BackgroundXARTEMIS™ XR (formerly MNK-795) is a combination oxycodone (OC) and acetaminophen (APAP) analgesic with both immediate-release and extended-release (ER) components (ER OC/APAP). The tablets are designed with gastric-retentive ER oral delivery technology that releases the ER component at a controlled rate in the upper gastrointestinal tract. Because consumption of food has demonstrated an impact on the pharmacokinetics (PK) of some marketed products using gastric-retentive ER oral delivery technology, a characterization of the effects of fed (high- and low-fat diets) versus fasted conditions on the PK of ER OC/APAP was performed.MethodsThis Phase I study used an open-label randomized single-dose three-period six-sequence crossover single-center design. Healthy adult participants (n=48) were randomized to receive two tablets of ER OC/APAP under three conditions: following a high-fat meal; following a low-fat meal; and fasted. Plasma concentration versus time data from predose throughout designated times up to 48 hours postdose was used to estimate the PK parameters of oxycodone and APAP.ResultsThirty-one participants completed all three treatment periods. Both oxycodone and APAP were rapidly absorbed under fasted conditions. Total oxycodone and APAP exposures (area under the plasma drug concentration-time curve [AUC]) from ER OC/APAP were not significantly affected by food, and minimal changes to maximum observed plasma concentration for oxycodone and APAP were also noted. However, food marginally delayed the time to maximum observed plasma concentration of oxycodone and APAP. There was no indication that tolerability was affected by food.ConclusionThe findings from this study suggest that ER OC/APAP can be administered with or without food.
Immediate-release/extended-release oxycodone/acetaminophen produced lower oxycodone C and longer t than immediate-release oxycodone/acetaminophen. Lower oxycodone concentrations, particularly at earlier time points, were strongly correlated with lesser positive subjective drug effects.
Androgens and estrogens exert potent divergent feedback effects on gonadotropin-releasing hormone (GnRH) production at the level of the hypothalamus and GnRH action at the level of the pituitary. Androgens exert generally suppressive effects on GnRH production and action, whereas rising levels of estradiol increase both GnRH release and action. In addition to its known endocrine actions, GnRH possesses immunomodulatory effects. We have previously demonstrated gender differences in immune responsiveness to GnRH that parallel gender differences in endocrine responsiveness: females appear to be more immunologically responsive to GnRH than males. GnRH exerts its actions via the stimulatory G protein Gαq and Gα11 (referred to collectively as Gαq/11) as well as via Gαs. We have recently demonstrated that the heightened immune responsiveness to GnRH in lupus-prone female mice correlated with increased expression of Gαq/11 in lymphoid cells from females compared to males. We hypothesize that the hormonal milieu of females may contribute to increased expression of stimulatory G proteins and to the heightened immune and endocrine responsiveness to GnRH. In this report, we document gender differences in expression of Gαq/11 protein in lymphoid organs in non-autoimmune DBA/2 mice. In an effort to address the mechanisms for the gender differences in G-protein expression, we used competitive reverse transcription PCR to quantitate mRNA for stimulatory G proteins in immune cells under various hormonal conditions. We quantitated the expression of Gαq/11 mRNA and protein under physiologic hormonal alterations, i.e. throughout the estrous cycle in female mice. We demonstrate that expression of Gαq/11 mRNA and protein in lymphoid organs is significantly increased on the afternoon of proestrus compared to metestrus. Additional studies demonstrate that exposure to GnRH or to estrogens significantly increases the expression of Gαq/11 mRNA in immune cells. These findings support an active role for hormonal modulation of G proteins in the gender differences in endocrinologic and immunologic responsiveness to GnRH.
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