ABSTRACT
Elagolix is an oral gonadotropin-releasing hormone receptor antagonist indicated for the management of endometriosis-associated pain and in combination with estradiol/norethindrone acetate indicated for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women. Elagolix coadministered with estradiol/norethindrone acetate is in late-stage development for the management of heavy menstrual bleeding associated with uterine fibroids. Based on the in vitro profile of elagolix metabolism and disposition, 9 drug-drug interaction (DDI) studies evaluating the victim and perpetrator characteristics of elagolix were conducted in 144 healthy volunteers. As a victim of cytochrome P450 (CYPs) and transporter-mediated DDIs, elagolix area under the curve (AUC) increased by â¼2-fold following coadministration with ketoconazole and by â¼5- and â¼2-fold with single and multiple doses of rifampin, respectively. As a perpetrator, elagolix decreased midazolam AUC (90% confidence interval) by 54% (50%-59%) and increased digoxin AUC by 32% (23%-41%). Elagolix decreased rosuvastatin AUC by 40% (29%-50%). No clinically significant changes in exposure on coadministration with sertraline or fluconazole occurred. A elagolix 150-mg once-daily regimen should be limited to 6 months with strong CYP3A inhibitors and rifampin because of the potential increase in bone mineral density loss, as described in the drug label. A 200-mg twice-daily regimen is recommended for no more than 1 month with strong CYP3A inhibitors and not recommended with rifampin. Elagolix is contraindicated with strong organic anion transporter polypeptide B1 inhibitors (eg, cyclosporine and gemfibrozil). Consider increasing the doses of midazolam and rosuvastatin when coadministered with elagolix, and individualize therapy based on patient response. Clinical monitoring is recommended for P-glycoprotein substrates with a narrow therapeutic window (eg, digoxin). Dose adjustments are not required for sertraline, fluconazole, bupropion (or any CYP2B6 substrate), or elagolix when coadministered.
Subject(s)
Hydrocarbons, Fluorinated/administration & dosage , Hydrocarbons, Fluorinated/pharmacokinetics , Pyrimidines/administration & dosage , Pyrimidines/pharmacokinetics , Receptors, LHRH/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B, Member 1/agonists , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Adult , Cytochrome P-450 CYP2B6/metabolism , Cytochrome P-450 CYP2B6 Inducers/administration & dosage , Cytochrome P-450 CYP2B6 Inducers/pharmacokinetics , Cytochrome P-450 CYP2C9 Inhibitors/administration & dosage , Cytochrome P-450 CYP2C9 Inhibitors/pharmacokinetics , Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 CYP3A Inducers/administration & dosage , Cytochrome P-450 CYP3A Inducers/pharmacokinetics , Cytochrome P-450 CYP3A Inhibitors/administration & dosage , Cytochrome P-450 CYP3A Inhibitors/pharmacokinetics , Drug Administration Schedule , Drug Interactions , Female , Healthy Volunteers , Humans , Hydrocarbons, Fluorinated/blood , Hydrocarbons, Fluorinated/pharmacology , Liver-Specific Organic Anion Transporter 1/antagonists & inhibitors , Liver-Specific Organic Anion Transporter 1/metabolism , Male , Middle Aged , Neoplasm Proteins/metabolism , Premenopause , Pyrimidines/blood , Pyrimidines/pharmacology , Solute Carrier Organic Anion Transporter Family Member 1B3/antagonists & inhibitors , Solute Carrier Organic Anion Transporter Family Member 1B3/metabolism , Young AdultABSTRACT
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.
Subject(s)
Contraceptive Agents, Female/administration & dosage , Estradiol/administration & dosage , Estrogens/administration & dosage , Hydrocarbons, Fluorinated/therapeutic use , Leiomyoma/drug therapy , Menorrhagia/drug therapy , Norethindrone Acetate/administration & dosage , Pyrimidines/therapeutic use , Uterine Neoplasms/drug therapy , Adult , Double-Blind Method , Drug Therapy, Combination , Female , Gonadotropin-Releasing Hormone/antagonists & inhibitors , Hemoglobins/metabolism , Humans , Hydrocarbons, Fluorinated/adverse effects , Leiomyoma/complications , Leiomyoma/pathology , Menorrhagia/blood , Menorrhagia/etiology , Middle Aged , Pyrimidines/adverse effects , Quality of Life , Tumor Burden/drug effects , Uterine Neoplasms/complications , Uterine Neoplasms/pathologyABSTRACT
BACKGROUND: Elevated intact parathyroid hormone (iPTH) levels can contribute to morbidity and mortality in children with chronic kidney disease (CKD). We evaluated the pharmacokinetics, efficacy, and safety of oral paricalcitol in reducing iPTH levels in children with stages 3-5 CKD. METHODS: Children aged 10-16 years with stages 3-5 CKD were enrolled in two phase 3 studies. The stage 3/4 CKD study characterized paricalcitol pharmacokinetics and compared the efficacy and safety of paricalcitol with placebo followed by an open-label period. The stage 5 CKD study evaluated the efficacy and safety of paricalcitol (no comparator) in children with stage 5 CKD undergoing dialysis. RESULTS: In the stage 3/4 CKD study, mean peak plasma concentration and area under the time curve from zero to infinity were 0.13 ng/mL and 2.87 ngâ¢h/((or ng×h/))mL, respectively, for 12 children who received 3 µg paricalcitol. Thirty-six children were randomized to paricalcitol or placebo; 27.8% of the paricalcitol group achieved two consecutive iPTH reductions of ≥30% from baseline versus none of the placebo group (P = 0.045). Adverse events were higher in children who received placebo than in those administered paricalcitol during the double-blind treatment (88.9 vs. 38.9%; P = 0.005). In the stage 5 CKD study, eight children (61.5%) had two consecutive iPTH reductions of ≥30% from baseline, and five (38.5%) had two consecutive iPTH values of between 150 and 300 pg/mL. Clinically meaningful hypercalcemia occurred in 21% of children. CONCLUSIONS: Oral paricalcitol in children aged 10-16 years with stages 3-5 CKD reduced iPTH levels and the treatment was well tolerated. Results support an initiating dose of 1 µg paricalcitol 3 times weekly in children aged 10-16 years.
Subject(s)
Bone Density Conservation Agents/therapeutic use , Ergocalciferols/therapeutic use , Hyperparathyroidism, Secondary/therapy , Kidney Failure, Chronic/therapy , Parathyroid Hormone/blood , Renal Dialysis , Adolescent , Bone Density Conservation Agents/pharmacokinetics , Calcium/blood , Child , Double-Blind Method , Ergocalciferols/pharmacokinetics , Female , Humans , Hypercalcemia/blood , Hypercalcemia/chemically induced , Hyperparathyroidism, Secondary/blood , Hyperparathyroidism, Secondary/etiology , Hyperphosphatemia/blood , Hyperphosphatemia/chemically induced , Kidney Failure, Chronic/blood , Kidney Failure, Chronic/complications , Male , Phosphorus/blood , Treatment OutcomeABSTRACT
Recent studies showed that P-glycoprotein (P-gp) increases the portal bioavailability (FG) of loperamide by sparing its intestinal first-pass metabolism. Loperamide is a drug whose oral absorption is strongly attenuated by intestinal P-gp-mediated efflux and first-pass metabolism by cytochrome P450 3A (CYP3A). Here the effect of the interplay of P-gp and Cyp3a in modulating intestinal first-pass metabolism and absorption was investigated for another Cyp3a/P-gp dual substrate amprenavir, which is less efficiently effluxed by P-gp than loperamide. After oral administration of amprenavir, the portal concentrations and FG of amprenavir were approximately equal in P-gp competent and P-gp deficient mice. Mechanistic studies on the effect of P-gp on Cyp3a-mediated metabolism of amprenavir using intestinal tissue from P-gp competent and P-gp deficient mice (Ussing-type diffusion chamber) revealed that P-gp-mediated efflux caused only a slight reduction of oxidative metabolism of amprenavir. Studies in which portal concentrations and FG were measured in P-gp competent and P-gp deficient mice whose cytochrome P450 (P450) enzymes were either intact or inactivated showed that intestinal first-pass metabolism attenuates the oral absorption of amprenavir by approximately 10-fold, whereas P-gp efflux has a relatively small effect (approximately 2-fold) in attenuating the intestinal absorption. Cumulatively, these studies demonstrate that P-gp has little influence on the intestinal first-pass metabolism and FG of amprenavir and that intestinal P450-mediated metabolism plays the dominant role in attenuating the oral absorption of this drug.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Carbamates/metabolism , Cytochrome P-450 CYP3A/metabolism , Intestinal Absorption/physiology , Intestinal Mucosa/metabolism , Intestines/enzymology , Sulfonamides/metabolism , Animals , Biological Availability , Biological Transport , Furans , Male , Mice , PermeabilityABSTRACT
P-glycoprotein (P-gp) and CYP3A (cytochrome P450 3A, generally; Cyp3a, rodent enzyme) in the intestine can attenuate absorption of orally administered drugs. While some suggest that P-gp enhances intestinal metabolism by CYP3A/Cyp3a during absorption of a dual substrate, others suggest that P-gp reduces the metabolism in the intestine when substrates are at subsaturating concentrations. Hence, to elucidate the cellular mechanisms that can address these divergent reports, we studied intestinal absorption of the dual substrate loperamide in portal vein-cannulated P-gp-competent and P-gp-deficient mice. These studies showed that at low doses of loperamide, which produced intestinal concentrations near the apparent K(m) for oxidative metabolism, the bioavailability across the intestine (F(G)) was 6-fold greater in the P-gp-competent mice than in P-gp-deficient mice. The higher F(G) of loperamide in the presence of P-gp was attributed to lower loperamide intestinal metabolism. However, at high doses of loperamide, the sparing of first-pass metabolism by P-gp was balanced against the attenuation of absorption by apical efflux, resulting in no net effect on F(G). In vitro studies with intestinal tissue from P-gp-competent and -deficient mice confirmed that P-gp reduced the metabolic rate of loperamide during absorptive flux at concentrations near K(m) but had little effect on metabolism at higher (saturating) concentrations. Further, studies in which Cyp3a was chemically inactivated by aminobenzotriazole in P-gp-competent and -deficient mice, showed that P-gp and Cyp3a individually attenuated F(G) by 8-fold and 70-fold, respectively. These results confirmed that P-gp effectively protects loperamide at low doses from intestinal first-pass metabolism during intestinal absorption.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B/metabolism , Intestinal Absorption , Intestinal Mucosa/metabolism , Loperamide/pharmacokinetics , ATP Binding Cassette Transporter, Subfamily B/deficiency , ATP Binding Cassette Transporter, Subfamily B/genetics , Administration, Oral , Animals , Biological Availability , Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 CYP3A Inhibitors , Enzyme Inhibitors/pharmacology , Intestinal Absorption/drug effects , Intestines/drug effects , Loperamide/administration & dosage , Loperamide/blood , Male , Mice , Mice, Knockout , Models, Biological , Models, Statistical , Permeability , Portal Vein , Triazoles/pharmacologyABSTRACT
INTRODUCTION: Vismodegib was assessed as being of low risk for QT interval prolongation based on prior nonclinical and clinical experience. A dedicated study was conducted to further assess the potential for vismodegib to prolong the QTc interval. METHODS AND RESULTS: Given the nonlinear pharmacokinetics of vismodegib, a thorough QTc study as is typically designed was not possible, and an innovative design was employed. This dedicated QTc study was powered to exclude a 20-millisecond change from the baseline QTc interval. The subjects were administered daily oral 150 mg of vismodegib for 7 days, or a single dose of 400 mg of moxifloxacin, with corresponding matching placebos. The upper limits of the 90% confidence intervals for the difference in ΔQTcF between vismodegib and placebo at steady state were <20 milliseconds at all timepoints with a maximum of 10 milliseconds at 12 hours postdose. Exposure-response analysis yielded an estimated slope equal to 0.11 ms/µM, which was not statistically significant. After a single dose of moxifloxacin was administered, the lower limits of the 90% confidence interval of the difference in ΔQTcF between moxifloxacin and placebo were >5 milliseconds from 1-12 hours postdose, thereby establishing assay sensitivity. CONCLUSIONS: There was no effect of vismodegib on the QTc interval when dosed daily at 150 mg to steady state.
Subject(s)
Anilides/administration & dosage , Antineoplastic Agents/administration & dosage , Pyridines/administration & dosage , Administration, Oral , Aged , Anilides/adverse effects , Anilides/pharmacokinetics , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Aza Compounds/administration & dosage , Double-Blind Method , Drug Administration Schedule , Electrocardiography , Female , Fluoroquinolones , France , Heart Rate/drug effects , Humans , Linear Models , Long QT Syndrome/chemically induced , Long QT Syndrome/physiopathology , Middle Aged , Models, Biological , Moxifloxacin , Pyridines/adverse effects , Pyridines/pharmacokinetics , Quinolines/administration & dosage , Risk Assessment , Time FactorsABSTRACT
Maternal tobacco use is associated with adverse developmental outcomes in offspring, including hyperactivity. Animal studies attempting to model this phenomenon have primarily used continuous s.c. nicotine infusion as the method of nicotine administration, which does not model the intermittent bolus delivery of nicotine associated with smoking in humans. The purpose of the present experiment was to examine the locomotor activity of pre-weanling offspring of pregnant rats exposed to an i.v. nicotine dosing protocol that approximates the pattern of nicotine exposure in moderate to heavy smokers. Pregnant rats were administered an i.v. bolus of 0.03 mg/kg nicotine (N=13) or saline (N=10) every 14 min for 16 h/day, resulting in a total daily dose of 2 mg/kg (base), from gestational day 4 to delivery. Pups from each litter were tested for spontaneous locomotor activity on postnatal days (PND) 19-21 and nicotine-induced locomotor activity on PND 22. Mean birth weight was significantly lower in nicotine-exposed pups compared to controls, but body weights were equivalent between groups by the time of behavioral testing. Mean total distance traveled, vertical counts, and stereotypy counts were lower on PND 19 in nicotine-exposed pups compared to controls, but only the difference in mean stereotypy counts was statistically significant. Within-session analysis revealed that both distance traveled and stereotypy were significantly decreased in nicotine-exposed pups in the first 5 min of the session on PND 19. Total time spent in the center of the field was also lower in nicotine-exposed pups. Nicotine-induced increases in activity on PND 22 did not differ according to gestational exposure. These findings demonstrate that prenatal nicotine exposure in a model that mimics the pattern of nicotine exposure from cigarette smoking in humans results in offspring that exhibit low birth weight and hypoactivity in a novel environment.
Subject(s)
Fetus/drug effects , Motor Activity/drug effects , Nicotine/toxicity , Animals , Birth Weight/drug effects , Female , Infusions, Intravenous , Nicotine/administration & dosage , Rats , Rats, Sprague-Dawley , Stereotyped Behavior/drug effectsABSTRACT
Nicotine is a teratogen in rats and possibly in humans. Vaccination against nicotine is being studied as a possible treatment for nicotine dependence. The safety of maternal vaccination against nicotine during or prior to pregnancy is not known. In this study, female rats were vaccinated and then administered acute or chronic nicotine during pregnancy at doses simulating nicotine exposure in smokers. Maternal vaccination reduced nicotine distribution to both maternal brain (44-47%) and fetal brain (17-39%) for up to 25 min after a single maternal nicotine dose administered on gestational day (GD) 20, but had a smaller effect on nicotine distribution to brain after continuous nicotine infusion. Nicotine distribution to maternal or fetal brain after repeated nicotine bolus doses was reduced immediately following an individual dose in vaccinated rats, but the chronic accumulation of nicotine in fetal brain was not altered. Nicotine distribution to whole fetus, in contrast to fetal brain, was generally not altered by vaccination. Nicotine-specific antibody concentration in fetal serum was 10% that of maternal serum, and in fetal brain was <1% of maternal serum. Although nicotine transfer to the whole fetus was not reduced by vaccination, protein binding data suggest that nicotine-specific antibody transferred from mother to fetus served to bind nicotine in fetal serum, reduce the unbound nicotine concentration, and thereby reduce nicotine distribution to fetal brain. These data comment on the safety of vaccination against nicotine during pregnancy, and suggest that vaccination may reduce the distribution of nicotine to fetal brain under some nicotine dosing conditions.
Subject(s)
Brain/metabolism , Nicotine/immunology , Nicotine/pharmacokinetics , Nicotinic Agonists/immunology , Nicotinic Agonists/pharmacology , Vaccination , Animals , Brain/drug effects , Enzyme-Linked Immunosorbent Assay , Female , Fetus , Maternal-Fetal Exchange , Pregnancy , Protein Binding , Rats , Rats, Sprague-Dawley , Time Factors , Tissue Distribution , Vaccines, Conjugate/administration & dosage , Vaccines, Conjugate/immunologyABSTRACT
The objective of the present study was to determine the relative efficacy of nicotine priming and nicotine-paired stimuli in reinstating extinguished NSA in rats. The relative efficacy of different stimulus conditions in reinstating NSA was also determined. Rats were trained to self-administer nicotine (0.03 mg/kg/inf) under an FR 5 schedule. Onset of a light above the active lever was correlated with nicotine availability, while offset of the light was paired with each nicotine infusion. In Experiment 1, saline extinction was arranged in the presence of these light stimuli. After extinction criteria were met, the effects of priming doses of nicotine (0.01, 0.03. and 0.06 mg/kg/inf, i.v.) on active lever pressing were determined. In Experiment 2, extinction of NSA was arranged in the absence of the light stimuli. After extinction criteria were met, reinstatement sessions were arranged involving either (1) a priming infusion of nicotine (0.03 mg/kg), (2) presentation of the same light stimuli as during NSA training, (3) constant illumination of the cue light, or (4) a combination of a nicotine priming infusion with one of the stimulus-light conditions. In Experiment 1, nicotine generally failed to reinstate NSA at any priming dose. In Experiment 2, both stimulus conditions reinstated NSA, with the stimulus condition identical to training producing a greater effect. Nicotine priming alone failed to significantly reinstate NSA. Nicotine priming combined with either stimulus condition was no more effective than each stimulus condition alone in reinstating NSA. These findings suggest that nicotine-paired cues are more effective than nicotine alone in reinstating extinguished NSA and are consistent with other studies showing that nicotine-paired stimuli play an important role in the reacquisition of NSA.