Single-dose Study Research Articles

549-P: A Premeal Drink of Low-Dose Whey Protein (WP) Microgel Rapidly Increases Bioavailability of Branched Chain Amino Acids (BCAA) in People with Type 2 Diabetes (T2D) : A Randomized, Placebo-Controlled Crossover Study

BCAAs are key ingredients of WPs with biomodulatory effects. We recently reported that a highly-concentrated low-dose (10g, 40 Cal) WP pre-meal drink (125 mL) , generated with novel micelle-technology (WP microgel [WPM]) , ingested 15 min ahead of a pizza-meal (622 Cal) , vs placebo (PBO) , reduced the 2h incremental area under the glucose curve (iAUC) by 22%, increased 2h GLP-1 iAUC by 61% and, delayed 1h gastric emptying by 17%, in 26 people with T2D. Here, we analyzed 2h free plasma BCAA trajectories in 25 persons (mean age 62 yrs, HbA1c 7,5%, BMI 29 kg/m2) that completed this single dose study. The pre-meal WPM drink significantly altered the BCAA trajectory vs. PBO (Figure) . For leucine, ΔiAUCWPM vs PBO increased by 267%, with a shorter time to maximum (median ΔTmax [min, max]: -60 [-120,0] min, p<0.0001) , and peak concentration (mean ΔCmax [SD]: 123 [49] umol/L, p<0.0001) . A similar pattern was seen for isoleucine (ΔiAUC +240%, ΔTmax: -60 [-120,0], p<0.0001, ΔCmax: 68 [31], p<0.0001) and valine (ΔiAUC +194%, ΔTmax: -60 [-120, 30], p < 0.0001, ΔCmax: 63 [38], p<0.0001) . We conclude that 10g WPM as a pre-meal drink, induced a rapid plasma increase, and high bioavailibilty, of BCAAs in people with T2D. The rapid BCAA availability might be a likely factor for the metabolic modulatory effects observed with WPM. Disclosure I.Neeland: Advisory Panel; Boehringer Ingelheim International GmbH, Merck & Co., Inc., Consultant; Nestlé Health Science. B.Ahrén: Speaker's Bureau; Nestlé, Novo Nordisk, Stock/Shareholder; AstraZeneca, Novo Nordisk A/S. J.V.Corthésy: Employee; Nestlé. Y.Grzywinski: None. Z.Magos: Consultant; Nestlé Health Science. M.Von eynatten: Employee; Nestlé Health Science. O.Johansen: Employee; Boehringer Ingelheim International GmbH, Nestlé Health Science. Funding Nestlé Health Science

Effects of enriched seafood sticks (heat-inactivated B. animalis subsp. lactis CECT 8145, inulin, omega-3) on cardiometabolic risk factors and gut microbiota in abdominally obese subjects: randomized controlled trial

PurposeTo assess the effects of enriched seafood sticks with postbiotic and bioactive compounds on CMD risk factors and the gut microbiota in abdominally obese individuals.MethodsRandomized, double-blind, parallel, placebo-controlled trial with abdominally obese individuals. Participants (n = 120) consumed 50 g/day of enriched seafood sticks containing SIAP: (1010 colony forming units (CFUs) of heat-inactivated B. animalis subsp. lactis CECT8145, 370 mg/day omega 3 and 1.7 g/day inulin), or 50 g/day of placebo seafood sticks for 12 weeks. At 12 weeks, an acute single-dose study of 4 h was performed.ResultsSustained SIAP2 consumption significantly decreased the insulin by − 5.25 mg/dL and HOMA-IR (homeostatic Model Assessment of Insulin Resistance) by − 1.33. In women, SIAP2 consumption significantly decreased the pulse pressure (PP) by − 4.69 mmHg. Gut microbiota analysis showed a negative association between glycemic parameter reduction and Alistipes finegoldii and Ruminococcaceae, and between PP reduction and Prevotella 9-ASV0283 and Christensenellaceae. In the acute single dose-study 4-h, SIAP2 consumption produced a lower increase in the postprandial circulating triglyceride levels [23.9 (7.03) mg/dL (mean [standard error])] than the observed with placebo [49.0 (9.52)] mg/dL.ConclusionIn abdominally obese individuals, enriched seafood sticks induce a potential protection against type 2 diabetes development by the reduction in the insulin and HOMA-IR; and in cardiovascular disease, in women, by the PP reduction. These effects are accompanied by partial changes in the gut microbiota composition. The enriched seafood sticks reduce the atherogenic triglyceride postprandial concentrations. Our results support the use of enriched seafood sticks as a complementary strategy in the management of CMD risk factors.Registration number of Clinical Trial(www.ClinicalTrials.gov): NCT03630588 (August 15, 2018).

Onasemnogene abeparvovec gene therapy for spinal muscular atrophy type 1: phase 3 study update (str1ve-eu)

Onasemnogene abeparvovec (formerly AVXS-101), a one-time intravenous AAV9-based gene therapy, addresses the genetic root cause of spinal muscular atrophy type 1 (SMA1). We report preliminary data from the phase 3 STR1VE-EU (2017-000266-29/NCT03461289) study evaluating efficacy and safety of onasemnogene abeparvovec infusion. STR1VE-EU is an ongoing, multicenter, open-label, single-arm, single-dose study in SMA1 patients aged <6 months (biallelicSMN1mutations, 1–2xSMN2). Outcomes: independent sitting ≥10 seconds throughout 18 months; survival (no death/permanent ventilation) at 14 months. Enrollment is complete (31 May 2019; N=33, all 2xSMN2). Mean age at dosing: 4.1 (1.4–6) months. Mean baseline CHOP INTEND score: 28 (14–55). Mean time in study: 4.8 (0.4–9.2) months. At baseline, 9/33 (27%) patients required nutritional support and 7/33 (17%) required ventilatory support. Relative to baseline, mean CHOP INTEND score increased 6.4,10.6, and 12.3 points at 1, 3, and 5 months post-dosing, respectively. Overall, 32 patients were surviving without permanent ventilation, including 9/10 patients who reached 10.5 months of age or experienced an event. One patient died (age 6.8 months, hypoxic- ischemic brain injury secondary to respiratory tract infection due to SMA1). Interim data from the ongoing STR1VE-EU study shows that onasemnogene abeparvovec has therapeutic benefit in patients with SMA1.1ik4ausar078@avexis.com

In vivo antihyperglycaemic and antihyperlipidemic activities and chemical constituents of Solanum anomalum

Solanum anomalum is a plant used ethnomedically for the treatment of diabetes. The study was aimed to validate ethnomedical claims in rat model and identify the likely antidiabetic compounds. Leaf extract (70–210 mg/kg/day) and fractions (140 mg/kg/day) of S. anomalum were evaluated in hyperglycaemic rats induced using alloxan for effects on blood glucose, lipids and pancreas histology. Phytochemical characterisation of isolated compounds and their identification were performed using mass spectrometry and NMR spectroscopy. Bioinformatics tool was used to predict the possible protein targets of the identified bioactive compounds. The leaf extract/fractions on administration to diabetic rats caused significant lowering of fasting blood glucose of the diabetic rats during single dose study and on repeated administration of the extract. The hydroethanolic leaf extracts also enhanced glucose utilization capacity of the diabetic rats and caused significant lowering of glycosylated hemoglobin levels and elevation of insulin levels in the serum. Furthermore, triglycerides, LDL-cholesterol, and VLDL-cholesterol levels were lowered significantly, while HDL–cholesterol levels were also elevated in the treated diabetic rats. There was absence or few pathological signs in the treated hyperglycaemic rat pancreas compared to that present in the pancreas of control group. Diosgenin, 25(R)-diosgenin-3-O-α-L-rhamnopyranosyl-(1→4)-β-D-glucopyranoside, uracil, thymine, 1-octacosanol, and octacosane were isolated and identified. Protein phosphatases along with secreted proteins are predicted to be the major targets of diosgenin and the diosgenin glycoside. These results suggest that the leaf extract/fractions of S. anomalum possess antidiabetic and antihyperlipidemic properties, offer protection to the pancreas and stimulate insulin secretion, which can be attributable to the activities of its phytochemical constituents.

Safety assessment of white colony-forming yeasts in kimchi

White colony-forming yeasts (WCFYs) have been reported to form a white colony on the surface of kimchi, resulting in the deterioration of kimchi sensory quality. However, toxicity of WCFY has rarely been studied. Thus, to evaluate the safety of WCFY (i.e., Kazachstania servazzii, Candia sake, and Pichia kudriavzevii), we conducted cell and animal experiments as well as genomic analysis. In vitro studies indicated that WCFY did not induce cytotoxic responses such as lactate dehydrogenase release, excessive oxidative stress, and mitochondrial damage at concentrations of up to 2.5 × 105 CFU/mL in human intestinal and liver cells. In animal studies using rats (single-dose and 14-day repeated-dose oral toxicity studies), WCFY did not induce death, clinical signs of toxicity, histological alterations of the liver, or increases in the expression of pro-inflammatory cytokines nor cytochrome P450-2E1 in liver tissue at concentrations of up to 5 × 108 CFU/head/day. Genomic analysis revealed that P. kudriavzevii did not harbor genes related to toxicity and antimicrobial resistance. Taken together, our data suggest that exposure to WCFY through kimchi intake did not induce toxic response in the Caco-2, HepG2, and Sprague-Dawley rats. The current work provides evidence for the safety of accidental major WCFY ingestion via kimchi.

Effect of a Ketohexokinase Inhibitor (PF‐06835919) on In Vivo OATP1B Activity: Integrative Risk Assessment Using Endogenous Biomarker and a Probe Drug

PF-06835919 is a first-in-class ketohexokinase inhibitor (KHKi), recently under development for the treatment of metabolic and fatty liver diseases, which inhibited organic anion transporting polypeptide (OATP)1B1 in vitro and presented drug-drug interaction (DDI) risk. This study aims to investigate the dose-dependent effect of KHKi on OATP1B in vivo activity. We performed an open-label study comparing pharmacokinetics of atorvastatin (OATP1B probe) dosed alone (20 mg single dose) and coadministered with two dose strengths of KHKi (50 and 280mg once daily) in 12 healthy participants. Additionally, changes in exposure of coproporphyrin-I (CP-I), an endogenous biomarker for OATP1B, were assessed in the atorvastatin study (1.12-fold and 1.49-fold increase in area under the plasma concentration-time profile (AUC) with once-daily 50 and 280mg, respectively), and a separate single oral dose study of KHKi alone (100-600mg, n=6 healthy participants; up to a 1.80-fold increase in AUC). Geometric mean ratios (90% confidence interval) of atorvastatin AUC following 50 and 280mg KHKi were 1.14 (1.00-1.30) and 1.54 (1.37-1.74), respectively. Physiologically-based pharmacokinetic modeling of CP-I plasma exposure following a single dose of KHKi predicted in vivo OATP1B inhibition from about 13% to 70% over the 100 to 600mg dose range, while using the in vitro inhibition potency (1.9µM). Model-based analysis correctly predicted "no-effect" (AUC ratio <1.25) at the low dose range and "weak" effect (AUC ratio <2) on atorvastatin pharmacokinetics at the high dose range of KHKi. This study exemplified the utility of biomarker-informed model-based approach in discerning even small effects on OATP1B activity in vivo, and to project DDI risk at the clinically relevant doses.

Physiologically based pharmacokinetic modeling and simulations to inform dissolution specifications and clinical relevance of release rates on elagolix exposure

The aim of this analysis was to use a physiologically based pharmacokinetic (PBPK) model to predict the impact of changes in dissolution rates on elagolix exposures and define clinically relevant acceptance criteria for dissolution. Varying in vitro dissolution profiles were utilized in a PBPK model to describe the absorption profiles of elagolix formulations used in Phase 3 clinical trials and for the to be marketed commercial formulations. Single dose studies of 200 mg elagolix formulations were used for model verification under fasted conditions. Additional dissolution scenarios were evaluated to assess the impact of dissolution rates on elagolix exposures. Compared to the Phase 3 clinical trial formulation, sensitivity analysis on dissolution rates suggested that a hypothetical scenario of ∼75% slower dissolution rate would result in 14% lower predicted elagolix plasma exposures, however, the predicted exposures are still within the bioequivalence boundaries of 0.8–1.25 for both Cmax and AUC. A clinically verified PBPK model of elagolix was utilized to evaluate the impact of wider dissolution specifications on elagolix plasma exposures. The simulation results indicated that a slower in vitro dissolution profile, would not have a clinically significant impact on elagolix exposures. These model results informed the setting of wider dissolution specifications without requiring in vivo studies.

A Randomized, Single Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Novel Insulin Dimer.

Insulin molecules of size much greater than natural insulin have been synthesized and studied with the intention of widening the therapeutic window between adequate glycemic control and hypoglycemia as compared with conventional insulins. MK-1092 is a synthetic insulin dimer with favorable properties demonstrated in preclinical studies. Here, we report the results of the first-in-human, randomized, double-blind, active-control, single ascending dose trial of MK-1092, conducted in healthy adults, adults with type 1 diabetes (T1D), and adults with type 2 diabetes (T2D). MK-1092 was well tolerated in all study populations, and no dose-related adverse events were identified across the evaluated dose range (4-64nmol/kg). Circulating concentrations of MK-1092 were approximately dose-proportional. Maximum glucose infusion rate (GIR) and 24-hour time-weighted average GIR were evaluated under euglycemic clamp conditions. These pharmacodynamic measurements were approximately dose-proportional in all study populations; at similar doses, the GIR parameters were lower in adults with T2D than in healthy adults or adults with T1D, likely due to the influence of insulin resistance. At doses ≥16nmol/kg, MK-1092 had similar or greater effects than glargine 3nmol/kg (0.5 units/kg) on increasing GIR in each study population and on suppressing free fatty acids and ketone generation in adults with T1D. MK-1092 did not prevent a subsequent high dose of lispro from increasing the GIR in healthy adults. Additional studies in adults with T1D and T2D are needed to further evaluate the safety, tolerability, and efficacy profile of MK-1092 and its potential for differentiation from more conventional insulins. (ClinicalTrials.gov: NCT03170544).

Enhanced Oral Bioavailability of β-Caryophyllene in Healthy Subjects Using the VESIsorb® Formulation Technology, a Novel Self-Emulsifying Drug Delivery System (SEDDS).

β-Caryophyllene (BCP), a common constituent of many spice and food plants, is gaining increased attention due to recent research identifying numerous potential health benefits. Due to limited oral bioavailability observed in preclinical models, the described benefits of BCP may be maximized by using a suitable delivery system. Additionally, human pharmacokinetics (PK) remain unknown. This study evaluates the relative oral bioavailability of BCP formulated in a self-emulsifying drug delivery system (SEDDS) based on VESIsorb® formulation technology (BCP-SEDDS) compared to BCP neat oil. Hence, a randomized, double-blind, cross-over design, single oral dose study (100 mg BCP) in 24 healthy subjects (12 men/12 women) was performed under fasting conditions. Pharmacokinetic parameters were analyzed from individual concentration-time curves. The data show that BCP-SEDDS resulted in a 2.2/2.0-fold increase in AUC0–12h/AUC0–24h and a 3.6-fold increase in Cmax compared to BCP neat oil. Moreover, BCP was absorbed faster from BCP-SEDDS (Tmax: 1.43 h) compared to BCP neat oil (Tmax: 3.07 h). Gender analysis revealed that there is no significant difference between men and women for both the investigated formulations and all investigated PK endpoints. In conclusion, BCP-SEDDS offers a well-tolerated and effective oral delivery system to significantly enhance the oral bioavailability of BCP in humans.

A community intervention effectiveness study of single dose or two doses of bivalent HPV vaccine (CERVARIX®) in female school students in Thailand.

Human papillomavirus (HPV) is a common infection principally spread through sexual activity. Most HPV infections are asymptomatic and resolve spontaneously. However, persistent infection may progress to cervical cancer. Highly efficacious HPV vaccines have been available since 2006, yet uptake into national programs has been slow in part due to cost. WHO guidelines call for a two-dose (0,6 month) schedule for girls 9-14 years of age. Post-hoc analyses of randomized trials have found high vaccine effectiveness following a single dose of vaccine. In order to provide additional data on the potential impact of single dose HPV vaccination in a real-world setting, we are conducting an effectiveness study among Thai schoolgirls. This is an observational study of a single dose (SD) or two doses (2D) of the bivalent HPV vaccine CERVARIX® (GlaxoSmithKline plc.) administered in a school-based program to 8-9,000 Grade 8 female students in two provinces of Thailand beginning in 2018; one province is assigned the SD, and the other the standard 2D regimen. The reduction in HPV vaccine-type prevalence will be assessed in each province two and four years after vaccination by comparing HPV prevalence in urine samples obtained through cross-sectional surveys of the immunized grade cohort as they age and compared to a historical "baseline" HPV prevalence of same age students.

Bioequivalence of two oral formulations of tebipenem pivoxil hydrobromide in healthy subjects.

Tebipenem pivoxil hydrobromide (TBP‐PI‐HBr) is a novel oral carbapenem prodrug of tebipenem (TBP), the active moiety, currently in development for treating serious bacterial infections. This study assessed the bioequivalence (BE) of the clinical trial and registration tablet formulations of TBP‐PI‐HBr and evaluated the effect of food on the pharmacokinetics (PKs) of tebipenem. This was a single center, open‐label, randomized, single‐dose, three‐sequence, four‐period crossover, BE, and food‐effect study. Subjects received single 600 mg oral doses of TBP‐PI‐HBr as the reference clinical trial tablet (treatment A) and test registration tablet (treatment B) formulations in alternating sequence while fasting, and then the test formulation under fed conditions. Whole blood samples were collected predose and at specified intervals up to 24 h postdose to evaluate TBP PK parameters. Safety and tolerability were monitored. Thirty‐six healthy, adult subjects were enrolled and completed the study. The criteria for BE were met for the TBP‐PI‐HBr test (registration tablet) and reference (clinical trial tablet) formulations as the 90% confidence intervals for the geometric mean ratios for TBP area under the curve (AUC)0‐t , AUC0‐inf, and maximum plasma concentration (C max) fell within the established 80% to 125% BE limits. Dosing with food had no meaningful effect on TBP PK parameters. Five (14%) subjects reported adverse events (AEs) of mild severity. No deaths, serious AEs, or discontinuations due to AEs were reported, and no clinically relevant electrocardiograms, vital signs, or safety laboratory findings were observed. The study results demonstrate the BE of oral TBP‐PI‐HBr registration and clinical trial tablet formulations and indicate that TBP‐PI‐HBr can be administered without regard to meals.

Hypoglycemic activity of Methanol Fraction of Solanum torvum (Swartz) fruits in normal and Streptozotocin induced Hyperglycemic rat models

Diabetes mellitus (DM) is a common endocrine disorder, now considered as a major global health problem which is affecting around 9.3% of world population and its incidence is increasing day by day. In India, several plants having hypoglycemic property are traditionally used in management of diabetes. Solanum torvum (Swartz) (ST) plant belonging to family Solanaceae; is medicinally reported and claims to cure various diseases in Indian traditional system of medicine (Ayurveda) and also in folklore and as per previous report, the decoction of its fruits is very useful in the treatment of diabetes. The thrust of this investigation is to examine the hypoglycemic efficacy of methanolic fractions (50, 100 and 200mg/kg body wt.) of ST fruits (MFST) from defatted hydro-alcoholic extract in normoglycemic, followed by Streptozotocin (45mg/kg) induced diabetic, and glucose loaded hyperglycemic rats by single as well as multiple oral administration in contrast to the standard drug glibenclamide (2.5mg/kg body wt.). In the beginning of the investigation, acute oral toxicity study of MFST was carried out in rats to determine the dose for experiment animals. The study report showed that the MFST (200mg/kg) significantly (p&lt;0.05 to p&lt;0.01) declines blood glucose level both in normoglycemic and diabetic rats induced by Streptozotocin, and oral glucose loaded hyperglycemic rats till the end of 8th hour and 3rd hour respectively during the single dose study and from the 15th day to 30th day in multi dose study. The blood glucose level decreasing activity of MFST may be due to the secondary metabolites such as flavonoids, tannins and phenolic compounds present in it. Hence the present investigation report reveals that MFST possess significant hypoglycemic and anti-diabetic activity which persuades the traditional use of the plant for the treatment or management of diabetes mellitus.

Opioid-sparing effect of cannabinoids for analgesia: an updated systematic review and meta-analysis of preclinical and clinical studies

Cannabinoid co-administration may enable reduced opioid doses for analgesia. This updated systematic review on the opioid-sparing effects of cannabinoids considered preclinical and clinical studies where the outcome was analgesia or opioid dose requirements. We searched Scopus, Cochrane Central Registry of Controlled Trials, Medline, and Embase (2016 onwards). Ninety-two studies met the search criteria including 15 ongoing trials. Meta-analysis of seven preclinical studies found the median effective dose (ED50) of morphine administered with delta-9-tetrahydrocannabinol was 3.5 times lower (95% CI 2.04, 6.03) than the ED50 of morphine alone. Six preclinical studies found no evidence of increased opioid abuse liability with cannabinoid administration. Of five healthy-volunteer experimental pain studies, two found increased pain, two found decreased pain and one found reduced pain bothersomeness with cannabinoid administration; three demonstrated that cannabinoid co-administration may increase opioid abuse liability. Three randomized controlled trials (RCTs) found no evidence of opioid-sparing effects of cannabinoids in acute pain. Meta-analysis of four RCTs in patients with cancer pain found no effect of cannabinoid administration on opioid dose (mean difference −3.8 mg, 95% CI −10.97, 3.37) or percentage change in pain scores (mean difference 1.84, 95% CI −2.05, 5.72); five studies found more adverse events with cannabinoids compared with placebo (risk ratio 1.13, 95% CI 1.03, 1.24). Of five controlled chronic non-cancer pain trials; one low-quality study with no control arm, and one single-dose study reported reduced pain scores with cannabinoids. Three RCTs found no treatment effect of dronabinol. Meta-analyses of observational studies found 39% reported opioid cessation (95% CI 0.15, 0.64, I2 95.5%, eight studies), and 85% reported reduction (95% CI 0.64, 0.99, I2 92.8%, seven studies). In summary, preclinical and observational studies demonstrate the potential opioid-sparing effects of cannabinoids in the context of analgesia, in contrast to higher-quality RCTs that did not provide evidence of opioid-sparing effects.

Safety, Tolerability, and Pharmacokinetic Study of 101BHG-D01 Nasal Spray, a Novel Long-Acting and Selective Cholinergic M Receptor Antagonist, in Healthy Chinese Volunteers: A Randomized, Double-Blind, Placebo-Controlled, Single-Dose Escalation, First-In-Human Study.

101BHG-D01 nasal spray is the first novel long-acting cholinergic M receptor antagonist under development to treat rhinorrhea in rhinitis. This first-in-human study aimed to evaluate the safety, tolerability, and pharmacokinetics of 101BHG-D01 nasal spray following single intranasal doses in healthy Chinese subjects. A randomized, double-blind, placebo-controlled, single-dose escalation study was conducted in healthy Chinese volunteers after intranasal doses of 101BHG-D01 nasal spray or placebo ranging from 40 µg to 960 µg (total of six doses). Blood samples were collected at scheduled time points, and plasma concentrations were determined using a validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. A non-compartmental method was used to calculate the main pharmacokinetic parameters, including the area under the plasma concentration-time curve from time zero to the time of the last measurable concentration (AUC0-t), the area under the plasma concentration-time curve from time zero to infinity (AUC0-∞), the maximum plasma concentration (Cmax), the time to maximum plasma concentration (Tmax), and the elimination half-life (t1/2). Safety was evaluated by monitoring adverse events, laboratory assays, vital signs, physical examinations, 12-lead electrocardiograms (ECGs), anterior rhinoscopy, ophthalmic examination, and ambulatory ECG monitoring. Following single intranasal dosing, 101BHG-D01 was rapidly absorbed with a median Tmax of 0.34-0.50 h and eliminated slowly with a mean t1/2 ranging from 4.29 to 46.76 h for different dose groups. The Cmax and AUC of 101BHG-D01 increased linearly across the examined dose range of 40-960 µg. 101BHG-D01 nasal spray was well tolerated, all AEs were mild, and no serious adverse events occurred during the study. 101BHG-D01 nasal spray was safe and well tolerated in healthy Chinese subjects when administered intranasally in single escalating doses. The mean Cmax and AUC increased proportionally to the studied dose. The pharmacokinetic, safety, and tolerability profiles of 101BHG-D01 nasal spray indicate that it is a good candidate for further development as a treatment for rhinorrhea in rhinitis.

Investigational New Drug Enabling Nonclinical Safety Assessment of the Iminosugar UV-4, a Broad-Spectrum Host-Targeted Antiviral Agent.

The iminosugar UV-4 is a broad-spectrum antiviral drug candidate with activity in vitro and in vivo against multiple, diverse viruses. The toxicological profile of UV-4, dosed as the hydrochloride salt, was evaluated in single-dose and repeat-dose oral toxicity studies in mice, rats, dogs, and non-human primates (NHP). No moribundity or deaths were associated with the drug up to the maximum tolerated dose. No treatment-related adverse effects were observed following single oral doses in dogs, rats, and mice up to 250, 400, 1000mg/kg, respectively, and in NHP up to 180mg/kg administered three times daily for 10days. UV-4-related findings were generally seen at higher doses after 7- or 14-day exposure. The most common clinical pathology findings (increase in aspartate aminotransferase and decreased platelet count) were consistently found across species and each appeared dose related. The kidney, mesenteric lymph nodes, stomach including gastrointestinal tract, and thymus were identified as target organs in mice, rats, and dogs. In 14-day repeat-dose toxicology studies in mice and dogs conducted in compliance with Good Laboratory Practice regulations, the dog was considered to be the most sensitive species to UV-4 exposure based on the treatment-related adverse effects noted in the identified target organs. The results of these studies demonstrate the safety profile of UV-4 hydrochloride and supported the selection of starting and maximal doses for a single ascending dose first-in-human clinical study.

Study of Single Dose of Antibiotic Prophylaxis in Clean Surgeries at a Tertiary Care Centre

Background: Pre-operative single dose antibiotic prophylaxis has shown to reduce the incidence of surgical site infections and thereby patient morbidity. Aims: To evaluate effectiveness of single dose antibiotic prophylaxis in clean surgeries at a tertiary care hospital. Material and Methods: A total of 72 patients undergoing clean surgeries were included after they satisfied the inclusion and exclusion criteria. Results: Single dose of an intravenous prophylaxis of ceftriaxone in clean surgeries excisional biopsy of lipoma, dermoid cyst, sebaceous cyst, enucleation of fibroadenoma, herniotomy, eversion of hydrocele etc. was efficacious in preventing surgical site infection. Surgical site infection was associated with patient’s age, lower haemoglobin levels and longer hospital stay in 3 out of 72 patients. Conclusion: In the present study it was observed that prophylactic single shot of antibiotic is efficacious in averting surgical site infection and is economical for patients undergoing clean surgeries. Factors associated with surgical site infection were patient’s age, haemoglobin and associated co-morbidity like diabetes.

Single Ascending Dose Study of a Short Interfering RNA Targeting Lipoprotein(a) Production in Individuals With Elevated Plasma Lipoprotein(a) Levels

ImportanceLipoprotein(a) (Lp[a]) is an important risk factor for atherothrombotic cardiovascular disease and aortic stenosis, for which there are no treatments approved by regulatory authorities.ObjectivesTo assess adverse events and tolerability of a short interfering RNA (siRNA) designed to reduce hepatic production of apolipoprotein(a) and to assess associated changes in plasma concentrations of Lp(a) at different doses.Design, Setting, and ParticipantsA single ascending dose study of SLN360, an siRNA targeting apolipoprotein(a) synthesis conducted at 5 clinical research unit sites located in the US, United Kingdom, and Australia. The study enrolled adults with Lp(a) plasma concentrations of 150 nmol/L or greater at screening and no known clinically overt cardiovascular disease. Participants were enrolled between November 18, 2020, and July 21, 2021, with last follow-up on December 29, 2021.InterventionsParticipants were randomized to receive placebo (n = 8) or single doses of SLN360 at 30 mg (n = 6), 100 mg (n = 6), 300 mg (n = 6), or 600 mg (n = 6), administered subcutaneously.Main Outcomes and MeasuresThe primary outcome was evaluation of safety and tolerability. Secondary outcomes included change in plasma concentrations of Lp(a) to a maximum follow-up of 150 days.ResultsAmong 32 participants who were randomized and received the study intervention (mean age, 50 [SD, 13.5] years; 17 women [53%]), 32 (100%) completed the trial. One participant experienced 2 serious adverse event episodes: admission to the hospital for headache following SARS-CoV-2 vaccination and later for complications of cholecystitis, both of which were judged to be unrelated to study drug. Median baseline Lp(a) concentrations were as follows: placebo, 238 (IQR, 203-308) nmol/L; 30-mg SLN360, 171 (IQR, 142-219) nmol/L; 100-mg SLN360, 217 (IQR, 202-274) nmol/L; 300-mg SLN360, 285 (IQR, 195-338) nmol/L; and 600-mg SLN360, 231 (IQR, 179-276) nmol/L. Maximal median changes in Lp(a) were −20 (IQR, −61 to 3) nmol/L, −89 (IQR, −119 to −61) nmol/L, −185 (IQR, −226 to −163) nmol/L, −268 (IQR, −292 to −189) nmol/L, and −227 (IQR, −270 to −174) nmol/L, with maximal median percentage changes of −10% (IQR, −16% to 1%), −46% (IQR, −64% to −40%), −86% (IQR, −92% to −82%), −96% (IQR, −98% to −89%), and −98% (IQR, −98% to −97%), for the placebo group and the 30-mg, 100-mg, 300-mg, and 600-mg SLN360 groups, respectively. The duration of Lp(a) lowering was dose dependent, persisting for at least 150 days after administration.Conclusions and RelevanceIn this phase 1 study of 32 participants with elevated Lp(a) levels and no known cardiovascular disease, the siRNA SLN360 was well tolerated, and a dose-dependent lowering of plasma Lp(a) concentrations was observed. The findings support further study to determine the safety and efficacy of this siRNA.Trial RegistrationClinicalTrials.gov Identifier: NCT04606602; EudraCT Identifier: 2020-002471-35

Bioequivalence of Esaxerenone Conventional Tablet and Orally Disintegrating Tablet: Two Single-Dose Crossover Studies in Healthy Japanese Men.

We assessed the bioequivalence of a single dose of 5‐mg of esaxerenone administered as an orally disintegrating tablet (ODT) with the conventional oral tablet in healthy Japanese men. This single‐center, open‐label, randomized, two‐drug, two‐stage crossover, single‐dose study was conducted in two parts. In study 1, both formulations were taken with water. In study 2, only the ODT formulation was taken without water. The primary outcome was the evaluation of bioequivalence of the ODT and conventional tablet using the pharmacokinetic (PK) parameters maximum plasma concentration (Cmax) and area under the plasma concentration–time curve to the last quantifiable time (AUClast). Plasma concentrations were measured using a validated liquid chromatography/mass spectrometry method and PK parameters were calculated by noncompartmental analysis. The ratios of the geometric least‐squares mean (2‐sided 90% confidence intervals [90%CIs]) for ODT with (study 1) and without (study 2) water to the conventional tablet were 1.03 (1.00–1.07) and 1.01 (0.96–1.06) for Cmax and 1.03 (1.00–1.07) and 0.96 (0.94–0.98) for AUClast, respectively. The 90%CIs fell within the predefined bioequivalence range of 0.80–1.25. Treatment‐emergent adverse events were similar between both formulations. In conclusion, esaxerenone 5‐mg ODT taken with or without water was bioequivalent to a single 5‐mg conventional oral tablet.

Investigating the Role of the Reduced Solubility of the Pirfenidone-Fumaric Acid Cocrystal in Sustaining the Release Rate from Its Tablet Dosage Form by Conducting Comparative Bioavailability Study in Healthy Human Volunteers.

Pirfenidone (PFD) is the first pharmacological agent approved by the US Food and Drug Administration (FDA) in 2014 for the treatment of idiopathic pulmonary fibrosis (IPF). The recommended daily dosage of PFD in patients with IPF is very high (2403 mg/day) and must be mitigated through additives. In the present work, sustained-release (SR) formulations of the PFD-FA cocrystal of two different strengths such as 200 and 600 mg were prepared and its comparative bioavailability in healthy human volunteers was studied against the reference formulation PIRFENEX (200 mg). A single-dose pharmacokinetic study (200 mg IR vs 200 mg SR) demonstrated that the test formulation exhibited lower Cmax and Tmax in comparison to the reference formulation, which showed that the cocrystal behaved like an SR formulation. Further in the multiple-dose comparative bioavailability study (200 mg IR thrice daily vs 600 mg SR once daily), the test formulation was found bioequivalent to the reference formulation. In conclusion, the present study suggests that cocrystallization offers a promising strategy to reduce the solubility of PFD and opens the door for potential new dosage forms of this important pharmaceutical.

A Phase I, Open-label, Single-Dose Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of AMG 986 in Healthy Japanese Subjects.

Background and ObjectiveAMG 986 is a first-in-class, novel apelin receptor small molecule agonist initially developed as a treatment for patients with heart failure (HF). Previously, a first-in-human study of AMG 986 was conducted in healthy and HF subjects; however, AMG 986 was not evaluated in Japanese subjects.MethodsThis was a phase I, open-label, single-dose, single-center study conducted to evaluate the safety and pharmacokinetics (PK) of AMG 986 200 mg and 400 mg in 12 healthy Japanese subjects. Six subjects received AMG 986 200 mg and six subjects received AMG 986 400 mg.ResultsFollowing oral administration, median time to maximum observed plasma concentration (tmax) was 1.0 h for both the AMG 986 200 mg and 400 mg groups, and mean terminal half-life (t½) was 15.1 h and 17.6 h, respectively. When comparing the AMG 986 200 mg and 400 mg groups, 1.33-fold and 1.18-fold higher maximum observed plasma concentration (Cmax) and AUC∞, respectively, were observed for the 2-fold increase in dose. AMG 986 exhibited an acceptable safety and tolerability profile; all adverse events were mild in severity.ConclusionAMG 986 exposure increased with increasing dose, and the increase was less than dose proportional in healthy Japanese subjects. The results of this study could facilitate the subsequent clinical development of AMG 986 for the treatment of Japanese patients with HF.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40268-022-00386-3.