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.

Development and validation of a combined liquid chromatography tandem-mass spectrometry assay for the quantification of aprepitant and dexamethasone in human plasma to support pharmacokinetic studies in pediatric patients.

A pharmacokinetic study was set up to investigate the pharmacokinetics of the anti-emetic agents aprepitant and dexamethasone and the drug-drug interaction between these drugs in children. In order to quantify aprepitant and dexamethasone, a liquid chromatography-tandem mass spectrometry assay was developed and validated for the simultaneous analysis of aprepitant and dexamethasone. Protein precipitation with acetonitrile-methanol (1:1, v/v) was used to extract the analytes from plasma. The assay was based on reversed-phase chromatography coupled with tandem mass spectrometry detection operating in the positive ion mode. The assay was validated based on the guidelines on bioanalytical methods by the US Food and Drug Administration and European Medicines Agency. The calibration model was linear and a weighting factor of 1/concentration2 was used over the range of 0.1-50 ng/mL for aprepitant and 1-500 ng/mL for dexamethasone. Intra-assay and inter-assay bias were within ±20% for all analytes at the lower limit of quantification and within ±15% at remaining concentrations. Dilution integrity tests showed that samples exceeding the upper limit of quantification can be diluted 100 times in control matrix. Stability experiments showed that the compounds are stable in the biomatrix for 25 h at room temperatures and 89 days at -20 °C. This assay is considered suitable for pharmacokinetic studies and will be used to study the drug-drug interaction between aprepitant and dexamethasone in pediatric patients.

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.

Understanding Mechanisms of Food Effect and Developing Reliable PBPK Models Using a Middle-out Approach.

Over the last 10 years, 40% of approved oral drugs exhibited a significant effect of food on their pharmacokinetics (PK) and currently the only method to characterize the effect of food on drug absorption, which is recognized by the authorities, is to conduct a clinical evaluation. Within the pharmaceutical industry, there is a significant effort to predict the mechanism and clinical relevance of a food effect. Physiologically based pharmacokinetic (PBPK) models combining both drug-specific and physiology-specific data have been used to predict the effect of food on absorption and to reveal the underlying mechanisms. This manuscript provides detailed descriptions of how a middle-out modeling approach, combining bottom-up in vitro-based predictions with limited top-down fitting of key model parameters for clinical data, can be successfully used to predict the magnitude and direction of food effect when it is predicted poorly by a bottom-up approach. For nefazodone, a mechanistic clearance for the gut and liver was added, for furosemide, an absorption window was introduced, and for aprepitant, the biorelevant solubility was refined using multiple solubility measurements. In all cases, these adjustments were supported by literature data and showcased a rational approach to assess the factors limiting absorption and exposure.

Simple Liquid Chromatography-Tandem Mass Spectrometry Method for Quantitation of Total and Free Aprepitant and Its Active N-Dealkylated Metabolites in Human Plasma.

BACKGROUND: Aprepitant, an antiemetic selective neurokinin-1 receptor antagonist, is primarily metabolized to the active N-dealkylated form (ND-AP) and then converted to its carbonyl form (ND-CAP) in humans. This study developed a simple liquid chromatography-tandem mass spectrometry method using electrospray ionization for the quantitation of plasma total and free aprepitant and its N-dealkylated metabolites and used them to analyze patient plasma. METHODS: Free aprepitant and ND-AP in plasma were fractionated using centrifugal ultrafiltration. The analytes in plasma or their ultrafiltered specimens treated with triethylamine/acetonitrile were isocratically separated using a 3-µm octadecylsilyl column with a total run time of 10 minutes and scanned using positive ion electrospray ionization. RESULTS: The calibration curves of total aprepitant, ND-AP, and ND-CAP were prepared at concentration ranges of 50-2500, 20-1000, and 5-250 ng/mL, respectively, whereas that of free aprepitant and ND-AP were at a concentration range of 2-150 ng/mL. The intraassay and interassay accuracy and imprecision values were 93.5%-107.7% and 94.6%-103.3%, and 2.1%-7.5% and 1.0%-8.9%, respectively. Aprepitant and its metabolites did not exhibit any matrix effects or instabilities in the plasma specimens. In cancer patients receiving oral aprepitant, the plasma concentration ranges of total aprepitant, ND-AP, and ND-CAP, and free aprepitant and ND-AP were 137-2170, 104-928, 22.4-97.6, 8.11-60.0, and 3.53-56.0 ng/mL, respectively. The median plasma free fraction proportion of aprepitant and ND-AP was 4.14% and 4.90%, respectively. CONCLUSIONS: The present developed method showed an acceptable analytical performance and can be used to evaluate total and free aprepitant and its N-dealkylated metabolites in patient plasma.

Comparison of Pharmacokinetics of Aprepitant in Healthy Chinese and Caucasian Subjects.

PURPOSE: Aprepitant is used to prevent nausea and vomiting associated with moderately and highly emetogenic chemotherapy. In this open-label, 2-period study, the safety, tolerability, and pharmacokinetics (PK) of aprepitant (EMEND®) were evaluated in healthy Chinese and Caucasian subjects. PATIENTS AND METHODS: Twelve Chinese and 12 Caucasian subjects were to receive a 125 mg single-dose of aprepitant during period 1; subsequently, after 15 days washout, only Chinese subjects were to receive the 3-day regimen in period 2. In each period, serial blood samples were collected and analyzed by a validated liquid chromatographic and mass spectrometric method to characterize aprepitant PK across both groups. RESULTS: In both Chinese and Caucasian subjects, there were no serious adverse events. AUC0-∞, Cmax, Tmax, and t1/2 were largely comparable between the two ethnicities. Comparing the result of period 1 in Chinese and Caucasian subjects, the geometric least-squares mean maximum plasma concentrations (Cmax) were 1482 ng/mL and 1435 ng/mL, and the area under the concentration-time curve (AUC0-∞) 34,035 hr·ng/mL and 34,188 hr·ng/mL. In period 2, the geometric mean AUC0-24 on Day 1 and Day 3 were 19,446 hr·ng/mL and 27,843 hr·ng/mL, and the geometric mean Cmax on Day 1 and Day 3 were 1423 ng/mL and 1757 ng/mL, respectively. CONCLUSION: Aprepitant is generally safe and well tolerated in healthy Chinese and Caucasian subjects. Aprepitant PK is comparable between Chinese and Caucasian subjects following single-dose administration. The PK following a clinical 3-day regimen on healthy Chinese subjects has been characterized.

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.

A pH-responsive nanoparticle targets the neurokinin 1 receptor in endosomes to prevent chronic pain.

Nanoparticle-mediated drug delivery is especially useful for targets within endosomes because of the endosomal transport mechanisms of many nanomedicines within cells. Here, we report the design of a pH-responsive, soft polymeric nanoparticle for the targeting of acidified endosomes to precisely inhibit endosomal signalling events leading to chronic pain. In chronic pain, the substance P (SP) neurokinin 1 receptor (NK1R) redistributes from the plasma membrane to acidified endosomes, where it signals to maintain pain. Therefore, the NK1R in endosomes provides an important target for pain relief. The pH-responsive nanoparticles enter cells by clathrin- and dynamin-dependent endocytosis and accumulate in NK1R-containing endosomes. Following intrathecal injection into rodents, the nanoparticles, containing the FDA-approved NK1R antagonist aprepitant, inhibit SP-induced activation of spinal neurons and thus prevent pain transmission. Treatment with the nanoparticles leads to complete and persistent relief from nociceptive, inflammatory and neuropathic nociception and offers a much-needed non-opioid treatment option for chronic pain.

Relative bioavailability of an extemporaneously prepared aprepitant oral suspension in healthy adults.

PURPOSE: Use of aprepitant for chemotherapy-induced nausea and vomiting prophylaxis in patients unable to swallow capsules is hindered by the lack of a commercially available oral liquid formulation in many jurisdictions. A stable oral suspension can be extemporaneously prepared using commercially available capsules. We aimed to determine the bioavailability of this aprepitant suspension relative to the capsule. METHODS: This two-period crossover study enrolled 17 healthy adult volunteers. Volunteers received a single 125 mg aprepitant dose during each study period. Order of formulation presentation (capsule vs suspension first) was randomized. Thirteen blood samples were collected over a 48-h period. Aprepitant plasma concentrations were determined using liquid chromatography-mass spectroscopy. Relative bioavailability was defined as the geometric least squares mean ratio for area under the concentration versus time curve (AUC) from time zero to infinity of the aprepitant suspension versus the capsule. Bioequivalence, defined as per Health Canada guidelines, was assessed as a secondary aim. RESULTS: Relative bioavailability of the aprepitant suspension was 82.3% (90% CI: 69.09-98.00%). Bioequivalence was not established: geometric least squares mean ratios (suspension/capsule) for AUC time zero to 48 h and maximum concentration were 87.8% (90% CI: 75.48-102.16%) and 86.1% (90% CI: 75.59-98.16%), respectively. No serious adverse events were observed. CONCLUSIONS: With a relative bioavailability of 82.3%, the extemporaneous aprepitant oral suspension was well-absorbed relative to the capsule. Though not bioequivalent to the oral capsule, the clinical use of this aprepitant oral suspension in adult and pediatric patients unable to swallow capsules is likely to be effective and safe.

Combining biorelevant in vitro and in silico tools to simulate and better understand the in vivo performance of a nano-sized formulation of aprepitant in the fasted and fed states.

INTRODUCTION: When developing bio-enabling formulations, innovative tools are required to understand and predict in vivo performance and may facilitate approval by regulatory authorities. EMEND® is an example of such a formulation, in which the active pharmaceutical ingredient, aprepitant, is nano-sized. The aims of this study were 1) to characterize the 80 mg and 125 mg EMEND® capsules in vitro using biorelevant tools, 2) to develop and parameterize a physiologically based pharmacokinetic (PBPK) model to simulate and better understand the in vivo performance of EMEND® capsules and 3) to assess which parameters primarily influence the in vivo performance of this formulation across the therapeutic dose range. METHODS: Solubility, dissolution and transfer experiments were performed in various biorelevant media simulating the fasted and fed state environment in the gastrointestinal tract. An in silico PBPK model for healthy volunteers was developed in the Simcyp Simulator, informed by the in vitro results and data available from the literature. RESULTS: In vitro experiments indicated a large effect of native surfactants on the solubility of aprepitant. Coupling the in vitro results with the PBPK model led to an appropriate simulation of aprepitant plasma concentrations after administration of 80 mg and 125 mg EMEND® capsules in both the fasted and fed states. Parameter Sensitivity Analysis (PSA) was conducted to investigate the effect of several parameters on the in vivo performance of EMEND®. While nano-sizing aprepitant improves its in vivo performance, intestinal solubility remains a barrier to its bioavailability and thus aprepitant should be classified as DCS IIb. CONCLUSIONS: The present study underlines the importance of combining in vitro and in silico biopharmaceutical tools to understand and predict the absorption of this poorly soluble compound from an enabling formulation. The approach can be applied to other poorly soluble compounds to support rational formulation design and to facilitate regulatory assessment of the bio-performance of enabling formulations.

Pharmacokinetics and pharmacodynamics of aprepitant for the prevention of postoperative nausea and vomiting in pediatric subjects.

BACKGROUND/PURPOSE: This multicenter, randomized, partially-blinded phase IIb study evaluated the pharmacokinetics (PK)/pharmacodynamics, safety, and tolerability of aprepitant in pediatric subjects for the prevention of postoperative nausea and vomiting (PONV). METHODS: Subjects aged birth to 17 years scheduled to undergo surgery and receive general anesthesia with ≥1 risk factor for PONV were randomly assigned to 1 of 3 aprepitant dose regimens (a single oral dose of aprepitant equivalent to adult doses of 10 mg, 40 mg, or 125 mg), or a control regimen of ondansetron before anesthesia. Assessments included PK, safety, and exploratory efficacy (complete response [CR; no emesis, retching, or dry heaves and no rescue therapy within 0-24 h following surgery] and no vomiting [NV; no emesis, retching, or dry heaves within 0-24 h following surgery]). RESULTS: Of 220 randomized and treated subjects, 119 receiving a single aprepitant dose were sampled for PK analysis and had evaluable aprepitant plasma concentrations. A dose-dependent relationship in exposure (AUC0-8 h and Cmax) was observed. Aprepitant was generally well tolerated, and the CR and NV rates were high (>80%) across treatment groups. CONCLUSIONS: PK, safety, and preliminary efficacy analyses support further clinical evaluation of aprepitant for PONV prophylaxis in pediatric patients. CLINICALTRIALS. GOV ID: NCT01732458 LEVEL OF EVIDENCE: Therapeutic, Level I.

HTX-019 via 2-min injection or 30-min infusion in healthy subjects.

AIM: HTX-019 (CINVANTI® [aprepitant injectable emulsion]) is a neurokinin 1 receptor antagonist approved for preventing acute and delayed chemotherapy-induced nausea and vomiting (CINV). HTX-019 is free of polysorbate 80 and other synthetic surfactants and showed bioequivalence to and a more favorable safety profile than fosaprepitant when administered as a 30-min infusion in healthy subjects. The shortage of small-volume parenteral solutions led to a recommendation to administer HTX-019 by intravenous push. The objectives were to evaluate pharmacokinetics, tolerability and safety following HTX-019 administration by injection versus infusion. MATERIALS & METHODS: Study comprised Part A, a pilot Phase I, single-center, randomized, pharmacokinetic, safety and tolerability, open-label study, followed by Part B, a two-sequence crossover study of HTX-019 130 mg in healthy adults, via injection and infusion. Blood samples were evaluated for aprepitant pharmacokinetics and bioequivalence. Safety evaluations included treatment-emergent adverse events (TEAEs), vital signs, clinical laboratory testing and electrocardiograms. RESULTS: In Part A, 24 subjects were randomly assigned to three cohorts (n = 8 per cohort) and received HTX-019 130 mg, administered intravenously over 15 min (cohort 1), 5 min (cohort 2) or 2 min (cohort 3). Progression to Part B occurred after acceptable tolerability was established in cohorts 2 and 3. In Part B, 50 randomized subjects received a 2-min injection (9 ml/min) and 30-min infusion (296 ml/h) of HTX-019 130 mg. Bioequivalence was demonstrated for HTX-019 injection and infusion. Both administration methods via a peripheral line were well tolerated; eight subjects experienced 11 TEAEs (six related) following injection and nine experienced 14 TEAEs (nine related) following infusion. Headache and fatigue were the most prevalent treatment-related TEAEs; one subject per group experienced feeling hot ≤30 min after drug administration. CONCLUSION: Pharmacokinetic and tolerability profiles of 2-min HTX-019 injection support this potential alternative administration method for CINV prevention.

Jejunal absorption of aprepitant from nanosuspensions: Role of particle size, prandial state and mucus layer.

The number of highly lipophilic active pharmaceutical ingredients (APIs) in pharmaceutical development has been constantly increasing over recent decades. These APIs often have inherent issues with solubility and dissolution, limiting their oral bioavailability. Traditionally, a reduction in particle size to the micrometer range has been used to improve dissolution. More recently, size reduction to the nanometer range has been introduced, which further increases the dissolution rate, but may also involve other mechanisms for increasing bioavailability. The effect of particle size on the absorption of aprepitant was investigated using the single-pass intestinal perfusion (SPIP) model in the rat jejunum. Phosphate buffer, fasted-state simulated intestinal fluid (FaSSIF), and fed-state simulated intestinal fluid (FeSSIF) were used as perfusion media to increase understanding of the processes involved and the effects of colloidal structures. The role of mucus on intestinal absorption was investigated by adding the mucolytic agent N-acetyl-cysteine (NAC). The absorption of aprepitant from the nanosuspensions was similar with all perfusion media (buffer = FaSSIF = FeSSIF), whereas food had a pronounced effect on absorption from the microsuspensions (FeSSIF > FaSSIF > buffer). The colloidal structures hence contributed to absorption from the microsuspensions. Partitioning of aprepitant from the nanosuspension into the colloidal structures decreased the amount of nanoparticles available, which offset the effect of food. The appearance flux of aprepitant in blood was non-significantly decreased for nanosuspensions of aprepitant with NAC versus without NAC in buffer (ratio of 2:1), indicating that particle deposition in the mucus may have been decreased as the layer thinned, with subsequently reduced intestinal absorption. The study also showed that the SPIP model is suitable for investigating detailed absorption mechanisms using complex perfusion media, which increase the biorelevance of the model.

Drug-drug interactions with aprepitant in antiemetic prophylaxis for chemotherapy.

In the current guidelines to prevent hemotherapyinduced nausea and vomiting, multiple antiemetic drugs are administered simultaneously. In patients who receive highly emetogenic chemotherapy, aprepitant, an NK1-receptor antagonist, is combined with ondansetron and dexamethasone. Aprepitant can influence the pharmacokinetics of other drugs, as it is an inhibitor and inducer of CYP3A4. Some anticancer drugs and other co-medication frequently used in cancer patients are CYP3A4 or CYP29C substrates. We give an overview of the metabolism and current data on clinically relevant drug-drug interactions with aprepitant during chemotherapy. Physicians should be aware of the potential risk of drug-drug interactions with aprepitant, especially in regimens with curative intent. More research should be performed on drug-drug interactions with aprepitant and their clinical consequences to make evidence-based recommendations.