Bioavailability of Cariban® Capsules: A Modified-Release Fixed-Dose Combination of Doxylamine and Pyridoxine to Relieve Nausea and Vomiting During Pregnancy.

BACKGROUND: Nausea and vomiting is a very prevalent condition during pregnancy. Combination of doxylamine and pyridoxine is placed as first-line pharmacological option for its treatment in most clinical guidelines. Among different release forms available, Cariban® is a fixed-dose combination of doxylamine/pyridoxine 10/10 mg, formulated as modified-release capsules. OBJECTIVES: In the present study, we aimed to characterize the bioavailability performance of Cariban® in vitro and in vivo. METHODS: An in vitro dissolution test was performed to evaluate the release profile of Cariban®, together with immediate- and delayed-release formulations available on the market. A single-center, single-dose, open-label bioavailability study following Cariban® administration in 12 healthy adult female patients was carried out to explore the drug behavior in vivo (protocol NBR-002-13; EUDRA-CT 2013-005422-35). These data were additionally used to perform a computational pharmacokinetic simulation of the posology approved for this drug. RESULTS: Cariban® capsules demonstrate a prolonged-release performance, with an early, gradual, and progressive release of both actives until reaching a complete dissolution after 4-5 h in solution. The pharmacokinetic features of these capsules show that doxylamine and pyridoxine metabolites are early absorbed, being all detectable in plasma within 1 h following oral administration. Computational pharmacokinetic simulation predicts that different posology provides distinct profiles of metabolites in plasma, with 1-1-2 (morning-midafternoon-night) being the one that concentrates higher plasma levels but lower dose dumping for 24 h. CONCLUSION: Cariban® behaves as a prolonged-release formulation, which correlates with rapid absorption and arising of the actives in the plasma, but also long-lasting and sustained bioavailability, especially when administered following the complete posology. These results would underlie its demonstrated efficacy to relieve nausea and vomiting of pregnancy (NVP) under clinical settings.

Pharmacokinetics of intramuscular maropitant in pigs (Sus scrofa domesticus).

Pigs are at risk of vomiting from medical conditions as well as the emetic side effects of drugs administered for peri-operative manipulations, but there is a lack of pharmacokinetic data for potential anti-emetic therapies, such as maropitant, in this species. The main objective of this study was to estimate plasma pharmacokinetic parameters for maropitant in pigs after a single intramuscular (IM) administration dosed at 1.0 mg/kg. A secondary objective was to estimate pilot pharmacokinetic parameters in pigs after oral (PO) administration at 2.0 mg/kg. Maropitant was administered to six commercial pigs at a dose of 1.0 mg/kg IM. Plasma samples were collected over 72 h. After a 7-day washout period, two pigs were administered maropitant at a dose of 2.0 mg/kg PO. Maropitant concentrations were measured via liquid chromatography/mass spectrometry (LC-MS/MS). A non-compartmental analysis was used to derive pharmacokinetics parameters. No adverse events were noted in any of the study pigs after administration. Following single IM administration, maximum plasma concentration was estimated at 412.7 ± 132.0 ng/mL and time to maximum concentration ranged from 0.083 to 1.0 h. Elimination half-life was estimated at 6.7 ± 1.28 h, and mean residence time was 6.1 ± 1.2 h. Volume of distribution after IM administration was 15.9 L/kg. Area under the curve was 1336 ± 132.0 h*ng/mL. The relative bioavailability of PO administration was noted to be 15.5% and 27.2% in the two pilot pigs. The maximum systemic concentration observed in the study pigs after IM administration was higher than what was observed after subcutaneous administration in dogs, cats, or rabbits. The achieved maximum concentration exceeded the concentrations for anti-emetic purposes in dogs and cats; however, a specific anti-emetic concentration is currently not known for pigs. Further research is needed into the pharmacodynamics of maropitant in pigs to determine specific therapeutic strategies for this drug.

15-hydroxystearate micelles for the delivery of aprepitant: Preparation, characterization, pharmacokinetics and tissue distribution in mice.

This study developed a novel Aprepitant micells (APPT-Ms) formulation that uses a mixture of 15-hydroxystearate (HS15) as surfactant to solubilize AAPT. This article determines the content of APPT by HPLC. The in vitro test results show that the optimized APPT-Ms has small particle size, excellent stability and long-lasting release. At a test dose of 20mg/kg, the pharmacokinetic study of APPT-Ms showed that it accorded with first-order kinetics in mice, and its AUC value was higher than the pure AAPT about 6 times. The tissue distribution study of mice showed that the APPT-Ms had higher tissue binding ability than pure AAPT. The APPT-Ms could be rapidly distributed to various tissues and it was easier to pass through the blood-brain barrier than APPT. In this study, the APPT-Ms has high antiemetic activity and improves the compliance of patient. The pharmacokinetics and tissue distribution of APPT-Ms after injection administration were studied, which may be of guiding significance for further research.

Formulation and optimization of dimenhydrinate emulgels for topical delivery using response surface methodology.

Development of dimenhydrinate (DMN) emulgel formulation has been described in this work with enhanced permeation for transdermal delivery of DMN for effective management of motion sickness. Various DMN emulgel formulations were prepared using central composite design in response surface methodology. Propylene glycol and olive oil were used in varying ratios as permeation enhancers along-with carbopol-934 as gelling agent. Prepared formulations were evaluated by physico-chemical properties, stability and Fourier transform infrared spectroscopy (FTIR) studies. In-vitro drug release was studied using cellophane membrane. Formulation F2 showed maximum drug permeation following diffusion-based release mechanism and was used in further studies. Rat skin was used in Franz cell for ex-vivo studies to determine various permeation kinetic parameters. FTIR studies provided no evidence of chemical interaction between DMN and polymers used, whereas molecular docking revealed formation of a stable complex in the presence of aqueous environment with stable intermolecular binding and the complex was well hydrated. No evidence of skin irritation was observed in human volunteers following application of the optimized formulation. Histopathology data of the rat skin showed a decreased proliferation of the lymphocytes whereas monocytes were induced. In conclusion, combination of propylene glycol and olive oil was successfully employed for delivery of DMN through transdermal route with good permeability and prolonged release time that can be highly beneficial in treating motion sickness in unusual circumstances.

Oral Drug Delivery Systems Based on Ordered Mesoporous Silica Nanoparticles for Modulating the Release of Aprepitant.

Two different types of ordered mesoporous nanoparticles, namely MCM-41 and MCM-48, with similar pore sizes but different pore connectivity, were loaded with aprepitant via a passive diffusion method. The percentage of the loaded active agent, along with the encapsulation efficiency, was evaluated using High-performance Liquid Chromatography (HPLC) analysis complemented by Thermogravimetric Analysis (TGA). The determination of the pore properties of the mesoporous particles before and after the drug loading revealed the presence of confined aprepitant in the pore structure of the particles, while Powder X-ray Diffractometry(pXRD), Differential Scanning Calorimetry (DSC), and FTIR experiments indicated that the drug is in an amorphous state. The release profiles of the drug from the two different mesoporous materials were studied in various release media and revealed an aprepitant release up to 45% when sink conditions are applied. The cytocompatibility of the silica nanoparticles was assessed in Caco-2 cell monolayers, in the presence and absence of the active agent, suggesting that they can be used as carriers of aprepitant without presenting any toxicity in vitro.

Pharmacokinetics of Dexamethasone when Administered with Fosaprepitant for Chemotherapy-Induced Nausea and Vomiting and Differences in Dose-Dependent Antiemetic Effects.

BACKGROUND: Fosaprepitant, an NK1 receptor antagonist, inhibits and induces cytochrome P450 3A4 (CYP3A4) as its substrate. Contrarily dexamethasone is metabolized by CYP3A4. Therefore, in combination therapy wherein both agents interact with each other, it is recommended that the dexamethasone dose be reduced in the first two days. Thus far, there are only a few studies on the optimum dose of dexamethasone after day 3. Thus, we aimed to determine the pharmacokinetics of dexamethasone on day3 when administered together with fosaprepitant and investigate the dose-dependent differences in its antiemetic effect in patients with cancer. METHODS: Twelve patients with esophageal, stomach, or lung cancer received primary highly emetogenic chemotherapy (HEC). We intravenously administered 9.9 mg and 6.6 mg of dexamethasone on days 1 and 2, respectively, and 6.6 mg or 13.2 mg on day 3 together with the administration of 150 mg fosaprepitant and 0.75 mg palonosetron. We assessed the pharmacokinetics of dexamethasone on day 3 by dose and examined the dose-dependent antiemetic effect. RESULTS: No differences were observed in the time-to-maximum concentration and blood half-life of dexamethasone between patient groups that received dexamethasone at doses of 6.6 mg and 13.2 mg. In contrast, the area under the blood concentration-time curve and the maximum concentration of dexamethasone correlated with its dose. Moreover, the blood dexamethasone concentration on day 3 increased by twofold after the administration of a higher dose than after a lower dose. The severity of nausea in the delayed phase significantly decreased in a dose-dependent manner. CONCLUSION: Administration of a higher dexamethasone dose on day 3 improved the antiemetic effect of the combined regimen in patients with cancer who underwent HEC.
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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.

Impaired Clearance From the Brain Increases the Brain Exposure to Metoclopramide in Elderly Subjects.

The antiemetic and gastroprokinetic drug metoclopramide is a weak substrate of the blood-brain barrier (BBB) efflux transporter P-gp and displays central nervous system (CNS) side effects (i.e., extrapyramidal symptoms and tardive dyskinesia) caused by dopamine D2 receptor blockade in the basal ganglia. These side effects occur with a higher incidence in elderly people. We used positron emission tomography to assess the brain distribution of [11 C]metoclopramide in young (n = 11, 26 ± 3 years) and elderly (n = 7, 68 ± 9 years) healthy men both after administration of a microdose (9 ± 7 µg) and a microdose co-injected with a therapeutic dose of unlabeled metoclopramide (10 mg). For both doses, elderly subjects had a significantly higher total volume of distribution (VT ) of [11 C]metoclopramide in the basal ganglia than young subjects (microdose: +26%, therapeutic dose: +41%). Increases in VT (= K1 /k2 ) were caused by significant decreases in the transfer rate constant of [11 C]metoclopramide from brain into plasma (k2 , microdose: -18%, therapeutic dose: -30%), whereas the distributional clearance from plasma into brain (K1 ) remained unaltered. This reduction in the clearance of [11 C]metoclopramide (k2 ) from the brains of elderly subjects may be caused by an age-related decrease in the activity of P-gp at the BBB and may contribute to the higher incidence of CNS side effects of metoclopramide in the aged population. Our data suggest that an age-associated decrease in the clearance properties of the BBB may modulate the CNS effects or side effects of clinically used P-gp substrates.

Pharmacokinetics and Safety of Fosaprepitant Dimeglumine in Healthy Chinese Volunteers: Bioequivalence Study.

Fosaprepitant dimeglumine (FD) is a precursor of aprepitant. FD can be metabolized into aprepitant. This randomized, single-center, open, 2-cycle, single-dose, crossover bioequivalence study compared the pharmacokinetics (PK) and safety of intravenously FD of test and reference products in healthy volunteers (HVs). HVs were assigned to the test group or reference group randomly and given FD intravenously. The plasma concentration of FD and aprepitant was measured using liquid chromatography-tandem mass spectrometry. PK parameters were ascertained based on a noncompartmental model. Data for 29 HVs were obtained. The geometric mean and 90% confidence intervals of maximum plasma concentration (Cmax ), area under the concentration-time curve from time 0 to time of last measurable plasma concentration (AUC0-t ), and area from the last datum point to time infinity (AUC0-∞ ) of test and reference groups were 101.69% (95.06%, 108.77%), 103.52% (99.15%, 108.09%), and 105.58% (99.51%, 112.01%), respectively. These 3 parameters were within the acceptance range of 80.0% to 125.00%, and the test product was bioequivalent to the reference product. The coefficient of variation (CV) of Cmax , AUC0-t , and AUC0-∞ was 15.14%, 9.67%, and 11.89%, respectively. Intravenously administered FD provided by 2 sponsors achieved bioequivalence. FD values from test and reference products were bioequivalent. All adverse events were mild and serious adverse events absent in HVs. This study indicated that FD may provide a safer alternative to aprepitant for chemotherapy-induced nausea and vomiting.

Effect of clarithromycin pre-treatment on the pharmacokinetics of metoclopramide after their simultaneous oral intake.

OBJECTIVE: The objective of this study was to assess the influence of enzyme suppression on the values of various pharmacokinetic factors of orally administered metoclopramide. METHOD: This study was conducted in two phases and a 4-week duration was adopted for drug washout. This randomized study involved 12 healthy human volunteers who received a single oral dose of metoclopramide 20 mg. After the washout period, volunteers received clarithromycin 500 mg two times per day for consecutive 5 days. On test day (fifth day), a single oral dose of metoclopramide 20 mg was also given to the volunteers, and collection of blood samples was conducted at pre-decided time points. Various pharmacokinetic parameters such as Cmax, Tmax, and AUC0-∞ of metoclopramide were determined by analyzing the blood samples using a validated HPLC-UV method. RESULTS: Clarithromycin increased the mean values of Cmax, AUC0-∞, and T1/2 of metoclopramide by 46%, 78.6%, and 9.8%, respectively. CONCLUSION: Clarithromycin noticeably increased the concentration of plasma metoclopramide. This study's results provide in vivo confirmation of the CYP3A4 involvement in metoclopramide metabolism, in addition to CYP2D6. Therefore, metoclopramide pharmacokinetics may be clinically affected by clarithromycin and other potent enzyme inhibitors.

Nanotechnology based blended chitosan-pectin hybrid for safe and efficient consolidative antiemetic and neuro-protective effect of meclizine hydrochloride in chemotherapy induced emesis.

The aim of this study was to formulate an easily-administered, safe and effective dosage form loaded with meclizine for treatment of chemotherapy-induced nausea and vomiting (CINV) through the buccal route. CINV comprises bothersome side effects accompanying cytotoxic drugs administration in cancer patients. Meclizine was loaded in chitosan-pectin nanoparticles which were further incorporated within a buccal film. Different formulations were prepared based on a 21.31 full factorial study using Design Expert®8. The optimum formulation possessed favorable characters regarding its particle size (129 nm), entrapment efficiency (90%) and release profile. Moreover, its permeation efficiency through sheep buccal mucosa was assessed via Franz cell diffusion and confocal laser microscopy methods. Enhanced permeation was achieved compared with the free drug form. In-vivo performance was assessed using cyclophosphamide induced emesis. The proposed formulation exerted significant relief of the measured responses (reduced body weight and motor coordination, elevated emesis, anorexia, proinflammatory mediators and neurotransmitters that were also associated with scattered degenerated neurons and glial cells). The developed formulation ameliorated all behavioral, biochemical and histopathological changes induced by cyclophosphamide. The obtained data were promising suggesting that our bioadhesive formulation can offer an auspicious medication for treating distressing symptoms associated with chemotherapy for cancer patients.

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.

Extrapolation of Adult Efficacy to Pediatric Patients With Chemotherapy-Induced Nausea and Vomiting.

Chemotherapy-induced nausea and vomiting (CINV) is a common treatment-related adverse event that negatively impacts the quality of life of cancer patients. During pediatric drug development, extrapolation of efficacy from adult to pediatric populations is a pathway that can minimize the exposure of children to unnecessary clinical trials, improve efficiency, and increase the likelihood of success in obtaining a pediatric indication. The acceptability of the use of extrapolation depends on a series of evidence-based assumptions regarding the similarity of disease, response to intervention, and exposure-response relationships between adult and pediatric patients. This study evaluated publicly available summaries of data submitted to the US Food and Drug Administration for drugs approved for CINV to assess the feasibility of extrapolation for future development programs. Extracted data included trial design, emetogenic potential of chemotherapy, primary end points, participant enrollment criteria, and antiemetic pharmacokinetics. Adult and pediatric clinical trial designs for assessment of efficacy and safety shared key design elements. Antiemetic drugs found to be efficacious in adults were also efficacious in pediatric patients. Systemic drug concentrations at approved doses were similar for ondansetron, granisetron, and aprepitant, but an exposure-response analysis of palonosetron in children suggested that higher palonosetron systemic exposure is necessary for the prevention of CINV in the pediatric population. For 5-hydroxytryptamine-3 and neurokinin-1 receptor antagonist antiemetic drugs, efficacy in adults predicts efficacy in children, supporting the extrapolation of effectiveness of an antiemetic product in children from adequate and well-controlled studies in adult patients with CINV.

Mucoadhesive thermoreversible formulation of metoclopramide for rectal administration: a promising strategy for potential management of chemotherapy-induced nausea and vomiting.

The study aimed to investigate the feasibility of incorporation of metoclopramide hydrochloride (MCP HCl) in mucoadhesive thermoreversible liquid suppository (MCP HCl-LS) to bypass the first-pass metabolism and maximize its efficacy to be a promising substitute for parenteral therapy. MCP HCl-LS was formulated using Pluronic (PF127/PF68) and hydroxypropylmethylcellulose (HPMC) and in vitro evaluated through their gelation temperature, gel strength (GS), mucoadhesive force, and in vitro release studies. Also, the MCP HCl-LS was evaluated for its rheological behavior and examined for rectal mucosal integrity after administration. The results revealed that the MCP HCl-LS; composed of PF127/PF68/HPMC (20/7/0.5% w/w) was in the liquid state at room temperature, experienced gelation at 30.23 °C, with suitable GS of 28.66 s and rectal retention force of 43.03 × 102 dyne/cm2. The pharmacokinetic data showed that the MCP HCl-LS exhibited a significant increase (p < 0.05) in AUC0-480 (219.688 vs 172.333 ng.h.mL-1 of the marketed) and 1.3-fold increase in relative bioavailability compared to Primperan® suppository, indicating that LS formula bypassed the first-pass metabolism. Moreover, MCP HCl-LS did not cause any morphological harm to the rectal tissues suggested that the developed formulation was safe and could be a potentially useful alternative drug carrier for rectal delivery of MCP HCl in patients experiencing chemotherapy-induced nausea and vomiting.

The effects of oral administration of Cola nitida on the pharmacokinetic profile of metoclopramide in rabbits.

BACKGROUND: Cola nitida is commonly chewed in many West African cultures to ease hunger pangs and sometimes for their stimulant and euphoriant qualities. Metoclopramide is a known substrate for P-gp, SULT2A1 and CYP2D6 and studies have revealed that caffeine- a major component of Cola nitida can induce P-glycoprotein (P-gp), SULT2A1 and SULT1A1, hence a possible drug interaction may occur on co-administration. The aim of this study was to investigate the pharmacokinetic interactions of Cola nitida and metoclopramide in rabbits. METHODS: The study was performed in two stages using five healthy male rabbits with a 1-week washout period between treatments. Stage one involved oral administration of metoclopramide (0.5 mg/kg) alone while in the second stage, metoclopramide (0.5 mg/kg) was administered concurrently with Cola nitida (0.7 mg/kg). Blood samples were collected after each stage at predetermined intervals and analyzed for plasma metoclopramide concentration using HPLC. RESULTS: Compared with control, the metoclopramide/Cola nitida co-administration produced a decrease in plasma concentration of metoclopramide at all the time intervals except at the 7th hour. The following pharmacokinetic parameters were also decreased: area under the curve (51%), peak plasma concentration (39%), half-life (51%); while an increase in elimination rate constant (113%) and clearance rate (98%) were noted indicating rapid elimination of the drug. A minimal decrease in absorption rate (10%) was also observed. CONCLUSIONS: The results of this study reveal a possible herb-drug interaction between Cola nitida and metoclopramide.

Sustained release formulation of Ondansetron HCl using osmotic drug delivery approach.

Ondansetron HCl (OSH) is a 5-HT3 receptor antagonist indicated for the prevention of nausea and vomiting associated with radiotherapy (adults: 8 mg, t.i.d) and/or chemotherapy (adults: 8 mg, b.i.d to t.i.d) and prevention of postoperative nausea and/or vomiting (adults: 8 mg, b.i.d). In elderly subjects, bioavailability may be somewhat higher (65%) and lower clearance, presumably due to reduced hepatic first-pass metabolism. OSH is extensively distributed in the body; about 70-75% of the drug in plasma is protein-bound and terminal elimination half-life is about 3 h after oral administration. The study was aimed to develop Push-pull Osmotic Pump (PPOP) bi-layered tablets for Ondansetron HCl ER tablets. The granulation was carried out using non-aqeous solvents followed by compression, seal coating, semi permeable coating, laser drilling (0.6 mm), and drug film coating with loading dose. The drug release was controlled by swelleable osmotic polymers of pull layer and push layer and orifice on the surface of tablet. The formulations were optimized for its core composition, extended release coating (Semipermeable membrane) polymer as to plasticizer ratio and orifice diameter. Optimized formulations were evaluated for micromeritic properties and in vitro drug release. The analytical methods were developed and validated to estimate in vitro drug potency, drug release, and in vivo pharmacokinetic parameters. Stability studies were done as per the ICH guidelines. The results of in vivo study concludes that the once OSH ER dose consistently maintains plasma concentration of drug within the therapeutic window over a period of 24 h.

Population pharmacokinetics of orally administrated bromopride: Focus on the absorption process.

Bromopride is a prokinetic and antiemetic drug used to treat nausea and vomiting. Although its prescription is common in Brazil, there is a lack of studies about bromopride pharmacokinetics. Therefore, the aims of this study were to investigate the population pharmacokinetics of bromopride and to evaluate the influence of covariates on its absorption. This study is a retrospective analysis of data collected from bioequivalence studies. The data was modeled using MONOLIX 2018R2. Assuming one-compartment and linear elimination, the absorption phase was evaluated with different structural models. The model of sequential first- and zero-order with combined error and exponential inter-individual variability in all parameters best described the atypical absorption profile of bromopride. Population estimates were first-order absorption rate (ka) of 0.08 h - 1, fraction of dose absorbed by first-order (Fr) of 32.60%, duration of the zero-order absorption (Tk0) of 0.88 h with latency time (Tlag) of 0.47 h, volume of distribution of 230 l and clearance of 46.80 l h - 1. Bodyweight affects Tk0, dosage form was found to correlate with Tk0 and Tlag, while gender affects Tlag. However, simulations evaluating the clinical importance of these covariates on steady-state indicated minimal changes on bromopride exposure. The mixed absorption model was reasonable to describe the absorption process of bromopride because it had the flexibility to fit multiple-peaks profile and shows good agreement with physicochemical properties of drug.

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.

The safety of rolapitant for the treatment of nausea and vomiting associated with chemotherapy.

Introduction: Chemotherapy-induced nausea and vomiting is a significant clinical issue that affects patients' quality of life as well as treatment decisions. Significant improvements in the control of chemotherapy-induced nausea and vomiting have occurred in the past 15 years with the introduction of new antiemetic agents 5-HT3, receptor antagonists, neurokinin-1 receptor antagonists, and olanzapine. Oral (aprepitant, 2003; netupitant, 2014; rolapitant, 2015) neurokinin-1 receptor antagonists have been developed along with intravenous formulations (fosaprepitant, NEPA, rolapitant, HTX-019) for the prevention of chemotherapy-induced nausea and vomiting.Areas covered: This review presents a description of the safety and efficacy of rolapitant along with a comparison to the other oral and intravenous formulations of the neurokinin-1 receptor antagonists.Expert opinion: Oral rolapitant has been demonstrated in clinical trials to be safe and effective in controlling chemotherapy-induced nausea and vomiting in patients receiving moderately and highly emetogenic chemotherapy. Rolapitant has a longer half-life (180 h) than other commercially available NK-1 receptor antagonists and does not induce or inhibit CYP34A, unlike the other NK-1 receptor antagonists. Future studies may determine if these may be important clinical issues.

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.