The secondary objective of the present study was to
The secondary objective of the present study was to evaluate the pharmacokinetics, safety, and tolerability of multiple oral doses of 450-mg delafloxacin to reach steady state in healthy male and female subjects. After multiple dosing of oral delafloxacin, steady state was reached after 4 days of dosing, and mean AUC0–12 increased 35% compared with the mean AUC0–12 after a single oral dose. The terminal t½ as determined in this study (~2.5 hours) would predict a shorter time to steady state. The delafloxacin t½ was determined based on data available over the first 12 hours after dosing. The limited data may account for the shorter t½ observed in this study compared with a previous study in which 48 hours of data were available to characterize delafloxacin pharmacokinetics, with delafloxacin’s terminal t½ ranging from 5.5 to 7.7 hours.
There were modest decreases in delafloxacin CL/F and Vz/F and increases in Cmax and t½ after multiple dosing. As mentioned earlier, steady state with regard to delafloxacin had been achieved after 4 days of dosing, indicating that the effect of delafloxacin on the pharmacokinetics of midazolam is deemed maximal. Other than t½, the pharmacokinetics of delafloxacin and safety in our study are consistent with those reported previously. Mean AUC0–∞, Cmax, Tmax, and CL/F values were similar whether after single or multiple doses of delafloxacin. Self-limiting, mild diarrhea was the most commonly reported treatment-emergent adverse event in ~14% of the subjects.
Delafloxacin has been shown to be effective in the treatment of serious gram-positive acute bacterial CPI-455 and skin structure infections19, 20 and is undergoing study in the treatment of patients with community-acquired bacterial pneumonia. In all of these disease states, an understanding of drug–drug interactions is critically important from the perspectives of safety, efficacy, and health economics. The number of drugs known to be substrates, inhibitors, or modifiers of CYP is considerable, and CYP3A represents 40% to 60% of all CYP isozymes. It is critically important to clinicians to have information demonstrating a lack of a clinically relevant pharmacokinetic interaction by delafloxacin on CYP3A and other CYP isozymes.
Conflicts of Interest
Introduction Cucurbitacins, a group of tetracyclic triterpenes with medicinal properties, are found in a large variety of plant families especially Cucurbitaceae (Chen et al., 2005). Cucurbitacin E (CuE, Fig. 1) has attracted much attention for its pharmacological properties, such as anti-cancer (Dong et al., 2010, Sun et al., 2010, Zhang et al., 2012), anti-inflammatory (Qiao et al., 2013), autophagic modulation (Arel-Dubeau et al., 2014), and immunomodulatory effects (Attard et al., 2005). Previous studies in our laboratory showed that CuE blocks breast cancer metastasis by suppressing tumor cell migration and invasion (Zhang et al., 2012) and inhibiting tumor angiogenesis through VEGFR2-mediated Jak2-STAT3 signaling pathway (Dong et al., 2010). Therefore, CuE is a promising antitumor candidate for drug development. In addition, CuE-containing herbal medicinal products, such as cucurbitacin tablets and cucurbitacin capsules, have been widely used for the treatment of chronic hepatitis and adjuvant therapy of primary hepatic carcinoma (China Pharmacopoeia Commission, 2015). Until now, however, few studies have been carried out on the hepatotoxicity of CuE. Human hepatocellular carcinoma HepG2 cells possess the biosynthetic characters of normal human hepatic parenchyma cells and express the main metabolic enzymes which are involved in drug metabolism and drug-drug interactions (DDI) mediated toxicity (Matuo et al., 2013). Therefore, HepG2 cells are a suitable substitution of primary cultured liver cells to assess chemical hepatotoxicity (Li et al., 2013).