Three-way Crossover Study Research Articles

Pharmacokinetics and Bioequivalence of Two Powders of Azithromycin for Suspension: A Nonblinded, Single-Dose, Randomized, Three-Way Crossover Study in Fed and Fasting States Among Healthy Chinese Volunteers.

Azithromycin, a macrolide antibiotic, is commonly used to treat mild-to-moderate bacterial infections. This research aimed to evaluate the pharmacokinetics (PK) properties and bioequivalence (BE) of two azithromycin (EQ 100 mg base/packet) powders for suspension in Chinese healthy participants in fed and fasting conditions. A total of 90 Chinese healthy participants were enrolled in this nonblinded, single-dose, randomized, semireplicate, three-period, three-sequence, crossover study. Of them, 42 and 40 were categorized to the fed and fasting conditions, respectively. The washout period between doses was 21 days. Blood specimens were harvested prior to administering the drug and 194 h following administration. The plasma levels of azithromycin were analyzed using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach. PK parameters were measured using noncompartmental analysis. This research compared BE between the reference and test products using the average bioequivalence (ABE) or reference-scaled average bioequivalence (RSABE) method, considering the within-subject variability (SWR) of the reference preparation. Adverse events (AEs) were monitored to examine safety and tolerability. The RSABE method (SWR ≥ 0.294) was used to determine the BE of maximal plasma concentration (Cmax) in both fed and fasting conditions. In the ABE approach, (SWR < 0.294) was adopted to assess the BE of the area under the plasma concentration-time curve from time zero to the last measurable time point (AUC0-t) and determine the area under the plasma concentration time curve from time zero to time infinity (AUC0-inf). In the fasting condition, the point estimate of the test/reference ratio for Cmax was 1.08, with a 95% upper confidence bound of - 0.05 < 0.00. The geometric mean ratio (GMRs) for AUC0-t and AUC0-inf was 115.21% [90% confidence interval (CI) 107.25-123.27%] and 113.07% (90% CI 105.14-121.61%), respectively. In the fed condition, the point estimate of the test/reference ratio for Cmax was 0.94, with a 95% upper confidence bound of - 0.10 < 0.00. The GMR for AUC0-t and AUC0-inf was 99.51% (90% CI of 91.03-108.78%) and 99.43% (90% CI 91.73-107.78%), respectively. These data all satisfied the BE criteria for drugs with high variability. All AEs were transient and mild, and no severe AEs were observed. Our study indicated that the test and reference products of azithromycin (EQ 100 mg base/packet) powder for suspension were bioequivalent and safe in healthy Chinese participants, irrespective of the feeding condition. CLINICAL TRIAL REGISTRATION (CHINADRUGTRIALS.ORG.CN): CTR20232646, registered on 25 August 2023.

The interactive walkway provides fit-for-purpose fall-risk biomarkers in the elderly: Comparison of zolpidem and suvorexant.

Dynamic balance assessments such as walking adaptability may yield a more realistic prediction of drug-induced falls compared with postural stability measurements, as falls often result from limited gait adjustments when walking. The Interactive Walkway (IWW) measures walking adaptability but sensitivity to medication effects is unknown. If proven sensitive and specific, IWW could serve as a biomarker for targeted fall-risk assessments in early clinical drug development. In this three-way crossover study, 18 healthy elderly (age: 65-80 years) subjects received 5 mg zolpidem, 10 mg suvorexant, or placebo in the morning. Assessments were performed pre-dose and approximately hourly until 9 h post-dose. IWW assessments included an 8-meter walking test, goal-directed stepping, obstacle-avoidance, and tandem-walking. Other pharmacodynamic measurements were the Timed-Up-and-Go (TUG) test at a comfortable and fast pace, adaptive tracking, and body sway. A decline in performance was observed for zolpidem compared with placebo for 3 h post-dose in IWW walking adaptability outcome measures, TUG, adaptive tracking, and body sway. For the IWW tasks, a decrease in walking speed (among others) was observed. IWW parameters were not affected by suvorexant compared with placebo at any timepoint. However, an increase of 9.8% (95%CI: 1.8%, 18.5%) in body sway was observed for suvorexant compared with placebo up to 3 h post-dose. The IWW successfully quantified drug effects of two hypnotic drugs and distinguished between zolpidem and suvorexant regarding their effects on walking. As a biomarker, the IWW demonstrated sensitivity in assessing dynamic balance and potential fall risk in early phase clinical drug development.

IMPROVEMENT OF RENAL HAEMODYNAMICS AND ECHOCARDIOGRAPHIC PARAMETERS IN PHARMACOLOGICAL CONTROLLED HYPERTENSIVES

Objective: A study was carried out to evaluate the influence of blood pressure lowering treatment with combined doses of olmesartan plus amplodipina compared with those of either drug at a single dose level. Design and method: By double-blind, three-way crossover study (balanced Latin square design) in 102 subjects (mean age 51.9 +/- 7.42 years) with essential hypertension we used Olmesartan 40 mg plus Amplodine 5 mg compared with those of either drug at a single and higher dose level (40 or 10 mg daily, respectively). Left ventricular mass and function were evaluated by M-B mode echocardiography, renal function by glomerular filtration rate (GFR) and by serum and 24-h urinary Na+ and K+ during wash-out period and after 24 weeks of treatment. Results: The supine blood pressure for subjects given placebo was 171/103 mmHg. After 24 weeks of treatment, systolic and diastolic supine blood pressure were significantly lower with 40 mg iolmesartan plus 5 mg amplodipine (134/84 mmHg) than with 10 mg amplodipine (137/84 mmHg) or with 40 mg olmesartan (144/85 mmHg). Left ventricular posterior wall and septal thickness were significantly and similarly reduced in all groups. Left ventricular systolic and diastolic end diameters were not significantly changed. Left ventricular mass (LVM) was significantly reduced in Olmesartan plus Amplodipine group and Olmesartan group. GFR was not significantly altered. The 24-h urinary Na+ significantly increased with olmesartan, more so than amplodipine. The combination was tolerated better than either monotherapy. We observed no clinically significant changes in laboratory variables including blood lipoproteins. Conclusions: The combination of olmesartan plus amplodipina reduced blood pressure more effectively and was better tolerated than other drug alone. All three groups showed similar changes in echocardiographic indices and no change in renal function.

Relative Bioavailability of Cenobamate Administered as a Crushed Tablet, Either Orally or via Nasogastric Tube, versus an Intact Whole Tablet.

Cenobamate is approved for the treatment of focal seizures in adults and is currently available as an oral tablet. Alternative methods of drug administration are needed for patients who are unable to swallow whole intact tablets. This phase 1, open-label, randomized, single-dose, three-way crossover (3-period, 3-treatment, 6-sequence) study (NCT05572255), conducted in healthy volunteers, assessed the relative bioavailability of a crushed 200-mg cenobamate tablet administered orally or via nasogastric (NG) tube compared with an intact 200-mg tablet. Each treatment was separated by a 13-day washout period. Plasma samples for cenobamate concentration analysis were collected pre-dose and at multiple time points up to 264 h post-dose. Standard bioequivalence study criteria were applied to the relative bioavailability assessments. All 90% confidence intervals of test-to-reference geometric mean ratios for cenobamate pharmacokinetic parameters (Cmax, AUClast, and AUCinf) were within 85-110% (predefined limit, 80-125%), suggesting no difference in cenobamate exposures following administration of an intact tablet orally or a crushed tablet orally or via NG tube. All treatment-emergent adverse events (TEAEs) were classified as mild and resolved. There were no deaths or other serious AEs (SAEs), and no TEAEs led to discontinuation. Our results indicate that the administration of cenobamate as a crushed tablet taken orally or via an NG tube can provide additional flexibility when patients cannot swallow intact tablets. Based on the results of this study, cenobamate is now approved by FDA to be taken whole or the tablets can be crushed. The crushed tablet can be mixed with water and either administered by mouth as an oral suspension or administered via a nasogastric tube.

Transdermal Flunixin Meglumine as a Pain Relief in Donkeys: A Pharmacokinetics Pilot Study.

Recent approval of transdermal flunixin meglumine (FM) (Banamine®) in cattle has opened the door for the drug's potential application in other species. Transdermal FM could provide a safe and effective form of pain relief in donkeys. In order to evaluate the pharmacokinetics and effects of FM on anti-inflammatory biomarkers in donkeys, a three-way crossover study design was employed. In total, 6 healthy donkeys were administered transdermal (TD) FM at a dosage of 3.3 mg/kg, and oral (PO) and intravenous (IV) doses of 1.1 mg/kg body weight. Blood samples were collected over 96 h to determine the concentration of flunixin, 5OH flunixin, and eicosanoids (TXB2 and PGF2 alpha) using LC-MS/MS. The results indicated that both flunixin and 5OH flunixin were detectable in blood samples collected during TD. The elimination of the drug was slower following the TD route compared to PO and IV. TD administration significantly decreased TXB2 levels in non-stimulated serum from 1 to 96 h post-administration, while IV and PO resulted in TXB2 reduction for 1 to 8 h. A significant reduction in PGF2 alpha was observed in PO and IV 1 h after administration, while TD resulted in a gradual decline from 4 to 72 h. The study concluded that the off-label use of transdermal FM at 3.3 mg/kg could be effective in controlling inflammation in donkeys.

Intragastric Carbon Dioxide Release Prolongs the Gastric Residence Time of Postprandially Administered Caffeine.

Sparkling water is said to increase gastric motility by the release of carbon dioxide, thereby potentially affecting the pharmacokinetics of orally administered drugs. The hypothesis of the present work was that the induction of gastric motility by intragastric release of carbon dioxide from effervescent granules could promote the mixing of drugs into the chyme under postprandial conditions, resulting in a prolonged drug absorption. For this purpose, an effervescent and a non-effervescent granule formulation of caffeine as a marker for gastric emptying were developed. In a three-way crossover study with twelve healthy volunteers, the salivary caffeine pharmacokinetics, after administration of the effervescent granules with still water and the administration of the non-effervescent granules with still and sparkling water, were investigated after intake of a standard meal. While the administration of the effervescent granules with 240 mL of still water led to a significantly prolonged gastric residence of the substance compared to the administration of the non-effervescent granules with 240 mL still water, the application of the non-effervescent granules with 240 mL sparkling water did not prolong gastric residence via mixing into caloric chyme. Overall, the mixing of caffeine into the chyme following the administration of the effervescent granules did not seem to be a motility mediated process.

Bioavailability of vitamin D biofortified pork meat: results of an acute human crossover study in healthy adults

Vitamin D intakes are concerningly low. Food-based strategies are urgently warranted to increase vitamin D intakes and subsequently improve 25-hydroxyvitamin D (25(OH)D) concentrations. This acute randomised three-way crossover study investigated the efficacy of vitamin D biofortified pork derived from pigs exposed to UVB light to increase serum 25(OH)D3 concentrations, compared to a dose-matched vitamin D3 supplement and control pork in adults (n = 14). Blood samples were obtained at baseline and then 1.5, 3, 6, 9 and 24 h postprandially. There was a significant effect of time (p < 0.01) and a significant treatment*time interaction (p < 0.05). UV pork and supplement significantly increased within-group serum 25(OH)D3 concentrations over timepoints (p < 0.05) (max. change 0.9 nmol/L (2.2%) UV pork, 1.5 nmol/L (3.5%) supplement, 0.7 nmol/L (1.9%) control). Vitamin D biofortified pork modestly increased 25(OH)D3 concentrations and produced a similar response pattern as a dose-matched vitamin D supplement, but biofortification protocols should be further optimised to ensure differentiation from standard pork.

Abstract 13051: Comparative Antiplatelet Effects of Chlorthalidone and Hydrochlorothiazide

Introduction: The ACC/AHA hypertension guidelines recommended chlorthalidone (CTD) over hydrochlorothiazide (HCTZ) due to its longer half-life and proven reduction in major adverse cardiovascular events. The mechanism of the potential benefit of CTD compared to HCTZ has not been established. Unlike other thiazide diuretics, studies suggest that CTD may affect platelet aggregation, gene transcription, angiogenesis, and vascular permeability. We aimed to compare the antiplatelet effects of CTD versus HCTZ. Methods: We conducted a prospective, double-blind, randomized, three-way crossover study comparing the antiplatelet effects of CTD, HCTZ, and aspirin (ASA) in healthy volunteers ≥ 19 years of age. ASA was included in the study as a known control for inhibition of platelet aggregation. Whole blood aggregometry was used to assess the impact of treatments on platelet activation and aggregation. Results: Of the 40 subjects, 34 (85%) completed the 3-way crossover comparison. Six subjects were excluded due to non-compliance and adverse effects. Compared to ASA, both CTD and HCTZ had no antiplatelet effects (Table 1). There was no statistically significant difference between CTD and HCTZ in terms of platelet function. Conclusions: Although recent studies showed increased cardiovascular benefit with CTD compared to HCTZ, CTD and HCTZ do not have antiplatelet effects. Larger studies are needed to confirm our findings.

Central nervous system effects of TAK-653, an investigational alpha-amino-3-hydroxy-5-methyl-4-isoxazole receptor (AMPAR) positive allosteric modulator in healthy volunteers

TAK-653 is a novel AMPA receptor positive allosteric modulator in clinical development for the treatment of major depressive disorder (MDD). This study aimed to measure the functional pharmacodynamic central nervous system (CNS) effects of TAK-653. A randomised, double-blind, placebo-controlled, three-way crossover (placebo, TAK-653 0.5 mg and 6 mg) study with 24 healthy volunteers was performed. NeuroCart tests consisting of body sway (BS), saccadic peak velocity (SPV), smooth pursuit eye movements (SP), adaptive tracking (AT), Bowdle and Bond and Lader Visual Analogue Scales (B-VAS and BL-VAS) and Stroop test were performed pre-dose and 3.5 and 4 h post-dose. Data were analysed using a mixed model analysis of covariance with baseline as covariate. It was found that TAK-653 did not affect BS and subjective drug effects as measured by B-VAS and BL-VAS at either dose level. TAK-653 0.5 mg increased SPV (degrees/second) (19.49 [5.98, 32.99], P = 0.02) and affected Stroop difference in reaction time between correct congruent and correct incongruent answers and number of correct responses in incongruent trials (22.0 [4.0, 40.0], P = 0.05 and −0.3 [−0.5, −0.1], P = 0.02, respectively). TAK-653 6 mg improved AT (%) (1.68 [0.51, 2.84], P = 0.02) and increased SPV (degrees/s) (15.40 [1.91, 28.90], P = 0.06) and SP (%) (2.32 [0.37, 4.27], P = 0.05). Based on these findings it can be concluded that TAK-653 demonstrated a psychostimulant-like pharmacodynamic profile on the NeuroCart consistent with previously reported increase of cortical excitability following Transcranial Magnetic Stimulation (TMS) of the human motor cortex.

Microbiota responses to different prebiotics are conserved within individuals and associated with habitual fiber intake

BackgroundShort-chain fatty acids (SCFAs) derived from gut bacteria are associated with protective roles in diseases ranging from obesity to colorectal cancers. Intake of microbially accessible dietary fibers (prebiotics) lead to varying effects on SCFA production in human studies, and gut microbial responses to nutritional interventions vary by individual. It is therefore possible that prebiotic therapies will require customizing to individuals.ResultsHere, we explored prebiotic personalization by conducting a three-way crossover study of three prebiotic treatments in healthy adults. We found that within individuals, metabolic responses were correlated across the three prebiotics. Individual identity, rather than prebiotic choice, was also the major determinant of SCFA response. Across individuals, prebiotic response was inversely related to basal fecal SCFA concentration, which, in turn, was associated with habitual fiber intake. Experimental measures of gut microbial SCFA production for each participant also negatively correlated with fiber consumption, supporting a model in which individuals’ gut microbiota are limited in their overall capacity to produce fecal SCFAs from fiber.ConclusionsOur findings support developing personalized prebiotic regimens that focus on selecting individuals who stand to benefit, and that such individuals are likely to be deficient in fiber intake.FLeuumVMoUypG_CgDJN_5gVideo

Pharmacokinetics of glaucine after intravenous and oral administrations and detection of systemic aporphine alkaloids after ingestion of tulip poplar shavings in horses.

Glaucine, an aporphine alkaloid with anti-tussive, anti-inflammatory, and anti-nociceptive properties, has been identified in post-race samples from racehorses. To investigate pharmacokinetics of glaucine in horses, a three-way crossover study of intravenous and oral glaucine (0.1mg/kg) and orally administered tulip poplar shavings (50 g shavings=0.001 mg/kg glaucine) was performed in six horses. A two-compartment model best described IV administration with alpha ( ) and beta ( ) half-life lives of 0.3 (0.1-0.7) and 3.1 (2.4-7.8) h, respectively. The area under the curve ( iv ) was 45.4 (34.7-52.3) h*ng/ml, and the volume of distribution of the central (Vdc ) and peripheral (Vdp ) compartments was 2.7 (1.3-4.6) and 4.9 (4.3-8.2) L/kg, respectively. A one compartment model best described the oral administration of glaucine with absorption ( ) and elimination ( ) half-lives of 0.09 (0.05-0.15) and 0.7 (0.6-0.8) h, respectively. The area under the curve ( PO ) was 15.1 (8.0-19.5) h·ng/ml. Bioavailability following oral administration was 17%-48%. Following ingestion of shavings, glaucine and liriodenine were detectable in plasma for up to 16 and 48 h, respectively. Glaucine was quantifiable briefly in the urine from two horses. Liriodenine was quantifiable in urine for 12-20 h in four horses and for 48 h in two horses. The presence of liriodenine indicates ingestion of tulip poplar tree parts, however, does not rule out co-administration of purified glaucine in horses.

HP58 : Effects of sodium channel blockers on “nerve exciatability threshold tracking“

Selective voltage gated sodium channel blockers are of growing interest as treatment for pain. For drug development of such compounds, it would be critical to have a biomarker that can be used for proof-of-mechanism. We aimed to evaluate whether drug-induced changes in sodium conductance can be detected using nerve excitability threshold tracking in 18 healthy subjects. In a randomized, double-blind, three-way crossover study, effects of single doses of mexiletine and lacosamide were compared to placebo. On each study visit, motor- and sensory nerve excitability measurements of the median nerve were performed (pre-dose; 2- and 5-hours post-dose). Stimulation was guided by QTRAC-S. Treatment effects were calculated using an ANCOVA, with baseline as covariate. Mexiletine and lacosamide had significant effects on a multitude of motor- and sensory nerve excitability parameters. In motor nerves, TEd 40-60ms was significantly decreased when compared to placebo, with an estimated difference -1.37% (95%CI:-2.20,-0.55;p=0.002) after mexiletine and -1.27% (95%CI:-2.0968,-0.4430; p=0.004) after lacosamide. Moreover, mexiletine and lacosamide significantly increased superexcitability in motor nerves, with an estimated difference of 1.74% (95%CI:0.61,2.87; p=0.004) and 1.47% (95%CI:0.34, 2.60;p=0.013), respectively. The strength-duration time constant decreased after lacosamide in both motor nerves -0.03ms (95%CI:-0.06,-0.01;p=0.005) and sensory nerves -0.08ms (95%CI:-0.12,-0.05;p<0.001). Mexiletine and lacosamide significantly decrease excitability of motor and sensory nerves, in line with the mechanism of action. This study shows that threshold tracking can be an effective biomarker in pharmacological studies. The method would therefore be a valuable tool in drug development, to help identifying target engagement in healthy subjects.

A multi-pronged investigation of option generation using depression, PET and modafinil.

Option generation is a critical process in decision making, but previous studies have largely focused on choices between options given by a researcher. Consequently, how we self-generate options for behaviour remain poorly understood. Here, we investigated option generation in major depressive disorder and how dopamine might modulate this process, as well as the effects of modafinil (a putative cognitive enhancer) on option generation in healthy individuals. We first compared differences in self-generated options between healthy non-depressed adults [n = 44, age = 26.3 years (SD 5.9)] and patients with major depressive disorder [n = 54, age = 24.8 years (SD 7.4)]. In the second study, a subset of depressed individuals [n = 22, age = 25.6 years (SD 7.8)] underwent PET scans with 11C-raclopride to examine the relationships between dopamine D2/D3 receptor availability and individual differences in option generation. Finally, a randomized, double-blind, placebo-controlled, three-way crossover study of modafinil (100 mg and 200 mg), was conducted in an independent sample of healthy people [n = 19, age = 23.2 years (SD 4.8)] to compare option generation under different doses of this drug. The first study revealed that patients with major depressive disorder produced significantly fewer options [t(96) = 2.68, P = 0.009, Cohen's d = 0.54], albeit with greater uniqueness [t(96) = -2.54, P = 0.01, Cohen's d = 0.52], on the option generation task compared to healthy controls. In the second study, we found that 11C-raclopride binding potential in the putamen was negatively correlated with fluency (r = -0.69, P = 0.001) but positively associated with uniqueness (r = 0.59, P = 0.007). Hence, depressed individuals with higher densities of unoccupied putamen D2/D3 receptors in the putamen generated fewer but more unique options, whereas patients with lower D2/D3 receptor availability were likely to produce a larger number of similar options. Finally, healthy participants were less unique [F(2,36) = 3.32, P = 0.048, partial η2 = 0.16] and diverse [F(2,36) = 4.31, P = 0.021, partial η2 = 0.19] after taking 200 mg versus 100 mg and 0 mg of modafinil, while fluency increased linearly with dosage at a trend level [F(1,18) = 4.11, P = 0.058, partial η2 = 0.19]. Our results show, for the first time, that option generation is affected in clinical depression and that dopaminergic activity in the putamen of patients with major depressive disorder may play a key role in the self-generation of options. Modafinil was also found to influence option generation in healthy people by reducing the creativity of options produced.

The effect of BI 409306 on heart rate in healthy volunteers: a randomised, double-blind, placebo-controlled, crossover study

PurposeThe potent, selective phosphodiesterase-9A inhibitor BI 409306 may be beneficial for patients with attenuated psychosis syndrome and could prevent relapse in patients with schizophrenia. Transient BI 409306-dependent increases in heart rate (HR) demonstrated previously necessitated cardiac safety characterisation. We evaluated cardiac effects of BI 409306 in healthy volunteers during rest and exercise.MethodsIn this double-blind, three-way crossover study, volunteers received placebo, BI 409306 50 mg or 200 mg in randomised order (same treatment on Days 1 [resting] and 3 [exercise]). Cardiopulmonary exercise testing was performed twice post treatment on Day 3 of each period. BI 409306-mediated effects on placebo-corrected change from baseline in resting HR (ΔΔHR) were evaluated based on exposure–response analysis and a random coefficient model. Adverse events (AEs) were recorded.ResultsOverall, 19/20 volunteers completed. Resting ΔΔHR versus BI 409306 concentration yielded a slope of 0.0029 beats/min/nmol/L. At the geometric mean (gMean) maximum plasma concentration (Cmax) for BI 409306 50 and 200 mg, predicted mean (90% CI) ΔΔHRs were 0.80 (− 0.76, 2.36) and 5.46 (2.44, 8.49) beats/min, respectively. Maximum adjusted mean differences from placebo (90% CI) in resting HR for BI 409306 50 and 200 mg were 3.85 (0.73, 6.97) and 4.93 (1.69, 8.16) beats/min. Maximum differences from placebo in resting HR occurred at/near gMean Cmax and returned to baseline after approximately 4 h. The proportion of volunteers with AEs increased with BI 409306 dose.ConclusionObserved hemodynamic effects following BI 409306 administration were of low amplitude, transient, and followed the pharmacokinetic profile of BI 409306.

The Effect of Gum Acacia on Post-Prandial Glucose and Insulin Levels in Healthy Subjects

This double-blind, controlled, randomized, three-way cross-over study evaluates the effect of 40 g (D1 group) and 20 g (D2 group) of acacia gum (AG) versus no treatment (NT group) on post-prandial glucose (PPG) levels in normal-weight and overweight subjects. Additionally, post-prandial insulin (PPI) levels as well as the safety and tolerability of gum acacia were assessed. 35 healthy subjects aged 25 - 60 years, body mass index 18.5 kg/m2 - 29.9 kg/m2, received one treatment of 20 g, 40 g, or 0 g of AG each. Glucose and insulin values were determined at -15 min and prior to the intake (time “0”) as well as 15, 30, 45, 60, 90 120, and 180 min after the “0 min” blood draw. The mean PPG levels were lower (34% in D1 group, p = 0.003; 35% in D2 group, p = 0.005) than in the NT group. PPI concentration was statistically significantly lower at all time points except baseline in both treatment groups compared to NT groups. Global benefit and tolerability were rated as “very good” or “good” by 100% of subjects in the treatment groups. This study provides robust evidence of the significant benefits of AG consumption on PPG and PPI levels in healthy subjects. Moreover, very good tolerability was demonstrated.

Pharmacokinetic Characterisation and Comparison of Bioavailability of Intranasal Fentanyl, Transmucosal, and Intravenous Administration through a Three-Way Crossover Study in 24 Healthy Volunteers.

Background For more than 60 years, the synthetic opioid fentanyl has been widely used in anaesthesia and analgesia. While the intravenous formulation is primarily used for general anaesthesia and intensive care settings, the drug's high lipophilic properties also allow various noninvasive routes of administration. Published data suggest that intranasal administration is also attractive for use as intranasal patient-controlled analgesia (PCA). A newly developed intranasal fentanyl formulation containing 47 μg fentanyl, intravenous fentanyl, and oral transmucosal fentanyl citrate were characterised, and bioavailability was compared to assess the suitability of the intranasal formulation for an intranasal PCA product. Methods 27 healthy volunteers were enrolled in a single-centre, open-label, randomised (order of treatments), single-dose study in a three-period crossover design. The pharmacokinetics of one intranasal puff of fentanyl formulation (47 μg, 140 mL per puff), one short intravenous infusion of 50 μg fentanyl, and one lozenge with an integrated applicator (200 μg fentanyl) were studied, and bioavailability was calculated. Blood samples were collected over 12 hours, and plasma concentrations of fentanyl were determined by HPLC with MS/MS detection. Results 24 volunteers completed the study. The geometric mean of AUC0-tlast was the highest with oral transmucosal administration (1106 h ∗ pg/ml, CV% = 32.86), followed by intravenous (672 h ∗ pg/ml, CV% = 32.18) and intranasal administration (515 h ∗ pg/ml, CV% = 30.10). Cmax was 886 pg/ml (CV% = 59.38) for intravenous, 338 pg/ml (CV% = 45.61) for intranasal, and 310 pg/ml (CV% = 29.58) for oral transmucosal administration. tmax was shortest for intravenous administration (0.06 h, SD = 0.056), followed by intranasal (0.21 h, SD = 0.078) and oral transmucosal administration (1.20 h, SD = 0.763). Dose-adjusted absolute bioavailability was determined to be 74.70% for the intranasal formulation and 41.25% for the oral transmucosal product. In total, 38 adverse events (AEs) occurred. Fourteen AEs were potentially related to the investigational items. No serious AE occurred. Conclusion Pharmacokinetic parameters and bioavailability of the investigated intranasal fentanyl indicated suitability for its intended use as an intranasal PCA option.

Bioequivalence of cefalexin in healthy Chinese subjects.

An earlier three-way crossover study evaluating bioequivalence of 3 cefalexin formulations (capsule for reference, capsule and tablet for test) in healthy subjects in Malaysia showed that the intra-individual coefficients of variation were 9.25% for AUC0-t, 9.54% for AUC0-∞, and 13.90% for Cmax. It is preliminarily stated that cefalexin is not a high-variation product. The here-presented clinical study in China was carried out to analyze the pharmacokinetic properties of two preparations in fasting and postprandial condition to assess the bioequivalence of the test preparation and reference preparation when administered on a fasting and postprandial basis in healthy Chinese subjects and to observe the safety of the test preparation and reference preparation in healthy Chinese subjects. In this trial, a total of 56 eligible subjects were randomly assigned to the fasting group and the postprandial group. The two groups were given 250 mg of the test and reference preparation, respectively. Liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was applied to determine the plasma concentration of cefalexin. PhoenixWinNonlin software (V7.0) was used to calculate the pharmacokinetic parameters of cefalexin using the non-compartmental model (NCA), and the bioequivalence and safety results were calculated by SAS (V9.4) software. The main pharmacokinetic parameters of the test and reference preparations were as follows, the fasting group: Cmax 12.59 ± 2.65 μg/mL, 12.72 ± 2.28 μg/mL; AUC0-8h 20.43 ± 3.47 h×μg/mL, 20.66 ± 3.38 h×μg/mL; AUC0-∞ 20.77 ± 3.53 h×μg/mL, 21.02 ± 3.45 h×μg/mL; the postprandial group: Cmax 5.25 ± 0.94 μg/mL, 5.23 ± 0.80 μg/mL; AUC0-10h 16.92 ± 2.03 h×μg/mL, 17.09 ± 2.31 h×μg/mL; AUC0-∞ 17.33 ± 2.09 h×μg/mL, 17.67 ± 2.45h×μg/mL. The 90% confidence intervals of geometric mean ratios of test preparation and reference preparation were calculated, and the 90% confidence intervals of geometric mean ratios of Cmax, AUC0-10h, and AUC0-∞ were within the 80.00% ~ 125.00% range in both groups. Both Cmax and AUC met the pre-determined criteria for assuming bioequivalence. The test and reference products were bioequivalent after administration under fasting as well as under fed conditions in healthy Chinese subjects. This study may suggest that successful generic versions of cefalexin not only guarantee the market supply of such drugs but can also improve the safety and effectiveness and quality controllability of cefalexin through a new process and a new drug composition ratio.

Association of autonomic function and brain activity with personality traits by paced breathing and su-soku practice: A three-way crossover study

ObjectivesThis study aimed to compare the effectiveness of paced breathing (PB) versus su-soku practice (spontaneous breathing with counting numbers) on autonomic function and brain activity and examine the associations between personality traits, brain activity, and autonomic function. DesignA three-way crossover study design. SettingThirty healthy Korean participants (15 men: 28.5 ± 4.7 years; 15 women: 27.7 ± 4.8 years) were asked to answer the Korean version of the 125-Temperament and Character Inventory (TCI). Three-way crossover design included normal PB (0.25 Hz), slow PB (0.1 Hz), and su-soku practice. Participants were randomly assigned to one of three groups (group A: su-soku/normal PB/slow PB; group B: normal PB/slow PB/su-soku; group C: slow PB/su-soku/normal PB). Main outcome measuresThe Korean version of the 125-TCI scores, electroencephalography (EEG), heart rate variability (HRV), and respiratory curve data. ResultsEEG parameters between normal PB, slow PB, and su-soku showed no significant differences. High frequency and approximate entropy during normal PB and su-soku were higher than those during slow PB. Alpha band power related to well-focused alertness had strong negative correlations with the standard deviation of R-R intervals and square root of the mean of the sum of the squares of differences between adjacent R-R intervals during su-soku practice, while theta band power related to drowsiness had strong positive correlations with very low-frequency power during normal PB. Reflective and analytical individuals tended to be highly focused and alert during su-soku and normal PB, while anxious and unwilling individuals tended to focus on counting in and be drowsier during normal PB. ConclusionsThis study’s findings suggest that the association between brain activity and autonomic function is affected by meditation type and personality traits.

A phase 1 double‐blind, placebo‐controlled study of zuranolone (SAGE‐217) in a phase advance model of insomnia in healthy adults

ObjectiveTo evaluate single zuranolone (SAGE‐217) 30 or 45 mg doses in a 5‐h phase advance insomnia model.MethodsIn this double‐blind, three‐way crossover study, healthy adults received placebo (n = 41), zuranolone 30 mg (n = 44), and zuranolone 45 mg (n = 42) across three treatment periods. Sleep was assessed by polysomnography and a postsleep questionnaire. Next‐day residual effects and safety/tolerability were evaluated.ResultsCompared with placebo, zuranolone resulted in significant improvements in median sleep efficiency (30 mg, 84.6%; 45 mg, 87.6%; placebo, 72.9%; p < 0.001 for both doses), wake after sleep onset (WASO; 30 mg, 55.0 min; 45 mg, 42.5 min; placebo, 113.0 min; p < 0.001 for both doses), duration of awakenings (30 mg, 4.2 min, p < 0.001; 45 mg, 3.7 min, p = 0.001; placebo, 7.4 min), and total sleep time (TST; 30 mg, 406.3 min; 45 mg, 420.3 min; placebo, 350.0 min; p < 0.001 for both doses). Subjective endpoints (WASO, TST, sleep latency, sleep quality) also improved relative to placebo. Zuranolone was generally well tolerated, and the most common adverse events (≥2 participants, any period) were headache and fatigue.ConclusionZuranolone improved sleep measures versus placebo in a phase advance model of insomnia in healthy adults, supporting future studies in patients with insomnia disorder.

FODMAPs, but Not Gluten, Affect Symptoms and the Fecal Environment in Subjects With Irritable Bowel Syndrome. A Double Blinded-Randomized Three-Way Crossover Study

Abstract Objectives Irritable bowel syndrome (IBS) symptoms have been associated with fermentable oligo-, di-, monosaccharides and polyols (FODMAPs) as well as gluten. We aimed to evaluate the effects of provocations with diets rich in such components on IBS symptoms. We further aimed to study effects of FODMAPs and gluten on microbiota and if the microbiota composition was related to the severity of IBS symptoms. Methods A double-blind, placebo-controlled, randomised three-way crossover design (n = 110) was conducted. From run-in and throughout the study, IBS subjects maintained a diet with minimal FODMAP content and no gluten. Participants were block-randomised to one-week interventions with FODMAPs (50 g/day), gluten (17.3 g/day) or placebo, separated by one week of wash-out. Fecal samples were collected after each study week and analyzed for gut microbiota composition by sequencing of 16S rRNA gene amplicons. IBS symptoms were monitored by the IBS severity scoring system (IBS-SSS). Results In subjects with moderate to severe IBS (n = 103), FODMAPs caused higher total IBS-SSS (mean [SE] = 240 [9]) than placebo (208 [9]; p = 0.00056) or gluten (198 [9]; p = 0.013), but with no difference between gluten and placebo (p = 1.0). Relative abundance of Anaerostipes, Bifidobacterium and Faecalibacterium were higher after FODMAP compared to placebo. We found no difference in gut microbiota composition between gluten and placebo and no significant correlations between genera and severity of IBS-SSS. Conclusions In subjects with IBS, FODMAPs had an adverse but modest effect on typical IBS symptoms, whereas gluten had no effect. The microbiota composition was affected by the FODMAP but not the gluten intervention, in comparison to placebo. None of these differences were correlated to the severity of symptoms reflected in IBS-SSS, suggesting no apparent link between gut microbiota composition and IBS symptoms following intervention. Funding Sources Formas and the Swedish Research Council.