Crossover Study In Healthy Subjects Research Articles

Pharmacokinetics and bioequivalence of two formulations of mifepristone tablets in healthy Chinese subjects under fasting conditions: a single-center, open, randomized, single-dose, double-period, two-sequence, crossover trial.

A bioequivalence (BE) study was performed to evaluate the pharmacokinetics, safety, and bioequivalence of two formulations of mifepristone tablets in healthy Chinese volunteers under fasting conditions. A single-center, open, randomized, single-dose, double-period, two-sequence, crossover study in healthy subjects under fasting conditions was performed. The subjects received a single fasting dose of mifepristone (10mg/tablet) during the first and second periods, followed by a 14-day washout period, during which frequent pharmacokinetic (PK) sampling occurred up to 120h. The pharmacokinetic parameters of mifepristone were calculated based on the plasma drug concentration-time profile. Primary endpoints were the BE of major pharmacokinetic parameters (AUC0-t and AUC0-∞) and the maximum observed serum concentration (Cmax). Secondary endpoints were safety parameters. Forty subjects (34 male and 6 female subjects) were randomly assigned to treatment, with 39 completing the two-period study. After the single administration of mifepristone tablets (test preparation vs. reference preparation) under fasting conditions, the geometric mean ratios (GMRs) of Cmax, AUC0-t, and AUC0-∞ were 98.76%, 104.28%, and 104.83%, respectively. The primary metabolites of mifepristone (RU42633 and RU42698),the GMRs of Cmax, AUC0-t, AUC0-∞ were 102.33% and 100.97%, 103.17% and 103.71%, 104.02% and 103.84%, respectively. Similarly, for another metabolite of mifepristone (RU42698), the GMRs of Cmax, AUC0-t, and AUC0-∞ were 100.97%, 103.71%, and 103.84%, respectively. All 90% confidence intervals (CIs) for the test/reference AUC ratio and Cmax ratio were within the acceptable range (80%-125%) for BE, which met the requirements of bioequivalence. No serious adverse events (AEs) occurred, and all AEs were classified as level 1 or 2. The PK parameters of mifepristone and its metabolites (RU42633 and RU42698) were measured using the (GMRs) of AUC0-t, AUC0-∞, and Cmax and were similar between the test and reference drug. The two formulations of mifepristone showed good tolerability and a similar safety profile. chinadrugtrials.org.cn, identifier CTR20182413.

NMDA and GABA Receptor-Mediated Plasticity Induced by 10-Hz Repetitive Transcranial Magnetic Stimulation.

Although 10-Hz repetitive transcranial magnetic stimulation (rTMS) is an FDA-approved treatment for depression, we have yet to fully understand the mechanism through which rTMS induces therapeutic and durable changes in the brain. Two competing theories have emerged suggesting that 10-Hz rTMS induces N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP), or alternatively, removal of inhibitory gamma-aminobutyric acid receptors (GABARs). We examined these two proposed mechanisms of action in the human motor cortex in a double-blind, randomized, four-arm crossover study in healthy subjects. We tested motor-evoked potentials (MEPs) before and after 10-Hz rTMS in the presence of four drugs separated by 1-week each: placebo, NMDAR partial agonist d-cycloserine (DCS 100mg), DCS 100mg + NMDAR partial antagonist dextromethorphan (DMO 150mg; designed to "knock down" DCS-mediated facilitation), and GABAR agonist lorazepam (LZP 2.5mg). NMDAR agonism by DCS enhanced rTMS-induced cortical excitability more than placebo. This enhancement was blocked by combining DCS with NMDAR antagonist, DMO. If GABARs are removed by rTMS, GABAR agonism via LZP should lack its inhibitory effect yielding higher post/pre MEPs. However, MEPs were reduced after rTMS indicating stability of GABAR numbers. These data suggest that 10-Hz rTMS facilitation in the healthy motor cortex may enact change in the brain through NMDAR-mediated LTP-like mechanisms rather than through GABAergic reduction.

Inclusion of Oat Polar Lipids in a Solid Breakfast Improves Glucose Tolerance, Triglyceridemia, and Gut Hormone Responses Postprandially and after a Standardized Second Meal: A Randomized Crossover Study in Healthy Subjects.

Previously, it has been indicated that oat polar lipids included in a liquid meal may have the potential to beneficially modulate various cardiometabolic variables. The purpose of this study was to evaluate the effects of oat polar lipids in a solid food matrix on acute and second meal glucose tolerance, blood lipids, and concentrations of gut-derived hormones. The oat polar lipids were consumed at breakfast and effects on the biomarkers were investigated in the postprandial period and following a standardized lunch. Twenty young, healthy subjects consumed in total four different breakfast meals in a crossover study design. The breakfasts consisted of 1. White wheat bread (WWB) with an added 7.5 g of oat polar lipids (PLL); 2. WWB with an added 15 g of oat polar lipids (PLH); 3. WWB with and added 16.6 g of rapeseed oil (RSO) as a representative of commonly consumed oils; and 4. WWB consumed alone, included as a reference. All products with added lipids contained equivalent amounts of fat (16.6 g) and available carbohydrates (50 g). Rapeseed oil was added to the oat polar lipid meals to equal 16.6 g of total fat. The standardized lunch was composed of WWB and meatballs and was served 3.5 h after the breakfast. Test variables (blood glucose, serum insulin, triglyceride (TG), free fatty acids (FFA), ghrelin, GLP-1, PYY, and GIP) were measured at fasting and repeatedly during the 5.5 h after ingestion of the breakfast. After breakfast, PLH substantially lowered postprandial glucose and insulin responses (iAUC 0-120 min) compared with RSO and WWB (p < 0.05). Furthermore, a reduced glycaemic response to lunch (210-330 min) was observed following the PLH breakfast compared to all of the other breakfasts served (p < 0.05). Oat polar lipids (PLH) significantly reduced TG and ghrelin and increased circulating gut hormones GLP-1 and PYY compared to RSO (p < 0.05). The results show that exchanging part of the dietary lipids with oat polar lipids has the potential to improve postprandial blood glucose regulation and gut hormones and thus may have a preventive effect against type 2 diabetes.

Model-Informed Dosing Regimen of Ticagrelor in Chinese Patients With Acute Coronary Syndrome.

The exposure to ticagrelor (BRILINTA) is higher in the East Asian population compared with the White population, thus, East Asians have an increased risk of bleeding. We developed a population pharmacokinetic (PopPK) model of ticagrelor based on a randomized 3 × 3 crossover study in healthy subjects. The area under the concentration-time curve (AUC) of Chinese patients with acute coronary syndrome was simulated based on this model. Following this, eight machine learning (ML) methods were used to construct bleeding risk models. Variables included in the final bleeding risk model were age, hypertension, body weight, AUC, drinking status, calcium channel blockers, antidiabetic medications, β-blockers, peripheral vascular disease, diabetes, transient ischemic attack, sex, and proton pump inhibitor. In terms of F1 scores and area under the curve of receiver operating characteristic curve (ROC-AUC), the Random Forest model performed best among all models, with an F1 score of 0.73 and ROC-AUC of 0.81. Moreover, the PopPK model and ML algorithm were used to bridge the real-world data to build a bleeding risk prediction model based on drug exposure and clinical information. Using this model, a ticagrelor regimen that is associated with a lower risk of bleeding in individuals can be obtained. This model should be further validated prospectively in clinical settings.

N°356 - Muscle velocity recovery cycles as pharmacodynamic biomarker in a first-in-human trial of a first-in-class chloride channel 1 inhibitor: A randomized, double-blind, placebo-controlled, cross-over study in healthy subjects and patients with myasthenia grav

N°356 - Muscle velocity recovery cycles as pharmacodynamic biomarker in a first-in-human trial of a first-in-class chloride channel 1 inhibitor: A randomized, double-blind, placebo-controlled, cross-over study in healthy subjects and patients with myasthenia grav

The effect of orally administered nitrate on renal function and blood pressure in a randomized, placebo-controlled, crossover study in healthy subjects

BackgroundSeveral studies have shown inorganic nitrate/nitrite to reduce blood pressure in both healthy subjects and hypertensive patients. An effect presumably caused through bioconversion to nitric oxide. However, studies on inorganic nitrate/nitrite have shown inconsistent results on renal functions such as GFR and sodium excretion. The current study investigated whether orally administered nitrate would decrease blood pressure and increase GFR and urinary sodium excretion. MethodsIn a randomized, placebo-controlled, double-blinded, crossover study, 18 healthy subjects received a daily dose of 24 mmol potassium nitrate and placebo (potassium chloride) during 4 days in a randomized order. Subjects also ingested a standardized diet and completed a 24-h urine collection. GFR was determined by the constant infusion technique and during GFR measurement, brachial blood pressure (BP) and central blood pressure (cBP), heart rate, and arterial stiffness were measured every half hour using the Mobil-O-Graph®. Blood samples was analyzed for nitrate, nitrite, cGMP, vasoactive hormones and electrolytes. Urine was analyzed for nitrate, nitrite, cGMP, electrolytes, ENaCγ, NCC, CrCl, CH2O and UO. ResultsNo differences in GFR, blood pressure or sodium excretion were found between the treatments with potassium nitrate and placebo. However, both nitrate and nitrite levels in plasma and urine were significantly increased by potassium nitrate intake and the 24-h urinary excretion of sodium and potassium were stable, showing adherence to the standardized diet and the study medication. ConclusionWe found no decrease in blood pressure or increase in GFR and sodium excretion of 24 mmol potassium nitrate capsules as compared to placebo after 4 days of treatment.Healthy subjects may be able to compensate the effects of nitrate supplementation during steady state conditions. Future research should focus on long-term studies on the difference in response between healthy subjects and patients with cardiac or renal disease.

Effect of Low- and High-Frequency Auricular Stimulation with Electro-Acupuncture on Cutaneous Microcirculation: A Cross-Over Study in Healthy Subjects

Background: The regulation of microcirculation depends on the dynamic interaction of different factors: the autonomic nervous system plays a pivotal role in the blood flow and acupuncture can modulate it, obtaining different results depending on the site, the frequency, and the intensity of the stimulation. Methods: 18 healthy subjects have been enrolled and have undergone two sessions of electroacupuncture stimulations: one session using high frequency and one with low frequency. Microcirculation has been monitored continuously during stimulation using the laser Doppler method. Results: The microcirculatory parameters have shown a significant difference between high and low-frequency stimulation, suggesting that low-frequency stimulation is more effective for obtaining a vasodilator effect. Discussion: Our results show that low-frequency stimulation can increase the cutaneous microcirculatory flux, without significantly modifying blood pressure and heart rate. The auricular stimulation causes an increase in the activity of the vagus nerve, increasing the cholinergic activity without acting on post-junctional muscarinic receptors. Conclusion: Auricular acupuncture has a significant impact on the regulation of microcirculation.

Effects on venous flow of transcutaneous electrical stimulation, neuromuscular stimulation, and sham stimulation on soleus muscle: A randomized crossover study in healthy subjects.

Background:Activation of venous flow has been shown with different types of electrical stimulation. The aim of this study is to compare the hemodynamic effects of transcutaneous electrical nerve stimulation (TENS), neuromuscular electrical stimulation (NMES), and sham stimulation on healthy young people.Methods:This randomized crossover study was conducted during June 2018 in the Faculty of Physical Therapy of A Coruña (Spain). Twenty-four university students (50% male) received in a randomized order 5 Hz-TENS, NMES, and sham stimulation on soleus muscle. Flow volume (FV) and peak velocity (PV) from popliteal vein were recorded via Doppler ultrasound, and relative changes from baseline were determined. Discomfort among the 3 stimulations was also compared.Results:The differences among the 3 stimulations were assessed using the ANOVA for repeated measured, the Friedman test and the Kendall tau test, according to the type of measurement to be compared. FV (mL/min) and PV (cm/s) increased significantly after NMES (percentual increase 37.2 ± 62.0%, P = .002; 264.4 ± 152.2%, P < .001, respectively) and TENS (226.2 ± 190.3%, P < .001; 202.7 ± 144.6%, P < .001, respectively). These percentual changes from basal level in hemodynamics were statistically different to those after placebo, which was ineffective enhancing hemodynamics. The improvements in FV were statistically higher with TENS than with NMES (P < .001), but there was no statistical difference in PV (P = .531). Despite NMES was applied at a significantly lower amplitude than TENS (P < .001), NMES protocol was the worst tolerated, though the differences in discomfort were not statistically significant.Conclusion:Both active electrical protocols but not sham stimulation increased hemodynamics in healthy people. TENS obtained higher flow volume increase from baseline than NMES, considered globally at not only in its on-time.

TH-186. Muscle velocity recovery cycles as pharmacodynamic biomarker: Effects of mexiletine in a randomized, double-blind, placebo-controlled, cross-over study in healthy subjects

TH-186. Muscle velocity recovery cycles as pharmacodynamic biomarker: Effects of mexiletine in a randomized, double-blind, placebo-controlled, cross-over study in healthy subjects

Effects of 3,4-Methylenedioxymethamphetamine on Conditioned Fear Extinction and Retention in a Crossover Study in Healthy Subjects.

Background: 3,4-Methylenedioxymethamphetamine (MDMA) has shown initial promise as an adjunct in psychotherapy to treat posttraumatic stress disorder (PTSD). Its efficacy and safety have been demonstrated across phase I–III studies. However, the mechanism underlying the potential utility of MDMA to treat PTSD in humans has not yet been thoroughly investigated. Preliminary evidence suggests that MDMA may facilitate fear extinction recall, which may be through the release of oxytocin. To test this hypothesis, we examined the efficacy of acute MDMA treatment to enhance fear extinction learning and recall. Methods: We used a two-period, double-blind, randomized, placebo-controlled crossover design in 30 healthy male subjects who received a placebo and a single dose of MDMA (125 mg). Fear extinction was tested using two separate Pavlovian fear conditioning paradigms, one using skin conductance response (SCR), and the other fear-potentiated startle (FPS) to conditioned cues. MDMA treatment occurred after fear conditioning and 2 h before extinction learning. Extinction recall was tested 23 h after MDMA intake. Additional outcome measures included subjective effects, emotion recognition tasks, plasma levels of oxytocin, and pharmacokinetics. Results: Fear conditioning and extinction learning were successful in both fear extinction paradigms (generalized eta–squared [ges] for SCR: 0.08; FPS: 0.07). Compared to placebo treatment, MDMA treatment significantly reduced SCRs to the reinforced conditioned stimulus (CS+) during extinction learning (ges = 0.03) and recall (ges = 0.06). Intensity of the subjective effects of MDMA (good effect, trust, and openness) during extinction learning negatively correlated with the discrimination between CS+ and the safety stimulus (CS−) during recall. MDMA did not influence FPS to conditioned cues. Oxytocin concentration was increased fourfold on average by MDMA during acute effects but was not associated with fear extinction outcomes. Conclusions: MDMA treatment facilitated rapid fear extinction and retention of extinction as measured by SCR to fear cues, in line with animal studies of MDMA facilitation of extinction. However, this effect may be limited to certain forms of learned fear responses, as it was not observed in the extinction model using startle reactivity as the outcome. This study provides further evidence for the facilitation of extinction with MDMA treatment and suggests this may be a component of its efficacy when paired with psychotherapy. Clinical Trial registration: clinicaltrials.gov identifier: NCT03527316

Increased Concentrations of Circulating Interleukins following Non-Invasive Vagus Nerve Stimulation: Results from a Randomized, Sham-Controlled, Crossover Study in Healthy Subjects

Objective: The vagus nerve constitutes the main component of the parasympathetic nervous system and plays an important role in the regulation of neuro-immune responses. Invasive stimulation of the vagus nerve produces anti-inflammatory effects; however, data on humoral immune responses of transcutaneous vagus nerve stimulation (tVNS) are rare. Therefore, the present study investigated changes in serum cytokine concentrations of interleukin-1β (IL-1β), IL-6, IL-8, and tumor necrosis factor α (TNFα) following a short-term, non-invasive stimulation of the vagus nerve. Methods: Whole blood samples were collected before and after a short-lived application of active tVNS at the inner tragus as well as sham stimulation of the earlobe. Cytokine serum concentrations were determined in two healthy cohorts of younger (n = 20) and older participants (n = 19). Differences between active and sham conditions were analyzed using linear mixed models and post hoc F tests after applying Yeo-Johnson power transformations. This trial was part of a larger study registered on ClinicalTrials.gov (NCT05007743). Results: In the young cohort, IL-6 and IL-1β concentrations were significantly increased after active stimulation, whereas they were slightly decreased after sham stimulation (IL-6: p = 0.012; IL-1β: p = 0.012). Likewise, in the older cohort, IL-1β and IL-8 concentrations were significantly elevated after active stimulation and reduced after sham application (IL-8: p = 0.007; IL-1β: p = 0.001). In contrast, circulating TNFα concentrations did not change significantly in either group. Conclusion: Our results show that active tVNS led to an immediate increase in the serum concentrations of certain pro-inflammatory cytokines such as IL-1β, IL-6, and/or IL-8 in two independent cohorts of healthy study participants.

Quantitative GC-TCD Measurements of Major Flatus Components: A Preliminary Analysis of the Diet Effect.

The impact of diet and digestive disorders in flatus composition remains largely unexplored. This is partially due to the lack of standardized sampling collection methods, and the easy atmospheric contamination. This paper describes a method to quantitatively determine the major gases in flatus and their application in a nutritional intervention. We describe how to direct sample flatus into Tedlar bags, and simultaneous analysis by gas chromatography–thermal conductivity detection (GC–TCD). Results are analyzed by univariate hypothesis testing and by multilevel principal component analysis. The reported methodology allows simultaneous determination of the five major gases with root mean measurement errors of 0.8% for oxygen (O2), 0.9% for nitrogen (N2), 0.14% for carbon dioxide (CO2), 0.11% for methane (CH4), and 0.26% for hydrogen (H2). The atmospheric contamination was limited to 0.86 (95% CI: [0.7–1.0])% for oxygen and 3.4 (95% CI: [1.4–5.3])% for nitrogen. As an illustration, the method has been successfully applied to measure the response to a nutritional intervention in a reduced crossover study in healthy subjects.

Acute Effects of Psilocybin After Escitalopram or Placebo Pretreatment in a Randomized, Double-Blind, Placebo-Controlled, Crossover Study in Healthy Subjects.

The psychedelic psilocybin is being investigated for the treatment of depression and anxiety. Unclear is whether antidepressant treatments interact with psilocybin. The present study used a double‐blind, placebo‐controlled, crossover design with two experimental test sessions to investigate the response to psilocybin (25 mg) in healthy subjects after pretreatment with escitalopram or placebo. The treatment order was random and counterbalanced. Pretreatment consisted of 10 mg escitalopram daily for 7 days, followed by 20 mg daily for 7 days, including the day of psilocybin administration, or 14 days of placebo pretreatment before psilocybin administration. Psilocybin treatments were separated by at least 16 days. The outcome measures included self‐rating scales that evaluated subjective effects, autonomic effects, adverse effects, plasma brain‐derived neurotrophic factor (BDNF) levels, electrocardiogram QTc time, whole‐blood HTR2A and SCL6A4 gene expression, and pharmacokinetics. Escitalopram pretreatment had no relevant effect on positive mood effects of psilocybin but significantly reduced bad drug effects, anxiety, adverse cardiovascular effects, and other adverse effects of psilocybin compared with placebo pretreatment. Escitalopram did not alter the pharmacokinetics of psilocin. The half‐life of psychoactive free (unconjugated) psilocin was 1.8 hours (range 1.1–2.2 hours), consistent with the short duration of action of psilocybin. Escitalopram did not alter HTR2A or SCL6A4 gene expression before psilocybin administration, QTc intervals, or circulating BDNF levels before or after psilocybin administration. Further studies are needed with a longer antidepressant pretreatment time and patients with psychiatric disorders to further define interactions between antidepressants and psilocybin.

Glycemic Control and Metabolic Adaptation in Response to High-Fat versus High-Carbohydrate Diets-Data from a Randomized Cross-Over Study in Healthy Subjects.

Granular study of metabolic responses to alterations in the ratio of dietary macro-nutrients can enhance our understanding of how dietary modifications influence patients with impaired glycemic control. In order to study the effect of diets enriched in fat or carbohydrates, fifteen healthy, normal-weight volunteers received, in a cross-over design, and in a randomized unblinded order, two weeks of an iso-caloric high-fat diet (HFD: 60E% from fat) and a high-carbohydrate diet (HCD: 60E% from carbohydrates). A mixed meal test (MMT) was performed at the end of each dietary period to examine glucose clearance kinetics and insulin and incretin hormone levels, as well as plasma metabolomic profiles. The MMT induced almost identical glycemia and insulinemia following the HFD or HCD. GLP-1 levels were higher after the HFD vs. HCD, whereas GIP did not differ. The HFD, compared to the HCD, increased the levels of several metabolomic markers of risk for the development of insulin resistance, e.g., branched-chain amino acid (valine and leucine), creatine and α-hydroxybutyric acid levels. In normal-weight, healthy volunteers, two weeks of the HFD vs. HCD showed similar profiles of meal-induced glycemia and insulinemia. Despite this, the HFD showed a metabolomic pattern implying a risk for a metabolic shift towards impaired insulin sensitivity in the long run.

Comparative Pharmacokinetics of a Novel, Patented Sustained Release Caffeine Versus Immediate Release Caffeine and Their Effects on Alertness & Mood

ObjectivesOral caffeine consumption results in rapid absorption with high blood levels followed by its sharp decline and is typically associated with reduction in beneficial effects of caffeine. To help extend the benefits of caffeine over a six-eight hour time period, we developed a new sustained release caffeine (SRC) formulation called XtenergyTM. The primary study objective was to compare the pharmacokinetic profile of SRC with immediate release caffeine (IRC). Secondary objectives were comparing the effects of SRC and IRC using caffeine research visual analogue scales (Caff - VAS) and evaluate its safety. MethodsTwenty-six subjects were randomized to receive 200 mg of caffeine from SRC and IRC in a double blind, single-dose, two-period, crossover study in healthy subjects under fasting state. A washout duration of 7 days was followed between the two periods. Blood samples were collected at –4, 0, 0.25, 0.50, 0.75, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 & 24 hours in each period. Plasma caffeine levels were analysed using a validated LCMS/MS method. The changes in Caff-VAS for relaxed, alert, jittery, tired, tense, headache & overall mood from baseline (0) to 1, 2, 4, 6, 8, 10 & 12 hrs were evaluated. ResultsTwenty-four male subjects with mean age 32.71 ± 6.18 yrs completed the study. Median tmax was 325.53% higher (4.00 vs 0.94 hrs) and mean t1/2 was 21.34% higher (9.24 ± 4.56 vs 7.61 ± 3.98 hrs) for SRC (P < 0.05) compared to IRC, respectively. Geometric least squares means (GLSM) for AUC4–8 (11,673.52 vs 10,930.25 hr.ng/mL) & AUC6–12 (14,043.79 vs 11,432.41 hr.ng/mL) were 6.80% and 22.84% higher for SRC compared to IRC, respectively. SRC showed an equivalent total absorption as IRC based on 90% CI for AUC0–24 (43,312.07 vs 44,009.64 hr*ng/mL). SRC demonstrated significant effects (P < 0.05) on feelings of being more alert, less tired, better overall mood, less jittery & less tense compared to IRC. SRC was well tolerated with no adverse events. ConclusionsThe SRC formulation resulted in slow & sustained levels of plasma caffeine associated with feelings of being more alert, less tired, better overall mood, less jittery and less tense for longer time periods without any safety concerns. SRC could be beneficial for those involved in sustained operations demanding peak cognitive & physical performance for a longer time. Funding SourcesOmniActive Health Technologies Ltd.

Subcutaneous Injection Site Pain of Formulation Matrices

The objective of this work was to systematically evaluate the effects of formulation composition on subcutaneous injection site pain (ISP) using matrices comprising of common pharmaceutical excipients. Two randomized, blinded, crossover studies in healthy subjects were conducted at a single site, where subjects received 1mL SC injections of the buffer matrices. ISP intensity was measured using a 100mm visual analogue scale (VAS), which was then analyzed via heatmap, categorical grouping, subgroup analysis, and paired delta analysis. Buffer type, buffer concentration and tonicity agent showed a substantial impact on ISP. Citrate buffer demonstrated a higher ISP than acetate buffer or saline). The 20mM citrate buffer was more painful than 10 or 5mM citrate buffers. NaCl and propylene glycol were significantly more painful than sugar alcohols (mannitol, sucrose, trehalose or glycerol). Histidine buffers exhibited ISP in the descending order of 150mM > 75mM > 25mM > 0mM NaCl, while histidine buffers containing Arginine-HCl at 0, 50, or 150mM all showed very low ISP. Histidine buffer at pH6.5 showed a lower ISP than pH5.7. This systematic study via orthogonal analyses demonstrated that subcutaneous ISP is significantly influenced by solution composition.

Clinical Investigation of Metabolic and Renal Clearance Pathways Contributing to the Elimination of Fevipiprant Using Probenecid as Perpetrator.

Fevipiprant, an oral, nonsteroidal, highly selective, reversible, and competitive prostaglandin D2 receptor 2 antagonist, is eliminated by glucuronidation and by direct renal excretion predominantly via organic anion transporter (OAT) 3. This study aimed to assess the effect of simultaneous UDP-glucuronosyltransferase (UGT) and OAT3 inhibition by probenecid on the pharmacokinetics of fevipiprant and its acyl glucuronide (AG) metabolite to support the dosing recommendation of fevipiprant in the presence of drugs inhibiting these pathways; however, phase III clinical trial results did not support its submission. This was a single-center, open-label, single-sequence, two-period crossover study in healthy subjects. Liquid chromatography with tandem mass spectrometry was used to measure concentrations of fevipiprant and its AG metabolite in plasma and urine. In the presence of probenecid, the mean maximum concentrations of fevipiprant increased approximately 1.7-fold, and the area under the concentration-time curve in plasma increased approximately 2.5-fold, whereas the mean apparent volume of distribution and the AG metabolite:fevipiprant ratio decreased. The apparent systemic clearance decreased by approximately 60% and the renal clearance decreased by approximately 88% in the presence of probenecid. Using these data and those from previous studies, the relative contribution of OAT and UGT inhibition to the overall effect of probenecid was estimated. Furthermore, a general disposition scheme for fevipiprant was developed, showing how a perpetrator drug such as probenecid, which interferes with two key elimination pathways of fevipiprant, causes only a moderate increase in exposure and allows estimation of the drug-drug inhibition when only one of the two pathways is inhibited. SIGNIFICANCE STATEMENT: In this drug-drug interaction (DDI) study, probenecid was used as a tool to inhibit both glucuronidation and active renal secretion of fevipiprant. The combination of plasma and urine pharmacokinetic data from this study with available data allowed the development of a quantitative scheme to describe the fate of fevipiprant in the body, illustrating why the DDI effect on fevipiprant is weak-to-moderate even if a perpetrator drug inhibits several elimination pathways.

Effects of Food on the Pharmacokinetic Properties of Surufatinib: A Phase I, Single-dose, Randomized, Open-label Crossover Study in Healthy Subjects

PurposeSurufatinib is a potent and orally active small-molecule tyrosine kinase inhibitor targeting VEGFRs 1 to 3, FGFR-1, and CSF-1R, and thus may exert antitumor and antiangiogenic effects. The objective of this study was to determine the tolerability and effects of food intake on the pharmacokinetic properties of surufatinib in healthy Chinese subjects. MethodsA total of 24 healthy Chinese male subjects aged between 18 and 55 years were enrolled. Subjects were administered a single dose of surufatinib 250–mg capsules in the fasted and fed states in succession. Pharmacokinetic analysis was performed through the collection of blood samples at predose and at several time points after surufatinib administration. Tolerability assessments comprised physical examination including vital sign measurements, laboratory testing, and ECG to determine adverse events (AEs). FindingsThe 90% CIs of the geometric mean ratios of AUC0–t and AUC0–∞ in the fasted and fed states was within 0.80 to 1.25; and for Cmax, within 0.70 to 1.43, indicating that food had no effect on the bioavailability of surufatinib in these healthy Chinese male subjects. Food intake delayed the time to peak absorption of surufatinib, as the median Tmax in the fed state was longer than that in the fasted state (4.0 vs 2.0 h). Surufatinib was marginally excreted from urine (mean [SD] cumulative excretion fraction, 1.2% [0.4%]). AEs occurred in 7 of the 24 subjects (29.2%) and included upper respiratory tract infection, dizziness, merycism, intervertebral disc protrusion, influenza-like disease, hematuria, prostatitis, and elevated blood urea nitrogen. All AEs were grade 1 or 2. ImplicationsThe bioavailability of surufatinib was not affected by food intake prior to dosing. However, food intake led to delated Tmax of surufatinib. The tolerability of a single oral dose of surufatinib 250 mg in the fasted and fed states was favorable in these healthy Chinese male subjects. These results indicate that surufatinib capsules could be administered before or after meals. ClinicalTrials.gov identifier: NCT02320409.

Acute effects of Amomum villosumLour. fruit extract on postprandial glycemia and insulin secretion: A single-blind, placebo-controlled, crossover study in healthy subjects.

BackgroundAmomum villosum Lour., (Zingiberaceae) an herbaceous plant in the ginger family, has been used to treat various diseases. In a single-blind, randomized, crossover study, we assessed the postprandial blood insulin and blood glucose responses in healthy subjects (n = 40) after the Amomum villosum water extract (AVE) (5 g/person) or a placebo (5 g/person) consumption.MethodsDuring each treatment course, the healthy subject consumed a regular late afternoon meal, followed by fasting for 12 h, and arrived at the clinical study center the next morning. Blood insulin and blood glucose levels were assessed at 0, 30, 60, 90, and 120 min after AVE consumption. Between each treatment, the subjects accomplished one week of a washout period.ResultsThe AVE intake demonstrated a significant (67.26%) decline in postprandial blood glucose AUC0–120 min (incremental area under the curve from 0 to 120 min) versus the placebo (P = 0.011). Furthermore, AVE reduced postprandial blood insulin AUC0–120 min by 59.95% compared to the placebo group (P < 0.003), supporting the blood glucose results.ConclusionThis study revealed that AVE consumption significantly reduced postprandial insulin and glucose levels in healthy individuals, due in part to inhibition of α-glucosidase, and glucose transport.

Validation and clinical application of dried blood spot assay for quantitative assessment of edoxaban in healthy adults.

Aim: Dried blood spot (DBS) is a sampling approach that offers several advantages over plasma and whole blood (WB) sampling, but several factors, such as hematocrit and temperature, can adversely affect quantitation. Methodology & results: In an open-label, three-way crossover study in healthy subjects, we explored the correlation between DBS, WB and plasma samples, and between DBS samples from finger-prick and venipuncture blood for measuring edoxaban and its metabolite M-4 using LC-MS/MS. The methods were validated comprehensively. The incurred sample reanalysis experiments demonstrated quantitation reproducibility in all three matrices. Overall, there was a good correlation (near perfect concordance for edoxaban) among plasma, WB and DBS measurements. M-4 concentrations in DBS and WB were lower than in plasma. Conclusion: These results indicate using DBS may be used as an alternative methodology to measure edoxaban pharmacokinetics.