Pharmacokinetics of maropitant citrate in Rhode Island Red chickens (Gallus gallus domesticus) following subcutaneous administration.

Maropitant citrate is a synthetic neurokinin-1 receptor antagonist and substance P inhibitor used for control of emesis in dogs in cats. Maropitant citrate is used empirically in birds, despite a lack of pharmacokinetic data in avian species. The objective of this study was to determine the pharmacokinetic profile of a single dose of maropitant citrate 1 and 2 mg/kg subcutaneously (SC) in eight Rhode Island Red hens (Gallus gallus domesticus). A crossover study design was used with 1-week washout between trials. Blood samples were collected over 36 h after drug administration. Plasma concentrations were measured using liquid chromatography-tandem mass spectrometry and pharmacokinetic parameters were determined via non-compartmental analysis. The mean maximum plasma concentration, time to maximum concentration, and elimination half-life following 1 and 2 mg/kg SC were 915.6 ± 312.8 ng/ml and 1195.2 ± 320.2 ng/ml, 0.49 ± 0.21 h and 1.6 ± 2.6 h, and 8.47 ± 2.24 h and 8.58 ± 2.6 h, respectively. Pharmacokinetic data suggests doses of 1 or 2 mg/kg SC may be administered every 12-24 h to maintain above target plasma concentration similar to dogs (90 ng/ml). These data provide a basis for further investigation of maropitant citrate pharmacokinetics and pharmacodynamics in birds.

A phase 1 pharmacokinetic study of oral NEPA, the fixed combination of netupitant and palonosetron, in Chinese healthy volunteers.

PURPOSE: Oral NEPA, the only fixed-combination antiemetic, is composed of the neurokinin-1 receptor antagonist netupitant (300 mg) and the 5-hydroxytryptamine-3 receptor antagonist palonosetron (0.50 mg). This study was conducted to evaluate the pharmacokinetic profile of netupitant and its main metabolites M1 and M3, and palonosetron in Chinese subjects. Oral NEPA tolerability and safety were also analyzed. METHODS: This was a single-center, single-dose phase 1 study in healthy, adult Chinese volunteers. Eligible subjects received oral NEPA, and blood samples were collected on day 1 predose and at various time points up until day 10 postdose. Pharmacokinetic parameters were analyzed using noncompartmental methods. For safety assessments, adverse events (AEs) were monitored during the study. RESULTS: In total 18 Chinese healthy volunteers received oral NEPA. Netupitant mean maximum plasma concentration (Cmax) [± standard deviation] of 698 ± 217 ng/mL was reached at 3-6 h, with a mean total exposure (AUC0-inf) of 22,000 ± 4410 h·ng/mL. For palonosetron, a mean Cmax of 1.8 ± 0.252 ng/mL was reached at 2-6 h postadministration, with a mean AUC0-inf of 81.0 ± 14.0 h·ng/mL. The most common treatment-related AEs in > 2 subjects were constipation (n = 9) and tiredness (n = 3). No severe AEs were observed, and no subject withdrew due to AEs. CONCLUSION: Following single-dose administration of oral NEPA in Chinese subjects, the pharmacokinetic profiles of the NEPA components were mostly similar to those reported previously in Caucasians. NEPA was well tolerated with a safety profile in line with that observed in pivotal trials in Caucasians.

Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Oral Venglustat in Healthy Volunteers.

Venglustat is a small-molecule glucosylceramide synthase (GCS) inhibitor designed to reduce the production of glucosylceramide (GL-1) and thus is expected to substantially reduce formation of glucosylceramide-based glycosphingolipids. Because of its effect on glycosphingolipid formation, GCS inhibition has therapeutic potential across many disorders affecting glycosphingolipid metabolism. Therefore, venglustat is under development for substrate reduction therapy in multiple diseases, including Gaucher disease type 3, Parkinson's disease associated with GBA mutations, Fabry disease, GM2 gangliosidosis, and autosomal dominant polycystic kidney disease. Phase 1 studies were conducted in healthy volunteers to determine venglustat pharmacokinetics, pharmacodynamics, safety, and tolerability and to assess food effects on pharmacokinetics (single-dose and food-effect studies: NCT01674036; repeated-dose study: NCT01710826). Following a single oral dose of venglustat l-malate (2, 5, 15, 25, 50, 100, or 150 mg), venglustat demonstrated linear pharmacokinetics, rapid absorption (median tmax , 3.00-5.50 hours), systemic exposure unaffected by food, low apparent total body clearance (mean CL/F, 5.18-6.43 L/h), and pooled geometric mean t1/2z of 28.9 hours. Following repeated once-daily oral doses of venglustat l-malate (5, 10, or 20 mg) for 14 days, apparent steady state occurred within 5 days of repeated dosing, with pooled accumulation ratios of 2.10 for Cmax and 2.22 for AUC0-24 , and no statistically significant effect of dose or sex on accumulation. The mean fraction of dose excreted unchanged in urine (fe0-24 ) was 26.3% to 33.1%. Plasma GL-1 and GM3 decreased time- and dose-dependently. Venglustat demonstrated a favorable safety and tolerability profile.

Pharmacokinetics of maropitant citrate after oral administration of multiple doses in adult horses.

The neurokinin-1 (NK-1) receptor antagonist, maropitant citrate, mitigates nausea and vomiting in dogs and cats. Nausea is poorly understood in horses, and clinical use of NK-1 receptor antagonists has not been reported. This study aimed to determine the pharmacokinetics and safety of maropitant after administration of multiple doses. We hypothesized that maropitant concentrations would be similar at steady state to those reported in dogs, with minimal adverse effects. Maropitant was administered at 4 mg/kg orally, once daily for 5 days in seven adult horses. Serial plasma maropitant concentrations were measured by liquid chromatography-mass spectrometry. Noncompartmental pharmacokinetic parameters were determined. The maximum, minimum, and average concentrations of maropitant achieved at steady state were 375.5 ± 200, 16.8 ± 7.7, and 73.5 ± 45.1 ng/ml, respectively. The terminal elimination half-life was 11.6 ± 1.4 hr, and the accumulation index was 1.3 ± 0.07. Heart rate decreased between Day 1 and Day 5 (p = .005), with three horses having heart rates of 20 beats per minute and atrioventricular block on Day 5. Pharmacokinetics of repeated maropitant administration suggests the drug could be considered for use in healthy horses. Further investigation on the clinical relevancy of its cardiac effects is warranted.

Population Pharmacokinetic Analysis of Fluticasone Furoate/Umeclidinium Bromide/Vilanterol in Patients with Chronic Obstructive Pulmonary Disease.

BACKGROUND: Population pharmacokinetic methods were used to characterize the pharmacokinetics of fluticasone furoate (FF), umeclidinium (UMEC), and vilanterol (VI) in patients with chronic obstructive pulmonary disease (COPD) when administered as a fixed-dose combination via a single closed inhaler. METHODS: Plasma concentration data from three studies were analyzed using non-linear mixed-effects modeling in NONMEM®. RESULTS: The pooled dataset consisted of 2948, 2589, and 3331 FF, UMEC, and VI observations from 714, 622, and 817 patients with COPD, respectively. There were 41%, 13%, and 21% of observations below the quantification limit for FF, UMEC, and VI, respectively. The pharmacokinetics of FF, UMEC, and VI were all adequately described by a two-compartment model with first-order absorption. The following covariates were statistically significant, but none were considered to be clinically relevant. For FF, Japanese heritage and FF/VI treatment on apparent inhaled clearance (CL/F) with FF CL/F 35% lower in patients of Japanese heritage across all treatments and FF CL/F 42% higher in patients with COPD following FF/VI administration. This is in line with the product label. For UMEC, weight, age, and smoking status on CL/F and weight on apparent volume of distribution (V2/F) with every 10% increase in age from 60 years of age leading to approximately a 6% decrease in UMEC CL/F and every 10% increase in weight from 70 kg leading to approximately a 6% increase in UMEC CL/F and approximately an 8% increase in UMEC V2/F. For a subject with COPD who smoked, UMEC CL/F was 28% higher. For VI, weight on CL/F and smoking status on V2/F with an approximately 4% increase in VI CL/F for every 10% increase in weight from 70 kg, and for a subject with COPD who smoked, VI V2/F was 46% higher. The majority of these covariates have been previously identified in historical analyses. None of these effects were clinically relevant in terms of systemic exposures and do not warrant dose adjustment. CONCLUSIONS: All FF, UMEC, and VI plasma concentrations were well interspersed with historical data and were all adequately described by a two-compartment model with first-order absorption. There were no clinically relevant differences in FF, UMEC, or VI systemic exposures when administered as FF/UMEC/VI, FF/VI + UMEC, or the dual combinations FF/VI and/or UMEC/VI.

Pharmacokinetics of morphine in combination with dexmedetomidine and maropitant following intramuscular injection in dogs anaesthetized with halothane.

The purpose of this study was to evaluate the pharmacokinetics of morphine in combination with dexmedetomidine and maropitant injected intramuscularly in dogs under general anaesthesia. Eight healthy dogs weighing 25.76 ± 3.16 kg and 3.87 ± 1.64 years of age were used in a crossover study. Dogs were randomly allocated to four groups: (1) morphine 0.6 mg/kg; (2) morphine 0.3 mg/kg + dexmedetomidine 5 µg/kg; (3) morphine 0.3 mg/kg + maropitant 1 mg/kg; (4) morphine 0.2 mg/kg + dexmedetomidine 3 µg/kg + maropitant 0.7 mg/kg. Blood samples were collected before, 15 and 30 min, and 1, 2, 3 4, 6 and 8 hr after injection of the test drugs. Plasma concentration of the drugs was determined by liquid chromatography-mass spectrometry. The elimination half-life (T1/2 ) of morphine was higher and the clearance rate (CL) was lower when combined with dexmedetomidine (T1/2  = 77.72 ± 20.27 min, CL = 119.41 ± 23.34 ml kg-1  min-1 ) compared to maropitant (T1/2  = 52.73 min ± 13.823 ml kg-1  min-1 , CL = 178.57 ± 70.55) or morphine alone at higher doses (T1/2  = 50.53 ± 12.55 min, CL = 187.24 ± 34.45 ml kg-1  min-1 ). Combining morphine with dexmedetomidine may increase the dosing interval of morphine and may have a clinical advantage.

Safety of the muscarinic receptor-antagonist (R,R)-penehyclidine fumarate in healthy subjects: A phase 1 randomized, double-blind, single-dose escalation study
.

PURPOSE: (R,R)-penehyclidine fumarate (R2PHF) is a highly selective muscarinic receptor antagonist used to suppress glandular secretions before general anesthesia or tracheal intubation and to treat organophosphorus poisoning. This is the first-in-human study to evaluate the safety, tolerability, and pharmacokinetics of R2PHF in healthy subjects. MATERIALS AND METHODS: In this single-center, double-blind, randomized study, 23 subjects received escalation doses of R2PHF (0.0625 mg, 0.25 mg, 0.50 mg, and 1.0 mg), 4 received the parent drug penehyclidine hydrochloride (PHC, 1.0 mg) as a reference, and 4 received a placebo. The pharmacokinetic parameters of R2PHF were determined. Tolerability was assessed based on adverse events and clinical laboratory tests. RESULTS: Single doses of 0.0625 mg, 0.25 mg, and 0.50 mg R2PHF were well-tolerated by healthy subjects. Delirium was set as the termination outcome and appeared in 1 case receiving 1.0 mg. For this reason, the escalation experiment was cut off. The mean half-life (T1/2) ranged from 30.57 to 32.27 hours. CONCLUSION: R2PHF was safe and well-tolerated at doses ranging from 0.0625 to 0.50 mg. A single administration of 0.50 mg was determined to be the maximum tolerated dose of R2PHF. Further pharmacodynamics, safety, and efficacy testing is required to advance R2PHF to the next stage of clinical development and application.

Pharmacokinetics of maropitant citrate in New Zealand White rabbits (Oryctolagus cuniculus).

OBJECTIVE: To determine the pharmacokinetics and adverse effects of maropitant citrate after IV and SC administration to New Zealand White rabbits (Oryctolagus cuniculus). ANIMALS: 11 sexually intact (3 males and 8 females) adult rabbits. PROCEDURES: Each rabbit received maropitant citrate (1 mg/kg) IV or SC. Blood samples were collected at 9 (SC) or 10 (IV) time points over 48 hours. After a 2-week washout period, rabbits received maropitant by the alternate administration route. Pharmacokinetic parameters were calculated. Body weight, food and water consumption, injection site, mentation, and urine and fecal output were monitored. RESULTS: Mean ± SD maximum concentration after SC administration was 14.4 ± 10.9 ng/mL and was detected at 1.25 ± 0.89 hours. Terminal half-life after IV and SC administration was 10.4 ± 1.6 hours and 13.1 ± 2.44 hours, respectively. Bioavailability after SC administration was 58.9 ± 13.3%. Plasma concentration at 24 hours was 2.87 ± 1.69 ng/mL after IV administration and 3.4 ± 1.2 ng/mL after SC administration. Four rabbits developed local dermal reactions at the injection site after SC injection. Increased fecal production was detected on the day of treatment and 1 day after treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Plasma concentrations of rabbits 24 hours after SC and IV administration of maropitant citrate (1 mg/kg) were similar to those of dogs at 24 hours. Reactions at the SC injection site were the most common adverse effect detected. Increased fecal output may suggest an effect on gastrointestinal motility. Additional pharmacodynamic and multidose studies are needed.

Fixed-dose combination of umeclidinium and vilanterol for patients with chronic obstructive pulmonary disease: A systematic review.

Chronic obstructive pulmonary disease (COPD) is a common respiratory disease that is predicted to be one of the leading causes of death worldwide. Pharmacologic treatment options of COPD are bronchodilators, using either long-acting ß2-agonists (LABAs), or long-acting muscarinic antagonists (LAMAs), or a combination of two. Anoro Ellipta (umeclidinium + vilanterol) dry powder inhaler, a fixed-dose combination of LAMA and LABA, was Food and Drug Administration (FDA) approved in 2013 for COPD. The objective of this study is to evaluate the efficacy and safety of once daily umeclidinium/vilanterol (62.5 mcg/25 mcg) in COPD patients, focusing on pharmacodynamic and pharmacokinetic characteristics, efficacy and safety in clinical studies and cost. Literature search was done through PubMed (2004-2017) using the terms umeclidinium, vilanterol, COPD, LABA and LAMA. Recent and significant clinical trials about the monocomponents and their combination were identified, in addition to reviews, guidelines for COPD, data from manufacturer and FDA product labels. The search was limited to English language studies on human subjects. Clinical data published on the combination of umeclidinium/vilanterol in patients with COPD have shown greater improvements in lung function compared to monotherapies. However, further studies comparing umeclidinium/vilanterol FDC (ANORO) to other LABA/LAMA combinations are needed.

Pharmacokinetic profile and safety of intravenous NEPA, a fixed combination of fosnetupitant and palonosetron, in cancer patients: Prevention of chemotherapy-induced nausea and vomiting associated with highly emetogenic chemotherapy.

NEPA is the fixed combination antiemetic composed of the neurokinin-1 receptor antagonist netupitant and the 5-hydroxytryptamine-3 receptor antagonist palonosetron. The intravenous (i.v.) formulation of NEPA (fosnetupitant 235 mg/palonosetron 0.25 mg) was developed to enhance the convenience of NEPA administration. In a phase 3 study, i.v. NEPA showed acceptable safety with low risk for injection-site reactions. This study evaluated the pharmacokinetics and safety of i.v. NEPA in cancer patients. This was a single-center, single-dose phase 1 study in patients receiving highly emetogenic chemotherapy. Patients received a 30-min infusion of i.v. NEPA plus oral dexamethasone (12 mg) prior to chemotherapy, and oral dexamethasone (8 mg/daily) on days 2-4. Twenty-four patients received the complete i.v. NEPA infusion volume. Fosnetupitant maximum plasma concentration (Cmax) was reached at the end of infusion and decreased to <1% of Cmax 30 min later. Netupitant was rapidly released from its prodrug and Cmax of 590 ng/ml was reached at the end of fosnetupitant infusion, with a mean exposure (AUC∞) of 15,588 h∙ng/ml. Palonosetron Cmax was reached at the end of infusion, with a mean AUC∞ of 36.07 h∙ng/ml. The most common adverse events were constipation (29%), nausea (17%), and vasospasm (8%). No i.v. NEPA-related injection site reactions occurred. Fosnetupitant conversion to netupitant occurred rapidly in cancer patients. Netupitant and palonosetron pharmacokinetic profiles in i.v. NEPA were similar to those reported for oral NEPA. i.v. NEPA was well tolerated with a similar safety profile to oral NEPA. i.v. NEPA provides additional administration convenience. Clinical trial registration number: EudraCT 2015-004750-18.

Multicenter, placebo-controlled, double-blind, randomized study of fosnetupitant in combination with palonosetron for the prevention of chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy.

BACKGROUND: The current randomized, double-blind, phase 2 study assessed the efficacy and safety profile of a single intravenous administration of fosnetupitant, a neurokinin 1 receptor antagonist prodrug, for the prevention of chemotherapy-induced nausea and vomiting in Japanese patients receiving cisplatin-based chemotherapy. METHODS: Patients scheduled to receive cisplatin (at a dose of ≥70 mg/m2 )-based regimens were randomly assigned to receive fosnetupitant at a dose of 81 mg or 235 mg or placebo in combination with palonosetron at a dose of 0.75 mg and dexamethasone. The primary endpoint was complete response (CR; no vomiting and no rescue medication) during the overall phase (0-120 hours). The overall CR rate was compared between each dose of fosnetupitant and the placebo group adjusting for the stratification factors of sex and age class (age <55 years vs age ≥55 years). Safety was assessed, with special attention given to events that potentially were suggestive of infusion site reactions. RESULTS: A total of 594 patients were randomized. Of these, 194 patients, 195 patients, and 195 patients, respectively, in the placebo and fosnetupitant 81-mg and 235-mg dose groups were evaluable for efficacy. The overall CR rate was 54.7% for the placebo group, 63.8% for the fosnetupitant 81-mg dose group (adjusted difference, 9.1%; 95% CI, -0.4% to 18.6% [P = .061]), and 76.8% for the fosnetupitant 235-mg dose group (adjusted difference, 22.0%; 97.5% CI, 11.7% to 32.3% [P < .001]). Safety profiles were comparable between the 3 groups. The incidence of infusion site reactions related to fosnetupitant was ≤1% in each dose group. CONCLUSIONS: Fosnetupitant at a dose of 235 mg provided superior prevention of chemotherapy-induced nausea and vomiting among patients receiving cisplatin-based chemotherapy compared with the control group, and with a satisfactory safety profile.

Evaluation of analgesic interaction between morphine, dexmedetomidine and maropitant using hot-plate and tail-flick tests in rats.

OBJECTIVE: To determine if the combinations of morphine, dexmedetomidine and maropitant enhance the analgesic effect and decrease the dose of individual drugs in rats subjected to noxious thermal stimulation with hot-plate and tail-flick tests. STUDY DESIGN: Randomized, blinded, prospective experimental study. ANIMALS: A total of 96 male Sprague-Dawley rats. METHODS: The rats were randomly assigned to the following groups: 1) morphine (3 mg kg-1; Mor); 2) dexmedetomidine (10 µg kg-1; Dex); 3) maropitant (20 mg kg-1; Maro); 4) morphine (1.5 mg kg-1) + dexmedetomidine (5 µg kg-1; Mor + Dex); 5) dexmedetomidine (5 µg kg-1) + maropitant (10 mg kg-1; Dex + Maro); 6) morphine (1.5 mg kg-1) + maropitant (10 mg kg-1; Mor + Maro); 7) morphine (1 mg kg-1) + dexmedetomidine (3.5 µg kg-1) + maropitant (6.5 mg kg-1; Mor + Dex + Maro); and 8) normal saline (0.5 mL; saline), all injected intravenously. The tail-flick and hot-plate tests were performed before and 5, 15, 30, 45, 60, 90 and 120 minutes after the injection of the drugs. These variables were analysed with the effect-time area under the curve (AUC) analysis and a mixed linear model. RESULTS: Data were analysed in 94 rats. The rank order of the total analgesic effects of the treatment groups shown by AUC analysis was found to be Mor > Maro + Mor > Dex + Mor > Dex > Maro > Dex + Maro + Mor > Dex + Maro > saline for the hot-plate test, and Maro + Mor > Mor > Dex + Mor > Dex + Maro + Mor > Maro > Dex > Dex + Maro > saline for the tail-flick test. The mixed model analysis showed a significant difference between latencies of the group morphine + maropitant versus all other treatment groups in the tail-flick test (p < 0.0001) and morphine versus saline in the hot-plate test (p < 0.05). CONCLUSIONS AND CLINICAL RELEVANCE: Morphine and maropitant appeared to show a supra-additive effect for analgesia in the tail-flick test. Clinical trials should be conducted to establish its use in treating pain.

Evidence-based review of data on the combination inhaler umeclidinium/vilanterol in patients with COPD.

The use of inhaled, fixed-dose, long-acting muscarinic antagonists (LAMA) combined with long-acting, beta2-adrenergic receptor agonists (LABA) has become a mainstay in the maintenance treatment of chronic obstructive pulmonary disease (COPD). One of the fixed-dose LAMA/LABA combinations is the dry powder inhaler (DPI) of umeclidinium bromide (UMEC) and vilanterol trifenatate (VI) (62.5 µg/25 µg) approved for once-a-day maintenance treatment of COPD. This paper reviews the use of fixed-dose combination LAMA/LABA agents focusing on the UMEC/VI DPI inhaler in the maintenance treatment of COPD. The fixed-dose combination LAMA/LABA inhaler offers a step beyond a single inhaled maintenance agent but is still a single device for the COPD patient having frequent COPD exacerbations and persistent symptoms not well controlled on one agent. Currently available clinical trials suggest that the once-a-day DPI of UMEC/VI is well-tolerated, safe and non-inferior or better than other currently available inhaled fixed-dose LAMA/LABA combinations for COPD.

Pharmacokinetics of single doses of maropitant citrate in adult horses.

The neurokinin-1 (NK) receptor antagonist, maropitant citrate, mitigates nausea and vomiting in dogs and cats. Nausea is poorly understood and likely under-recognized in horses. Use of NK-1 receptor antagonists in horses has not been reported. The purpose of this study was to determine the pharmacokinetic profile of maropitant in seven adult horses after single intravenous (IV; 1 mg/kg) and intragastric (IG; 2 mg/kg) doses. A randomized, crossover design was performed. Serial blood samples were collected after dosing; maropitant concentrations were measured using LC-MS/MS. Pharmacokinetic parameters were determined using noncompartmental analysis. The mean plasma maropitant concentration 3 min after IV administration was 800 ± 140 ng/ml, elimination half-life was 10.37 ± 2.07 h, and volume of distribution was 6.54 ± 1.84 L/kg. The maximum concentration following IG administration was 80 ± 40 ng/ml, and elimination half-life was 9.64 ± 1.27 hr. Oral bioavailability was variable at 13.3 ± 5.3%. Maropitant concentrations achieved after IG administration were comparable to those in small animals. Concentrations after IV administration were lower than in dogs and cats. Elimination half-life was longer than in dogs and shorter than in cats. This study is the basis for further investigations into using maropitant in horses.

Pharmacokinetics of Single and Repeat Doses of Fluticasone Furoate/Umeclidinium/Vilanterol in Healthy Chinese Adults.

The pharmacokinetics (PK) and safety of single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) after single and repeat dosing in healthy Chinese adults were assessed. In this open-label study (NCT02837380), subjects received once-daily FF/UMEC/VI 100/62.5/25 µg on day 1 and repeat doses on days 2-7. PK parameters (days 1 and 7) included maximum observed concentration (Cmax ) and area under the plasma concentration-time curve (AUC) from time zero (predose) to last time of quantifiable concentration (AUC0-t ). Terminal phase half-life (t½ ) on day 1 was estimated. The primary objective was to assess systemic exposure of FF 100 µg, UMEC 62.5 µg, and VI 25 µg following single-inhaler triple therapy on days 1 and 7. On day 1, geometric mean t½ of UMEC and VI was 0.36 and 0.52 hours, respectively; t½ of FF was not representative because of nonquantifiable concentration data. On days 1 and 7, geometric mean Cmax of FF was 10.46 and 27.32 pg/mL, respectively; Cmax of UMEC was 144.14 and 241.35 pg/mL, respectively; and Cmax of VI was 120.42 and 196.78 pg/mL, respectively. AUC0-t of FF was 1.77 and 276.96 pg·h/mL, respectively; AUC0-t of UMEC was 28.44 and 117.19 pg·h/mL, respectively; and AUC0-t of VI, 42.46 and 101.12 pg·h/mL, respectively. The PK of FF/UMEC/VI was as expected for the individual-component PK previously reported in healthy Chinese adults. No new safety signals were observed.

Population Pharmacokinetic Analysis of Fluticasone Furoate/Umeclidinium/Vilanterol via a Single Inhaler in Patients with COPD.

A population pharmacokinetic analysis was conducted from a subset of samples obtained from the Lung Function and Quality of Life Assessment in Chronic Obstructive Pulmonary Disease with Closed Triple Therapy trial to characterize the pharmacokinetics of fluticasone furoate, umeclidinium, and vilanterol in patients with symptomatic COPD following treatment with fluticason furoate-umeclidinium-vilanterol combined in a single inhaler. This was a randomized, double-blind, double-dummy study comparing 24 weeks of once-daily triple therapy (fluticason furoate-umeclidinium-vilanterol, 100 µg/62.5 µg/25 µg; Ellipta inhaler) with twice-daily dual therapy (budesonide/formoterol 400 µg/12 µg; Turbuhaler). The analyses were conducted in a subset of 74 patients who received fluticason furoate-umeclidinium-vilanterol and provided serial or sparse samples. Monte Carlo simulations and a model-based estimation approach both indicated that systemic drug concentrations of fluticasone furoate, umeclidinium, and vilanterol after administration of fluticason furoate-umeclidinium-vilanterol triple combination therapy from a single inhaler were within the ranges observed following administration of these drugs as monotherapy (fluticasone furoate, umeclidinium, and vilanterol) or as dual-combination therapy (fluticasone furoate/vilanterol or umeclidinium/vilanterol).

Assessment of pre-operative maropitant citrate use in macaque (Macaca fasicularis & Macaca mulatta) neurosurgical procedures.

BACKGROUND: Retrospective analysis of post-operative vomiting (POV) in non-human primates at our institution was 11%. Based on this additional risk factor for post-operative complications, we aimed to eliminate or decrease POV by adding an antiemetic, maropitant citrate, to the pre-medication protocol. METHODS: Retrospective and prospective data were collected over a 5-year period from 46 macaques of two species during 155 procedures. Additionally, blood was collected from five Macaca mulatta to perform a pharmacokinetic analysis. RESULTS: A 1 mg/kg subcutaneous dose of maropitant given pre-operatively significantly decreased POV. Findings indicated post-neurosurgical emesis in Macaca fasicularis was significantly greater than in Macaca mulatta. Pharmacokinetic analysis of maropitant in Macaca mulatta determined the mean maximum plasma concentration to be 113 ng/mL. CONCLUSIONS: Maropitant administration prior to anesthesia for neurosurgeries decreased our incidence of POV to 1%. The plasma concentration reaches the proposed plasma level for clinical efficacy approximately 20 minutes after administration.

A phase 2a randomized controlled study to evaluate the pharmacokinetic, safety, tolerability and clinical effect of topically applied Umeclidinium in subjects with primary axillary hyperhidrosis.

BACKGROUND: Hyperhidrosis is a common medical condition which can have a significant impact on quality of life. Umeclidinium (UMEC) is a long-acting muscarinic antagonist (LAMA) developed as a dermal formulation. OBJECTIVES: This 2-week, double-blind, randomized, vehicle-controlled study evaluated systemic exposure, safety and tolerability of topically administered UMEC in subjects with primary axillary hyperhidrosis. Clinical effect was a secondary objective, measured by gravimetry and the hyperhidrosis disease severity scale (HDSS). Vehicle was included to evaluate safety. METHODS: Twenty-three subjects were randomized to either 1.85% UMEC (N = 18) or vehicle (N = 5) once daily. RESULTS: Measurable plasma concentrations were observed in 78% of subjects after the treatment. Nine subjects (50%) on UMEC and two subjects (40%) on vehicle reported AEs, most commonly application site reactions. At Day 15, seven subjects (41%) in UMEC and two subjects (40%) in vehicle had at least a 50% reduction in sweat production. Eight subjects (47%) in UMEC and one subject (20%) in vehicle had at least a two-point reduction in HDSS. No comparisons of treatment arms were planned prospectively. CONCLUSIONS: The measurable exposure, acceptable safety and preliminary clinical activity observed in this proof-of-concept study suggest the potential clinical utility of topical UMEC in subjects with axillary hyperhidrosis.

Granisetron in the treatment of chemotherapy-induced nausea and vomiting (CINV) - is there still a role after comparison with palonosetron?

INTRODUCTION: Chemotherapy-induced nausea and vomiting (CINV) has a negative impact on the lives of subjects receiving chemotherapy. In 2009, the second generation 5-HT3-receptor antagonist, palonosetron, which is longer-acting than granisetron, was shown, as part of dual therapy with dexamethasone, to be superior to intravenous granisetron in the delayed phase of CINV. Area covered: In an attempt to maintain plasma levels of granisetron during the delayed phase of CINV, longer-acting preparations of granisetron have been manufactured. In addition to comparing intravenous/oral granisetron with palonosetron, this review considers the new longer-acting preparations of granisetron (transdermal and subcutanous) with emphasis on whether they are effective in the delayed phase of CINV. Expert opinion: Comparison of intravenous/oral granisetron and palonosetron, as part of triple therapy against the delayed phase of CINV, do not give clear-cut results as to non-inferiority or superiority of either agent. Subcutaneous granisetron is more convenient to use than transdermal granisetron, and has been shown to be non-inferior to palonosetron, as part of dual therapy, in the treatment of the acute and delayed phases of CINV. At present, it seems likely that there will be ongoing roles for intravenous and subcutaneous granisetron in CINV, but further data is required to ascertain the future of transdermal granisetron.

Population Pharmacokinetics Modeling of Inhaled Umeclidinium for Adult Patients with Asthma.

BACKGROUND: Umeclidinium (UMEC; a long-acting anti-muscarinic) in combination with fluticasone furoate (an inhaled corticosteroid) is in development for asthma treatment. This secondary analysis aimed to develop a population pharmacokinetic model characterizing UMEC in adults with asthma, and evaluated the impact of covariates on pharmacokinetic parameters. METHODS: Plasma concentration data from study NCT01641692 (assessing once-daily UMEC 15.6, 31.25, 62.5, 125, and 250 mcg, twice daily UMEC 15.6 and 31.25 mcg, and placebo) were analyzed using non-linear mixed-effect modeling in NONMEM®. Full likelihood, including observed data and data below the quantification limit (treated as censored), was maximized. Study endpoints were population pharmacokinetics (including apparent inhaled clearance [CL/F] and apparent distribution volume in the central compartment [V c/F]) and derived pharmacokinetic parameters (area under the concentration-time curve [AUC] and maximum concentration [C max] at steady-state). RESULTS: In total, 128 patients provided 3757 data points. The pharmacokinetics of UMEC were best described using a two-compartment model with intravenous bolus input, due to fast absorption following inhalation. CL/F was 257 L/h and V c/F was 804 L. Creatinine clearance was a significant covariate for CL/F, as were age and body weight for V c/F. AUC and C max increased with increasing UMEC dose (once-daily 15.6-250 mcg: AUC0-24 median: 64.7-863 pg h/mL; C max median: 10.6-256 pg/mL). CONCLUSION: The final population pharmacokinetic model adequately described the data, demonstrating minimal creatinine clearance, age, and body weight effects on overall plasma UMEC pharmacokinetics and systemic exposure.