This phase 1 study conducted in the United States was not registered.

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.

No abstract

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 Gα_q and Gα₁₁ (referred to collectively as Gα_q/11) as well as via Gα_s. We have recently demonstrated that the heightened immune responsiveness to GnRH in lupus-prone female mice correlated with increased expression of Gα_q/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 Gα_q/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 Gα_q/11 mRNA and protein under physiologic hormonal alterations, i.e. throughout the estrous cycle in female mice. We demonstrate that expression of Gα_q/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 Gα_q/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.

IR/ER OC/APAP tablets may have less potential for abuse involving tampering compared with IR OC/APAP tablets.

This analysis evaluated the single-dose population pharmacokinetics (PK) of biphasic immediate-release (IR)/extended-release (ER) oxycodone (OC)/acetaminophen (APAP) 7.5/325 mg tablets administered under fasted conditions and the effects of a meal on their single-dose population PK. Data were pooled from four randomized, single-dose crossover trials enrolling healthy adult (18–55 years old) participants (three trials) and nondependent recreational users of prescription opioids (one trial) with a body weight of ≥59 kg. Participants received IR/ER OC/APAP 7.5/325 mg tablets in single doses of 7.5/325 mg (one tablet), 15/650 mg (two tablets), or 30/1,300 mg (four tablets) under fasted or fed conditions. Six variables were examined: sex, race, age, weight, height, and body mass index. Single-dose population PK was analyzed using first-order conditional estimation methods. A total of 151 participants were included in the analysis under fasted conditions, and 31 participants were included in the fed analysis. Under fasted conditions, a 10% change in body weight was accompanied by ~7.5% change in total body clearance (CL/F) and volume of distribution (V/F) of OC and APAP. Black participants had 17.3% lower CL/F and a 16.9% lower V/F of OC compared with white participants. Under fed conditions, the absorption rate constant of OC and APAP decreased significantly, although there was no effect on CL/F and V/F. Considering that the recommended dose for IR/ER OC/APAP 7.5/325 mg tablets is two tablets every 12 hours, adjustments of <50% are not clinically relevant. Dose adjustment may be necessary for large deviations from average body weight, but the small PK effects associated with race and consumption of a meal are not clinically relevant.

Background To detect interaction between nebivolol (N), a unique cardioselective β‐blocker shown to possess vascular endothelial nitric oxide releasing capabilities, and spironolactone by comparing pharmacokinetic (PK) parameters for spironolactone (S) and metabolites, canrenone (C) and 7α‐thiomethyl spirolactone (TMS), in healthy subjects. This potassium‐sparing diuretic (S) is used with β‐blockers to treat CHF. Previously, S showed no effect on the PK of N. Methods Thirty‐six healthy subjects were enrolled, without regard to CYP2D6 genotype, in this open‐label, randomized, one period study. Subjects received once‐daily oral S (25 mg) on Days 1–10 and oral S (25 mg) plus N (10 mg) once‐daily on Days 11–20. Blood samples were collected on Days 10 and 20 and prior to dosing on Days 8, 9, 18, and 19. Plasma concentrations of S, C and TMS were measured by LC/MS. Pharmacokinetic parameter estimates for S, C and TMS were compared by statistical analyses using 90% confidence intervals (CIs). Results All treatments were well tolerated. (see Table) Conclusion Co‐administration of N (10 mg) with S (25 mg) results in no clinically significant changes in the PK profile of S, C or TMS. Clinical Pharmacology & Therapeutics (2005) 77, P46–P46; doi: Cmax AUCT Analyte Ratio 90% CI Ratio 90% CI S1.060.95–1.190.950.90–1.02C1.041.00–1.091.051.03–1.08TMS1.191.10–1.291.141.07–1.20