Bioequivalence of Elagolix/Estradiol/Norethindrone Acetate Fixed-Dose Combination Product: Phase 1 Results in Healthy Pre- and Postmenopausal Women.

Fixed-dose combination (FDC) therapies can enhance patient convenience and adherence to prescribed treatment regimens. Elagolix is a novel oral gonadotropin-releasing hormone receptor antagonist approved for management of moderate to severe pain associated with endometriosis and heavy menstrual bleeding associated with uterine fibroids. Hormonal add-back therapy can attenuate the reversible hypoestrogenic effects of elagolix. An FDC formulation containing elagolix/estradiol (E2)/norethindrone acetate (NETA) 300/1/0.5 mg as the morning dose and an elagolix 300 mg capsule as the evening dose, were evaluated in 2 bioequivalence studies including the effects of food. Study 1 in premenopausal women assessed the bioavailability of the elagolix 300-mg capsule relative to the commercially available elagolix 300-mg tablet. Study 2 in postmenopausal women, elagolix/E2/NETA (300 mg/1 mg/0.5 mg) FDC capsule was assessed relative to the elagolix 300-mg tablet coadministered with E2/NETA 1-mg/0.5-mg tablet, the regimen that was studied in Phase 3 uterine fibroid studies. Under fasting conditions, the test elagolix 300-mg capsule was bioequivalent to the reference elagolix 300-mg tablet. Under fasting conditions, the elagolix/E2/NETA FDC capsule was bioequivalent to the coadministered elagolix 300-mg tablet and E2/NETA 1/0.5-mg tablet. Following administration of elagolix/E2/NETA FDC capsule after a high-fat breakfast, elagolix mean maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) were 38% and 28% lower, relative to fasting conditions. NETA mean Cmax was 51% lower and AUC from time 0 to infinity was 20% higher, while baseline-adjusted total estrone mean Cmax and AUC were 46% and 14% lower, respectively. No safety concerns were identified. These results enabled bridging the elagolix/E2/NETA FDC capsule.

Interdisciplinary model-informed drug development for extending duration of elagolix treatment in patients with uterine fibroids.

AIM: Elagolix, a gonadotropin-releasing hormone receptor antagonist, was recently approved for heavy menstrual bleeding associated with uterine fibroids (UF, Oriahnn) at a dose of 300 mg twice daily (BID) in combination with add-back therapy (oestradiol 1 mg/norethindrone acetate 0.5 mg [E2/NETA] once daily) for 24 months use. The limited duration of treatment is related to elagolix dose- and duration-dependent decrease in oestrogen that is mechanistically linked to changes in bone mineral density (BMD). The work herein supported the extended treatment duration of 24 months. METHODS: An integrated exposure-response and epidemiological modelling framework of elagolix effects on femoral neck BMD (FN-BMD), informed by real-world data and phase 3 clinical trials data, was developed to predict the time course and magnitude of changes in BMD and its relation to risk of bone fracture in women with UF. RESULTS: Model results indicated that women treated with elagolix 300 mg BID + E2/NETA in the long term (ie, >24 months) may experience less than 1% loss in FN-BMD per year, relative to placebo. The exposure-response model simulations and clinical risk factors were used to estimate 10-year risk of fractures using the clinically validated Fracture Risk Assessment Tool (FRAX). The impact of elagolix 300 mg BID + E2/NETA treatment on the 10-year risk of hip or major osteoporotic fractures estimated from the FRAX model was minimal compared to that of placebo. CONCLUSION: The elagolix integrated exposure-BMD analysis and translation to fracture risk provided an interdisciplinary model-informed drug development framework for clinical benefit-risk evaluation and enabled approval of longer treatment duration to benefit the patient.

Multi-organ system failure secondary to difluoroethane toxicity in a patient "huffing" air duster: a case report.

Inhalant misuse is a growing concern among Americans. According to recent reports by the National Institutes of Health and the Substance Abuse and Mental Health Services Administration, the prevalence of teenage inhalant misuse is increasing. Of the many household items that are "huffed", refrigerant-based propellant cleaners or air dusters, are one of the most misused. Although commonly referred to as "compressed air", refrigerant-based propellant cleaners contain harmful fluorinated hydrocarbons, such as 1,1-difluoroethane, that have significant toxic effects when inhaled. While the central nervous system is primarily affected, there are case reports of cardiovascular, renal, hepatic, and musculoskeletal injury secondary to 1,1-difluoroethane toxicity. However, there are few cases that have presented 1,1-difluoroethane toxicity leading to multi-organ system failure in adults with a long history of inhalant misuse. We present a unique case of multi-system organ failure secondary to 1,1-difluoroethane toxicity in a middle-aged female that was "huffing" a refrigerant-based propellant aerosol duster for more than three months. This case stresses the importance of obtaining a detailed social history to identify inhalant misuse in patients that present with acute illness of unknown etiology. This case also highlights the importance of early communication with toxicology professionals for treatment and supportive care recommendations in patients presenting the life-threatening 1,1-difluoroethane toxicity. Furthermore, this case demonstrates that 1,1-difluoroethane toxicity in the setting of "huffing" air duster has the potential to cause multi-organ system failure.

Per- and poly-fluoroalkyl substances (PFAS) and female reproductive outcomes: PFAS elimination, endocrine-mediated effects, and disease.

Per- and poly-fluoroalkyl substances (PFAS) are widespread environmental contaminants frequently detected in drinking water supplies worldwide that have been linked to a variety of adverse reproductive health outcomes in women. Compared to men, reproductive health effects in women are generally understudied while global trends in female reproduction rates are declining. Many factors may contribute to the observed decline in female reproduction, one of which is environmental contaminant exposure. PFAS have been used in home, food storage, personal care and industrial products for decades. Despite the phase-out of some legacy PFAS due to their environmental persistence and adverse health effects, alternative, short-chain and legacy PFAS mixtures will continue to pollute water and air and adversely influence women's health. Studies have shown that both long- and short-chain PFAS disrupt normal reproductive function in women through altering hormone secretion, menstrual cyclicity, and fertility. Here, we summarize the role of a variety of PFAS and PFAS mixtures in female reproductive tract dysfunction and disease. Since these chemicals may affect reproductive tissues directly or indirectly through endocrine disruption, the role of PFAS in breast, thyroid, and hypothalamic-pituitary-gonadal axis function are also discussed as the interplay between these tissues may be critical in understanding the long-term reproductive health effects of PFAS in women. A major research gap is the need for mechanism of action data - the targets for PFAS in the female reproductive and endocrine systems are not evident, but the effects are many. Given the global decline in female fecundity and the ability of PFAS to negatively impact female reproductive health, further studies are needed to examine effects on endocrine target tissues involved in the onset of reproductive disorders of women.

Extrafine HFA-beclomethasone-formoterol vs. nonextrafine combination of an inhaled corticosteroid and a long acting ß2-agonist in patients with persistent asthma: A systematic review and meta-analysis.

OBJECTIVE: Airway inflammation in asthma involves not only the central airways but extends to peripheral airways. Lung deposition may be key for an appropriate treatment of asthma. We compared the clinical effects of extrafine hydrofluoroalkane (HFA)-beclomethasone-formoterol (BDP-F) versus equipotent doses of nonextrafine combination of an inhaled corticosteroid and a long acting ß2-agonist (ICS-LABA) in asthma. METHODS: We identified eligible studies by a comprehensive literature search of PubMed, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL). Data analysis was performed with the Review Manager 5.3.5 software (Cochrane IMS, 2014). RESULTS: A total of 2326 patients with asthma from ten published randomized controlled trials (RCTs) were enrolled for analysis. Change from baseline in morning pre-dose peak expiratory flow (PEF), evening pre-dose PEF and forced expiratory volume in one second (FEV1) were detected no significant differences between extrafine HFA-BDP-F and nonextrafine ICS-LABAs (p = 0.23, p = 0.99 and p = 0.23, respectively). Extrafine HFA-BDP-F did not show any greater benefit in forced expiratory flow between 25% and 75% of forced vital capacity (FEF25-75%), the parameter concerning peripheral airways (MD 0.03L/s, p = 0.65; n = 877). There were no substantial differences between interventions in fractional exhaled nitric oxide (FeNO) levels or in its alveolar fraction. The overall analysis showed no significant benefit of extrafine HFA-BDP-F over nonextrafine ICS-LABA in improving Asthma Control Test (ACT) score (p = 0.30) or decreasing the number of puffs of rescue medication use (p = 0.16). Extrafine HFA-BDP-F did not lead to less exacerbations than nonextrafine ICS-LABA (RR 0.61, 95% CI: 0.31 to 1.20; I2 = 0; p = 0.15). CONCLUSION: Enrolled RCTs of extrafine HFA-BDP-F have demonstrated no significant advantages over the equivalent combination of nonextrafine ICS-LABA in improving pulmonary function concerning central airways or peripheral airways, improving asthma symptom control or reducing exacerbation rate.

Associations of Prenatal Exposure to Per- and Polyfluoroalkyl Substances with the Neonatal Birth Size and Hormones in the Growth Hormone/Insulin-Like Growth Factor Axis.

Toxicological data suggest a significant developmental toxicity of per- and polyfluoroalkyl substances (PFASs); however, evidence in humans remains inconclusive. Furthermore, the effects of prenatal exposure to PFASs on hormones in the growth hormone (GH)/insulin-like growth factor (IGF) axis of newborns remain largely unclear. We aimed to investigate the associations of prenatal exposure to PFASs with the neonatal birth size, GH, IGF-1, and IGF-binding protein 3 (IGFBP-3). The concentrations of 22 PFASs were measured in the plasma of 224 pregnant women collected within 3 days before delivery (39.3 weeks) in Guangzhou, China, and the anthropometric data were gathered from medical records. Paired cord blood was collected at delivery to determine GH, IGF-1, and IGFBP-3 levels. Multivariable linear regression models revealed the inverse associations of several long-chain PFASs with birth weight and ponderal index as well as the significant associations of perfluorobutanoic acid and perfluorooctanoic acid (PFOA) with IGFBP-3 levels. The Bayesian kernel machine regression confirmed the association of perfluorooctane sulfonate with birth weight and ponderal index and of PFOA with IGFBP-3 and identified an inverse joint effect of exposure to a mixture of multiple PFASs on birth weight. The findings provide the first comprehensive evidence on the individual and joint effects of multiple PFASs on the neonatal birth size and hormones in the GH/IGF axis, which requires further confirmation.

1,1,1,2,3,4,4,5,5,5-Decafluoropentane (HFC-4310mee).

HFC-43-10mee is a volatile liquid at room temperature and used as a cleaning agent, aerosol, etc. HFC-43-10mee has low acute inhalation toxicity; 4-hour LC50 in rats of approximately 11,000 ppm. The compound was not a skin or eye irritant and was not a skin sensitizer. A cardiac sensitization response was not observed at 5000 ppm. Inhalation exposure resulted in neurotoxicity consisting of tremors, convulsions, jerking, ataxia, abnormal gait, etc. at exposure concentrations of 2000 ppm and above. Within approximately 30 min of exposure the clinical signs appeared and resolved within 1-2 h during exposure; the rats appeared to adapt such that these clinical signs were no longer observed. The neurotoxicity observed was considered an acute response to HFC-43-10mee. In a 90-day study, rats exposed to 2000 ppm resulted in sporadic clinical signs of neurotoxicity. At 3500 ppm, the clinical signs were evident on most exposure days although as the study progressed the apparent incidence declined likely reflecting adaptation. The NOAEL was 500 ppm. Based on the occurrence of the clinical signs in this and other studies, an acute threshold for neurotoxicity was evident at approximately 2000 ppm and above. No developmental or reproductive toxicity were evident at 2000 ppm, although clinical signs of neurotoxicity occurred in maternal or parental rats at 2000 ppm. No effects on offspring were observed. HFC-43-10mee was not genotoxic in vitro or in vivo. Based on the data, the 8-h TWA WEEL value is 225 ppm (2320 mg/m3). The 15-min STEL is 700 ppm (7217 mg/m3).

Oxidative stress and Liver X Receptor agonist induce hepatocellular carcinoma in Non-alcoholic steatohepatitis model.

BACKGROUND AND AIM: The incidence of non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) is progressively increasing. However, the pathophysiology and etiology of NASH progression to HCC are unknown. We hypothesized that steatosis was the key factor in NASH-related hepatocarcinogenesis and aimed to evaluate the effects of long-term liver X receptor (LXR) agonist stimulation on hepatic steatosis induced by a high-fat diet and oxidative stress. METHODS: We used an LXR agonist (T0901317) and CCl4 to induce hepatic steatosis and oxidative stress, respectively. C57BL/6 mice fed with a high-fat diet were treated with either T0901317 + CCl4 (T09 + CCl4 group) or CCl4 alone (CCl4 group). T0901317 (2.5 mg/kg) and CCl4 (0.1 mL/kg) were intraperitoneally administered twice weekly for 24 weeks. RESULTS: The liver-to-body weight ratio was significantly higher in the T09 + CCl4 group than in the CCl4 group. Mice in the T09 + CCl4 group exhibited abnormal lipid metabolism and NASH-like histopathological features. Additionally, all mice in the T09 + CCl4 group developed liver tumors diagnosed as well-differentiated HCC. The genes identified via microarray analysis were related to NASH and HCC development. CONCLUSIONS: By combining long-term LXR agonist stimulation with oxidative stress and a high-fat diet, we successfully reproduced liver conditions in mice similar to those in humans with NASH and progression to HCC. Our results provide new insight into NASH-related HCC progression and therapy.

Patient preferences for elagolix and leuprolide for treating endometriosis-related pain in the United States.

INTRODUCTION: We evaluated elagolix and leuprolide from the patient's perspective for the treatment of endometriosis-related pain. AREA COVERED: Preference weights from a published discrete choice experiment were used to evaluate preferences for treatment profiles simulating elagolix (150 mg/day and 200 mg/twice-daily dosages) and leuprolide for the treatment of moderate to severe endometriosis-related pain. Sensitivity analyses were conducted by varying the range of risk for pregnancy-related problems, moderate to severe hot flashes, and bone fracture across scenarios. EXPERT OPINION: The 200 mg twice daily dosage of elagolix is more likely to be preferred over leuprolide by patients with moderate to severe endometriosis-related pain in all scenarios explored in the evaluation and sensitivity analyses. The probability that an average respondent would select a treatment was sensitive to increases in risk of moderate to severe hot flashes for leuprolide and possible variations in the risk of pregnancy-related problems for both treatments but was not influenced by an increased risk of bone fracture. CONCLUSIONS: Patients' preferences for treatment of endometriosis-related pain should be evaluated using the benefits and risks of each pharmacological option. Respondents were more likely to prefer the treatment profile similar to 200 mg twice daily elagolix over that of leuprolide in all scenarios.

Exposure-Safety Analyses Identify Predictors of Change in Bone Mineral Density and Support Elagolix Labeling for Endometriosis-Associated Pain.

Elagolix is a novel oral gonadotropin releasing hormone receptor antagonist, that can suppress estradiol in a dose-dependent manner. It is indicated for management of moderate-to-severe pain associated with endometriosis. A population exposure-response model describing the relationship between elagolix exposure and changes in bone mineral density (BMD) was developed using data from four phase III studies in premenopausal women with endometriosis-associated pain. Elagolix pharmacokinetic exposure-dependent changes in BMD were described by an indirect-response maximum effect (Emax ) model through stimulation of bone resorption. African American race, higher body mass index (BMI), and lower type-I collagen C-telopeptide concentrations were significantly associated with higher baseline BMD. Higher BMI was significantly associated with higher bone formation rates. Simulations using the final model demonstrated that elagolix 150 mg q.d. dosing for 24 months is predicted to result in -1.45% (-2.04 to -0.814) decrease from baseline in BMD and were used to support corresponding dosing recommendations in the label.

The potential role of elagolix for treating uterine bleeding associated to uterine myomas.

INTRODUCTION: Uterine myomas represents a widespread gynecological disease of women in reproductive age. Although surgery remains the first choice for treating most patients, in the last years, new medical approaches have been considered in order to ameliorate heavy menstrual bleeding (HMB) related to their presence. Elagolix is a second-generation gonadotropin-releasing hormone (GnRH) antagonist under investigation for the long-term treatment of uterine myomas. AREAS COVERED: The aim of this drug evaluation is to give a complete overview of pharmacokinetic and pharmacodynamic data on elagolix for treating HMB related to uterine myomas and to report the results of the current clinical trials in this setting. EXPERT OPINION: In two previous phase II studies, this drug succeeded in ameliorating blood loss and quality of life of patients affected by uterine myomas with a good safety profile. Three phase III trials (ELARIS UF-I, UF-II, and EXTEND) investigated the efficacy, tolerability, and safety of elagolix at 300 mg twice daily with add-back therapy. The primary endpoint, consisting in the reduction in HMB compared to placebo, was met in the majority of patients under treatment. Currently, elagolix is under investigation in two other ongoing multicenter phase III clinical studies.

Phase I study of DFP-11207, a novel oral fluoropyrimidine with reasonable AUC and low Cmax and improved tolerability, in patients with solid tumors.

5-fluorouracil (5-FU) and 5-FU derivatives, such as capecitabine, UFT, and S-1, are the mainstay of chemotherapy treatment for gastrointestinal cancers, and other solid tumors. Compared with other cytotoxic chemotherapies, these drugs generally have a favorable safety profile, but hematologic and gastrointestinal toxicities remain common. DFP-11207 is a novel oral cytotoxic agent that combines a 5-FU pro-drug with a reversible DPD inhibitor and a potent inhibitor of OPRT, resulting in enhanced pharmacological activity of 5-FU with decreased gastrointestinal and myelosuppressive toxicities. In this Phase I study (NCT02171221), DFP-11207 was administered orally daily, in doses escalating from 40 mg/m2/day to 400 mg/m2/day in patients with esophageal, colorectal, gastric, pancreatic or gallbladder cancer (n = 23). It was determined that DFP-11207 at the dose of 330 mg/m2/day administered every 12 hours was well-tolerated with mild myelosuppressive and gastrointestinal toxicities. The pharmacokinetic analysis determined that the 5-FU levels were in the therapeutic range at this dose. In addition, fasted or fed states had no influence on the 5-FU levels (patients serving as their own controls). Among 21 efficacy evaluable patients, 7 patients had stable disease (33.3%), of which two had prolonged stable disease of >6 months duration. DFP-11207 can be explored as monotherapy or easily substitute 5-FU, capecitabine, or S-1 in combination regimens.

Elagolix Treatment for Up to 12 Months in Women With Heavy Menstrual Bleeding and Uterine Leiomyomas.

OBJECTIVE: To investigate the safety and efficacy of elagolix, an oral gonadotropin-releasing hormone antagonist, with hormonal add-back therapy for up to 12 months in women with heavy menstrual bleeding associated with uterine leiomyomas. METHODS: Elaris UF-EXTEND was a phase 3 extension study that evaluated an additional 6 months (up to 12 months total) of elagolix 300 mg twice daily with hormonal add-back therapy (estradiol 1 mg and norethindrone acetate 0.5 mg once daily) in women who completed an initial 6 months of the same treatment in one of two preceding phase 3 studies. The primary endpoint was the percentage of women with both less than 80 mL menstrual blood loss during final month and a 50% or greater reduction in menstrual blood loss from baseline to final month. Safety evaluations included adverse events and bone mineral density changes. The planned sample size of UF-EXTEND was based on estimated rollover and discontinuation rates in the two preceding studies. RESULTS: From September 2016 to March 2019, 433 women were enrolled in UF-EXTEND. Of these women, 218 received up to 12 months of elagolix with add-back therapy; the mean±SD age of this group was 42.4±5.4 years and 67.3% were black. The percentage of women who met the primary endpoint in this elagolix with add-back group was 87.9% (95% CI [83.4-92.3]). The most frequently reported adverse events with up to 12 months of elagolix plus add-back therapy were hot flush (6.9%), night sweats (3.2%), headache (5.5%), and nausea (4.1%). Mean percent decreases in bone mineral density from baseline to extension month 6 were significantly less with elagolix plus add-back therapy than with elagolix alone {between-group difference in lumbar spine: -3.3 (95% CI [-4.1 to -2.5])}. CONCLUSION: Up to 12 months of elagolix with add-back therapy provided sustained reduction in menstrual blood loss in women with uterine leiomyomas, with the addition of add-back therapy attenuating the hypoestrogenic effects of elagolix alone. No new or unexpected safety concerns were associated with an additional 6 months of elagolix with addback therapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02925494. FUNDING SOURCE: AbbVie Inc funded this study.

Elagolix for Heavy Menstrual Bleeding in Women with Uterine Fibroids.

BACKGROUND: Uterine fibroids are hormone-responsive neoplasms that are associated with heavy menstrual bleeding. Elagolix, an oral gonadotropin-releasing hormone antagonist resulting in rapid, reversible suppression of ovarian sex hormones, may reduce fibroid-associated bleeding. METHODS: We conducted two identical, double-blind, randomized, placebo-controlled, 6-month phase 3 trials (Elaris Uterine Fibroids 1 and 2 [UF-1 and UF-2]) to evaluate the efficacy and safety of elagolix at a dose of 300 mg twice daily with hormonal "add-back" therapy (to replace reduced levels of endogenous hormones; in this case, estradiol, 1 mg, and norethindrone acetate, 0.5 mg, once daily) in women with fibroid-associated bleeding. An elagolix-alone group was included to assess the impact of add-back therapy on the hypoestrogenic effects of elagolix. The primary end point was menstrual blood loss of less than 80 ml during the final month of treatment and at least a 50% reduction in menstrual blood loss from baseline to the final month; missing data were imputed with the use of multiple imputation. RESULTS: A total of 412 women in UF-1 and 378 women in UF-2 underwent randomization, received elagolix or placebo, and were included in the analyses. Criteria for the primary end point were met in 68.5% of 206 women in UF-1 and in 76.5% of 189 women in UF-2 who received elagolix plus add-back therapy, as compared with 8.7% of 102 women and 10% of 94 women, respectively, who received placebo (P<0.001 for both trials). Among the women who received elagolix alone, the primary end point was met in 84.1% of 104 women in UF-1 and in 77% of 95 women in UF-2. Hot flushes (in both trials) and metrorrhagia (in UF-1) occurred significantly more commonly with elagolix plus add-back therapy than with placebo. Hypoestrogenic effects of elagolix, especially decreases in bone mineral density, were attenuated with add-back therapy. CONCLUSIONS: Elagolix with add-back therapy was effective in reducing heavy menstrual bleeding in women with uterine fibroids. (Funded by AbbVie; Elaris UF-1 and Elaris UF-2 ClinicalTrials.gov numbers, NCT02654054 and NCT02691494.).

Effect of Topical Periocular Steroid Use on Intraocular Pressure: A Retrospective Analysis.

PURPOSE: To study the effect of periocular steroid use on intraocular pressure (IOP). METHODS: Charts of adult patients with atopic dermatitis or eczema treated with topical periocular steroid creams and ointments from January 1st, 2007 to October 1st, 2017 were reviewed. Patients with the following were excluded: glaucoma, ocular hypertension, known systemic/topical/injectable steroid history, and lack of documented IOP prior to or during treatment with periocular steroid ointment. Patient data were collected regarding gender, treatment regimen, as well as IOP prior to and during treatment. Steroid responders were identified. Statistical analysis was performed using linear mixed effects models adjusting for follow-up time to test the relationship between pre and posttreatment IOP change adjusting for intereye correlations. RESULTS: Thirty-one patients were identified. Twenty-one were treated bilaterally and 10 unilaterally. Five patients were glaucoma suspects. The mean treatment period was 14.2 weeks with a range of 0.1-83.9 weeks. Patients were treated with fluorometholone (42%), loteprednol etabonate (23%), dexamethasone-neomycin-polymyxin B (13%), hydrocortisone 1% or 2.5% (3%), and tobramycin-dexamethasone (19%). In the combined sample, there was no significant IOP change even after adjusting for follow-up time (mean change: +0.44 mm Hg, p = 0.126). However, eyes with baseline IOP ≥ 14 mm Hg had a significant increase (+0.73 mm Hg/year, p = 0.032). Individual steroid responses included the following: 1 intermediate and 30 low responders, of which 19 patients had an IOP change of <1 mm Hg. One patient had a clinically significant intermediate steroid response of 7 mm Hg. CONCLUSIONS: Periocular steroid treatment causes a statistically significant rise in IOP in eyes with higher baseline IOP measurements, the risk of which increases with follow up. While this change is not always correlated with a clinically significant rise in IOP, clinicians should monitor more closely patients at greatest risk of steroid response.

Contaminants in Atlantic walruses in Svalbard part 1: Relationships between exposure, diet and pathogen prevalence.

This study investigated relationships between organohalogen compound (OHC) exposure, feeding habits, and pathogen exposure in a recovering population of Atlantic walruses (Odobenus rosmarus rosmarus) from the Svalbard Archipelago, Norway. Various samples were collected from 39 free-living, apparently healthy, adult male walruses immobilised at three sampling locations during the summers of 2014 and 2015. Concentrations of lipophilic compounds (polychlorinated biphenyls, organochlorine pesticides and polybrominated diphenyl ethers) were analysed in blubber samples, and concentrations of perfluoroalkylated substances (PFASs) were determined in plasma samples. Stable isotopes of carbon and nitrogen were measured in seven tissue types and surveys for three infectious pathogens were conducted. Despite an overall decline in lipophilic compound concentrations since this population was last studied (2006), the contaminant pattern was similar, including extremely large inter-individual variation. Stable isotope ratios of carbon and nitrogen showed that the variation in OHC concentrations could not be explained by some walruses consuming higher trophic level diets, since all animals were found to feed at a similar trophic level. Antibodies against the bacteria Brucella spp. and the parasite Toxoplasma gondii were detected in 26% and 15% of the walruses, respectively. Given the absence of seal-predation, T. gondii exposure likely took place via the consumption of contaminated bivalves. The source of exposure to Brucella spp. in walruses is still unknown. Parapoxvirus DNA was detected in a single individual, representing the first documented evidence of parapoxvirus in wild walruses. Antibody prevalence was not related to contaminant exposure. Despite this, dynamic relationships between diet composition, contaminant bioaccumulation and pathogen exposure warrant continuing attention given the likelihood of climate change induced habitat and food web changes, and consequently OHC exposure, for Svalbard walruses in the coming decades.

Elagolix Pharmacokinetic Profiles in Women With Renal or Hepatic Impairment.

The aim of these studies was to assess the safety and pharmacokinetics of elagolix, an oral nonpeptide gonadotropin-releasing hormone antagonist following oral administration in women with renal or hepatic impairment. Two phase 1 studies were conducted in adult women with normal renal function versus renal impairment (reduced study), and normal hepatic function versus hepatic impairment (full study design). All women received a single dose of elagolix 200 mg (renal) or 150 mg (hepatic). Intensive pharmacokinetic blood samples were collected. Elagolix exposures were comparable in women with normal renal function and those with moderate/severe renal impairment or end-stage renal disease. Elagolix exposures also appeared to be similar in women with normal hepatic function and women with mild hepatic impairment. Elagolix area under the curve in women with moderate hepatic impairment and with severe hepatic impairment was approximately 3-fold and 7-fold higher than in women with normal hepatic function. The adverse event incidence was low, with the main events being mild nausea and headache. No dosage adjustment was needed in women with renal impairment or women with mild hepatic impairment. Although an elagolix dose of 150 mg once daily may be used in women with moderate hepatic impairment for up to 6 months, this elagolix dose should not be used in women with severe hepatic impairment.

Elagolix Alone or With Add-Back Therapy in Women With Heavy Menstrual Bleeding and Uterine Leiomyomas: A Randomized Controlled Trial.

OBJECTIVE: To evaluate elagolix, an oral gonadotropin-releasing hormone receptor antagonist, alone or with add-back therapy, in premenopausal women with heavy menstrual bleeding (greater than 80 mL per month) associated with uterine leiomyomas. METHODS: This double-blind, randomized, placebo-controlled, parallel-group study evaluated efficacy and safety of elagolix in cohorts 1 (300 mg twice daily) and 2 (600 mg daily) with four arms per cohort: placebo, elagolix alone, elagolix with 0.5 mg estradiol/0.1 norethindrone acetate, and elagolix with 1.0 mg estradiol/0.5 mg norethindrone acetate. A sample size of 65 per group was planned to compare elagolix with add-back to placebo on the primary end point: the percentage of women who had less than 80 mL menstrual blood loss and 50% or greater reduction in menstrual blood loss from baseline to the last 28 days of treatment. Safety assessments included changes in bone mineral density. RESULTS: From April 8, 2013, to December 8, 2015, 571 women were enrolled, 567 were randomized and treated (cohort 1=259; cohort 2=308), and 80% and 75% completed treatment, respectively. Participants had a mean±SD age of 43±5 years (cohort 2, 42±5 years), and 70% were black (cohort 2, 74%). Primary end point responder rates in cohort 1 (cohort 2) were 92% (90%) for elagolix alone, 85% (73%) for elagolix with 0.5 mg estradiol/0.1 mg norethindrone acetate, 79% (82%) for elagolix with 1.0 mg estradiol/0.5 mg norethindrone acetate, and 27% (32%) for placebo (all P<.001 vs placebo). Elagolix groups had significant decreases compared with placebo in lumbar spine bone mineral density, which was attenuated by adding 1.0 mg estradiol/0.5 mg norethindrone acetate. CONCLUSION: Elagolix with and without add-back significantly reduced menstrual blood loss in women with uterine leiomyomas. Add-back therapy reduced hypoestrogenic effects on bone mineral density. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01817530; EU Clinical Trial Register, 2013-000082-37.