Single- and Multiple-Dose Pharmacokinetics of Gefapixant (MK-7264), a P2X3 Receptor Antagonist, in Healthy Adults.

Gefapixant (MK-7264, RO4926219, AF-219) is a first-in-class P2X3 antagonists being developed to treat refractory or unexplained chronic cough. The initial single- and multiple-dose safety, tolerability, and pharmacokinetics of gefapixant at doses ranging from 7.5 to 1800 mg were assessed in four clinical trials. Following single-dose administration of 10-450 mg, the pharmacokinetic (PK) profile of gefapixant in plasma and urine demonstrated low inter-subject variability and a dose-proportional exposure. Following administration of multiple doses twice daily, the plasma exposures were dose-proportional at doses ranging from 7.5 to 50 mg and less than dose-proportional at doses ranging from 100 to 1800 mg. The time to mean peak drug concentration ranged from 2 to 3 h post-dose, and steady state was achieved by 7 days after dosing, with an accumulation ratio of approximately 2, comparing data from day 1 to steady state. The mean apparent terminal half-life ranged from 8.2 to 9.6 h. Gefapixant was primarily excreted unmodified in urine. Gefapixant was well tolerated following single-dose administration up to 1800 mg and multiple doses up to 1800 mg twice daily; there were no serious adverse events (AEs) reported. The most common AE reported was dysgeusia. The PK profile supports a twice-daily dosing regimen.

A Randomized, Placebo-Controlled Study to Investigate the Safety, Tolerability, and Pharmacokinetics of 3 Weeks of Orally Administered Gefapixant in Healthy Younger and Older Adults.

PURPOSE: Patients with chronic cough are typically female and have a mean age of ~ 60 years. However, initial pharmacokinetic (PK) characterization of the P2X3-receptor antagonist gefapixant, developed to treat refractory or unexplained chronic cough, was performed in healthy participants who were predominantly younger adult males. The objective of this Phase 1 study was to assess the safety, tolerability, and PK of gefapixant in younger (18-55 years) and older (65-80 years) males and females. METHODS: A randomized, double-blind, placebo-controlled study was conducted. Healthy adult participants were stratified into 4 cohorts by age and sex (younger males/females and older males/females) and randomized 4:1 (younger adults) or 3:1 (older adults) to receive gefapixant 300 mg twice daily (BID) for 1 week, followed by gefapixant 600 mg BID for 2 weeks or placebo. Safety, tolerability, and PK were assessed. RESULTS: Of 36 randomized and treated participants, 28 (100%) receiving gefapixant and 6 (75%) receiving placebo reported ≥ 1 adverse event (AE). The most common treatment-related AEs in the gefapixant group were taste related. Predefined renal/urologic AEs were reported by 7 (25%) participants receiving gefapixant (all mild to moderate in severity). Gefapixant exposure was generally lower in younger males compared with younger females and older adults; however, differences may have been due to estimated glomerular filtration rate. CONCLUSION: The safety profile of gefapixant 300-600 mg BID was generally consistent with previous studies. Additional characterization of gefapixant PK as a function of age and sex using population PK modeling is warranted.

Gefapixant in two randomised dose-escalation studies in chronic cough.

BACKGROUND AND OBJECTIVES: Gefapixant has previously demonstrated efficacy in the treatment of refractory chronic cough at a high daily dose. The current investigations explore efficacy and tolerability of gefapixant, a P2X3 receptor antagonist, for the treatment of chronic cough using a dose-escalation approach. MATERIALS AND METHODS: Two randomised, double-blind, placebo-controlled, crossover, dose-escalation studies recruited participants with refractory chronic cough. Patients were assigned to receive ascending doses of gefapixant (study 1: 50-200 mg, study 2: 7.5-50 mg) or placebo for 16 days, then crossed-over after washout. The primary end-point was awake cough frequency assessed using a 24-h ambulatory cough monitor at baseline and on day 4 of each dose. Patient-reported outcomes included a cough severity visual analogue scale and the cough severity diary. RESULTS: In clinical studies, gefapixant doses ≥30 mg produced maximal improvements in cough frequency compared with placebo (p<0.05); reported cough severity measures improved at similar doses. Taste disturbance exhibited a different relationship with dose, apparently maximal at doses ≥150 mg. CONCLUSIONS: P2X3 antagonism with gefapixant demonstrates anti-tussive efficacy and improved tolerability at lower doses than previously investigated. Studies of longer duration are warranted.

Cyclic estradiol treatment modulates the orexigenic effects of ghrelin in ovariectomized rats.

Data from a wide variety of mammalian species indicate that feeding behavior can be influenced by changes in endogenous estrogens and exogenous estrogenic treatments. Ghrelin is an important physiological signal for the regulation of energy balance, and ghrelin treatment increases eating and body weight in male rodents. The following studies evaluated the hypothesis that the inhibitory effects of estradiol on feeding involve interactions with orexigenic peptides by examining the ability of estradiol to modulate the behavioral effects of ghrelin in female rats. In these experiments, adult rats were ovariectomized and assigned to an estradiol benzoate (EB) or an oil (control) group. Three weeks after ovariectomy, animals received two daily subcutaneous injections of EB or the oil vehicle. Animals then received intraperitoneal (ip) injections of ghrelin (6.0 or 12.0 nmol) or saline during the nocturnal and diurnal periods three days after the first injection of estradiol or oil. Food intake, meal size, and meal number were determined during the 2-hour period following ghrelin or saline treatments. Ghrelin significantly increased food intake during nocturnal tests in oil-treated but not estradiol-treated rats. The hyperphagic effects of ghrelin on nocturnal food intake were also accompanied by an increase in meal size, and this effect of ghrelin on meal size was attenuated in estradiol-treated females. These findings support the hypothesis that the effects of estradiol on feeding behavior involve an attenuation of orexigenic signals, possibly by modulating the effects of the peripheral ghrelin signal on hypothalamic neuropeptides involved in the control of food intake.

Estradiol and the control of food intake.

Gonadal steroids are among the many factors that influence food intake and body weight in mammals. Hormonal effects on these processes are particularly striking in female rats, which show large increases in food intake and body weight after ovariectomy. A key role of estradiol in the control of food intake and energy balance in humans is evidenced by the fact that the incidence of obesity increases greatly after menopause [American College of Obstetricians and Gynecologists. Body mass index and insulin resistance. Obstet Gynecol 2004;104:5s-10]. The actions of estradiol on neural systems that regulate eating may also account in part for sex differences in food intake and eating disorders, which occur much more frequently in young women [Sodersten P, Bergh C. Anorexia nervosa: towards a neurobiologically based therapy. Eur J Pharmacol 2003;480:67-74]. This paper presents a minireview of research examining the changes in feeding that occur during the ovarian cycle, the effects of estradiol withdrawal and replacement on food intake and body weight, and the neurobiological mechanisms by which estradiol influences feeding behavior. A model of hormone action on food intake that emerges from this research views estradiol as an indirect control of eating and meal size, producing changes in feeding behavior by modulating the central processing of both satiating and orexigenic peptides that represent direct controls of eating. Some of the shortcomings of the model and directions for future research are discussed.

Effects of estradiol on food intake and meal patterns for diets that differ in flavor and fat content.

Apart from the well known inhibitory effects of estradiol on food intake, meal size, and body weight in female rats that have been documented over the past thirty years, a more recent report presents the opposite finding; that a large dose of estradiol can increase food intake and weight gain in gonadally intact female rats presented with a palatable diet. The purpose of the present experiment was to further examine this hypothesis by evaluating the ability of estradiol to influence feeding behavior in ovariectomized rats presented with diets that differ in flavor and fat content. Female rats were given a cyclic regimen of estradiol benzoate treatment (5.0 or 20.0 microg) or the oil vehicle and were presented with the standard chow diet or a diet with a higher fat content and chocolate flavor. Food intake, meal size, and meal number were monitored three days after the first injection of estradiol or oil. Compared to the chow diet, food intake increased when animals had access to the chocolate/fat diet during the vehicle treatment condition. Both doses of estradiol significantly decreased food intake, meal size, and body weight gain when animals were presented with either the standard chow diet or the chocolate/fat diet. These findings indicate that estradiol does not stimulate the intake of a palatable diet in ovariectomized rats, and suggest that previous results showing that estradiol enhanced eating and weight gain stemmed from a disruption of the hypothalamic-pituitary-gonadal axis when intact females received a large dose of exogenous estradiol.

Oxytrex minimizes physical dependence while providing effective analgesia: a randomized controlled trial in low back pain.

UNLABELLED: Physical dependence or withdrawal is an expected effect of prolonged opioid therapy. Oxytrex (oxycodone + ultralow-dose naltrexone) is an investigational drug shown here to minimize physical dependence while providing strong analgesia with twice-daily dosing. In this 719-patient, double-blind, placebo- and active-controlled Phase III clinical trial in chronic low back pain, patients were randomized to receive placebo, oxycodone qid, or oxytrex qid or bid. Each oxytrex tablet contains 1 microg naltrexone; oxytrex bid and qid treatments provide 2 and 4 microg naltrexone/day, respectively. Following a washout, patients with pain >or=5 on a 0-10 scale were dose-escalated weekly from 10 up to 80 mg/day until reaching adequate pain relief (

Adding ultralow-dose naltrexone to oxycodone enhances and prolongs analgesia: a randomized, controlled trial of Oxytrex.

UNLABELLED: Oxytrex is a novel drug that combines oxycodone with ultralow-dose naltrexone, an opioid antagonist. Ultralow-dose opioid antagonists have been demonstrated to enhance and prolong opiate analgesia and alleviate opioid tolerance and withdrawal in rodents. This 3-week, Phase II clinical trial assessed safety and analgesic efficacy of Oxytrex in patients with moderate to severe pain from osteoarthritis. Patients with a pain score > or =5 received placebo, oxycodone 4 times a day (qid), Oxytrex qid, or Oxytrex twice a day (bid). All active treatment groups received the same total daily dose and dose escalation of oxycodone starting at 10 and ending at 40 mg/day. Importantly, the Oxytrex bid group received a lower daily dose of naltrexone than Oxytrex qid (0.002 vs 0.004 mg/day). Oxytrex bid produced a 39% reduction in pain intensity, which was significantly greater than that of placebo (P < .001), oxycodone qid (P = .006), and Oxytrex qid (P = .003). Oxytrex bid was also superior to placebo in quality of analgesia (P = .002), duration of pain control each day (P = .05), patients' global assessments (P = .04), and the Western Ontario and MacMaster Universities Osteoarthritis Index total score (P = .03). The incidence of side effects was comparable between active treatments. In this Phase II dose-ranging study, Oxytrex bid demonstrated greater pain relief with a more convenient dosing schedule compared to oxycodone qid. PERSPECTIVE: Preclinical data have shown ultralow-dose opioid antagonists to enhance and prolong opioid analgesia while reducing analgesic tolerance and physical dependence. Recent molecular pharmacology data show a mechanism of action to be the prevention of aberrant G protein coupling by opioid receptors that underlies opioid tolerance and dependence.

Devazepide fails to reverse the inhibitory effect of interleukin-1beta on food intake in female rats.

Proinflammatory cytokines released during the course of infection elicit numerous behavioral and metabolic changes. The decrease in food intake that accompanies infection is mediated in part by interleukin-1 (IL-1). Cholecystokinin (CCK) is a neuropeptide released during a meal, decreases food intake, and previous research suggests that CCK mediates the anorectic action of IL-1. The effects of estrogen on food intake are also thought to involve CCK, as the satiety action of CCK is increased by estradiol in both intact and ovariectomized rats. Estradiol also modulates many of the behavioral and physiological effects of IL-1. The present experiment examined the ability of the CCK(A) receptor antagonist devazepide to block the effects of IL-1 and estradiol on food intake in female rats. Adult animals were ovariectomized and given two daily subcutaneous injections of estradiol benzoate (EB; 5.0 microg) or the oil vehicle 3 weeks after surgery. Three days after treatment onset, animals were pretreated with devazepide or its vehicle 30 min prior to intraperitoneal injections of IL-1beta (4.0 microg/kg) or saline given 1 h before light offset. Food and water intake was measured following 2 h of spontaneous feeding. The results indicate that devazepide failed to reverse the anorectic action of IL-1beta, although the effects of estradiol on food intake were blocked by devazepide. These data do not support a role for CCK in IL-1-induced anorexia, and suggest that cytokines may act directly on neural systems involved in the control of food intake.

Cyclic estradiol treatment enhances the effects of interleukin-1beta on food intake in female rats.

Proinflammatory cytokines elicit behavioral and physiological responses that include decreased food intake, fever, and a general disinterest in usual activities. Ovarian hormones modulate immune system activity and responsiveness to cytokines in female mammals, suggesting that sex differences in immune function may be influenced by gonadal steroids. In this experiment, female adult rats were ovariectomized and given two daily subcutaneous injections of 5.0 or 20.0 microg of estradiol benzoate or the oil vehicle 3 weeks after surgery. Following 2 days of hormone treatment, animals received ip injections of interleukin-1beta (IL-1beta) or saline 1 h before light offset. Food and water intake was measured 2 h after light offset. The results indicate that a cyclic pattern of estradiol treatment enhances the anorectic effect of IL-1beta and suggest that responses to immune system activation are influenced by estradiol.