h/ml. The next most abundant species was metabolite M4, with a mean AUC(0-∞) 147 ng · h/ml. The mass balance of edoxaban was well described, with unchanged edoxaban as the most abundant component of total radioactivity. Edoxaban is eliminated through multiple pathways, but each accounts for only a small amount of overall elimination.

Quantitative structure-property relationships modeling to predict in vitro and in vivo binding of drugs to the bile sequestrant, colesevelam (Welchol).

Quantitative structure-property relationship (QSPR) models were developed to correlate physicochemical properties of structurally unrelated drugs with extent of in vitro binding to colesevelam, and predicted values were compared with drug exposure changes in vivo following coadministration. The binding of 17 drugs to colesevelam was determined by an in vitro dissolution drug-binding assay. Data from several clinical studies in healthy volunteers to support administration of colesevelam in diabetic patients were also collected along with existing in vivo literature data and compared with in vitro results. Steric, electronic, and hydrophobic descriptors were calculated for test compounds, and univariate and partial least squares regression approaches were used to derive QSPR models to evaluate which of the molecular descriptors correlated best with in vitro binding. A quadrant analysis evaluated the correlation between predicted/actual in vitro binding results and the in vivo data. The in vitro binding assay exhibited high sensitivity, identifying those compounds with a low probability of producing relevant in vivo drug interactions. Drug lipophilicity was identified as the primary determinant of in vitro binding to colesevelam by the final univariate and partial least squares models (R(2) = 0.69 and 0.98; Q(2) = 0.48 and 0.59). The in vitro assay and in silico models represent predictive tools that may allow investigators to conduct only informative clinical drug interaction studies with colesevelam.

Bioavailability enhancement of a poorly water-soluble drug by solid dispersion in polyethylene glycol-polysorbate 80 mixture.

Oral bioavailability of a poorly water-soluble drug was greatly enhanced by using its solid dispersion in a surface-active carrier. The weakly basic drug (pK(a) approximately 5.5) had the highest solubility of 0.1mg/ml at pH 1.5, < 1 microg/ml aqueous solubility between pH 3.5 and 5.5 at 24+/-1 degrees C, and no detectable solubility (< 0.02 microg/ml) at pH greater than 5.5. Two solid dispersion formulations of the drug, one in Gelucire 44/14 and another one in a mixture of polyethylene glycol 3350 (PEG 3350) with polysorbate 80, were prepared by dissolving the drug in the molten carrier (65 degrees C) and filling the melt in hard gelatin capsules. From the two solid dispersion formulations, the PEG 3350-polysorbate 80 was selected for further development. The oral bioavailability of this formulation in dogs was compared with that of a capsule containing micronized drug blended with lactose and microcrystalline cellulose and a liquid solution in a mixture of PEG 400, polysorbate 80 and water. For intravenous administration, a solution in a mixture of propylene glycol, polysorbate 80 and water was used. Absolute oral bioavailability values from the capsule containing micronized drug, the capsule containing solid dispersion and the oral liquid were 1.7+/-1.0%, 35.8+/-5.2% and 59.6+/-21.4%, respectively. Thus, the solid dispersion provided a 21-fold increase in bioavailability of the drug as compared to the capsule containing micronized drug. A capsule formulation containing 25 mg of drug with a total fill weight of 600 mg was subsequently selected for further development. The selected solid dispersion formulation was physically and chemically stable under accelerated storage conditions for at least 6 months. It is hypothesized that polysorbate 80 ensures complete release of drug in a metastable finely dispersed state having a large surface area, which facilitates further solubilization by bile acids in the GI tract and the absorption into the enterocytes. Thus, the bioavailability of this poorly water-soluble drug was greatly enhanced by formulation as a solid dispersion in a surface-active carrier.

In vivo characterization of the mitochondrial selective K(ATP) opener (3R)-trans-4-((4-chlorophenyl)-N-(1H-imidazol-2-ylmethyl)dimethyl-2H-1-benzopyran-6-carbonitril monohydrochloride (BMS-191095): cardioprotective, hemodynamic, and electrophysiological effects.

Recent studies have shown the importance of mitochondrial ATP-sensitive potassium channels (K(ATP)) in cardioprotection, and studies in vitro have shown that the benzopyran analog (3R)-trans- 4-((4-chlorophenyl)-N-(1H-imidazol-2-ylmethyl)dimethyl-2H-1-benzopyran-6-carbonitril monohydrochloride (BMS-191095) is a selective mitochondrial K(ATP) opener with cardioprotective activity. The goal of this study was to show selective cardioprotection for BMS-191095 in vivo without hemodynamic or cardiac electrophysiological effects expected for nonselective K(ATP) openers. BMS-191095 reduced infarct size in anesthetized dogs (90-min ischemia + 5-h reperfusion) in a dose-dependent manner (ED(25) = 0.4 mg/kg i.v.) with efficacious plasma concentrations of 0.3 to 1.0 microM, which were consistent with potency in vitro. None of the doses of BMS-191095 tested caused any effect on peripheral or coronary hemodynamic status. Further studies in dogs showed no effects of BMS-191095 on cardiac conduction or action potential configuration within the cardioprotective dose range. In a programmed electrical stimulation model, BMS-191095 showed no proarrhythmic effects, which is consistent with its lack of effects on cardiac electrophysiological status. BMS-191095 is a potent and efficacious cardioprotectant that is devoid of hemodynamic and cardiac electrophysiological side effects of first generation K(ATP) openers, which open both sarcolemmal and mitochondrial K(ATP). Selective opening or activation of mitochondrial K(ATP) seems to be a potentially effective strategy for developing well tolerated and efficacious K(ATP) openers.