Administration In Healthy Volunteers Research Articles

Inhaled fentanyl aerosol through a drug-device combination for breakthrough cancer pain: A multicenter, randomized, double-blind, placebo-controlled trial.

e24058 Background: Breakthrough cancer pain (BTcP) can significantly impact the life quality of the cancer patient. Wide-used rapid-onset opioids (ROOs) for BTcP are transmucosal fentanyl-based preparations. Inhaled fentanyl demonstrated similar pharmacokinetic properties as intravenous administration in healthy volunteers. Fentanyl aerosol can be generated via hand-held drug-device delivery system, providing rapid, consistent multi-dose administration. Fentanyl inhalant was explored as alternative treatment of BTcP in cancer patients in this study to evaluate its efficacy, safety, and tolerability in BTcP patients with well-controlled background cancer pain. Methods: Adults ≥18 years with cancer are eligible if they were experiencing persistent cancer- or treatment-related pain with above mild severity and 1-4 episode occurrences daily. Each patient was treated and observed for 6 BTcP episodes (4 with fentanyl inhalant, 2 with placebo). During each episode, patients were allowed to inhale up to six shots within 1 hour. Pain intensity was recorded using 11-point Numerical Rating Scale (NRS) at predefined time points. The primary endpoint was the time-weighted Sum of Pain Intensity Difference scores at 30 minutes (SPID30) after the first inhalation. Results: 335 BTcP episodes in 59 patients were treated. SPID30 was analyzed using mixed model of repeated measures with treatment (fentanyl inhalant or placebo), BTcP episode, baseline pain intensity score as fixed factors, and subject as random factor. Mean SPID30 ± SD was -97.4 ± 48.43 for fentanyl-treated episodes, and -64.6 ± 40.25 for placebo-treated episodes. Based on treatment adjustment in the mixed covariance model, significant difference (p < 0.001) was reported with mean treatment difference of -27.7 (LS-mean ± SD, -94.2 ± 4.49 for fentanyl and -66.5 ± 4.86 for placebo). It enlarged at 60 minutes (SPID60) with a mean treatment difference of -57.9 (LS-mean ± SD, -231.4 ±105.14 for fentanyl and -162.2 ± 91.21 for placebo, p < 0.001). Significant differences in PID for episodes treated with fentanyl versus placebo were seen 4 minutes after the first dosing and maintained up to 60 minutes. Other endpoints showed statistical significance favoring fentanyl treatment, including the proportion of NRS ≤ 3, NRS pain scores decreased ≥ 33% or ≥ 50% from baseline after completion of BTcP treatment within 30 minutes of first dose, and Pain Relief Score Within 30 Minutes of the First Dose (PR30). Only 4.4% of BTcP episodes required rescue medication in fentanyl group. Major adverse events were mild or moderate in severity and were typical for opioid drugs. Conclusions: Fentanyl inhalant is safe, effective, and well-tolerated for managing BTcP. It provides a non-invasive route for systemic drug delivery and can be self-administered or given by family caregivers as personalized and regular pain management. Clinical trial information: NCT05531422 .

How PBPK Can Help to Understand Old Drugs and Inform their Dosing in Elderly: Amantadine Case Study.

Amantadine, despite being on the market for 55 years, has several unknown aspects of its pharmacokinetics especially related to the influence of covariates such as age, disease, or interactions linked to amantadine's renal elimination. As amantadine is used in Parkinson's disease and is considered a potential candidate in COVIDtreatment and other diseases, there is an unmet need for thorough understanding of its pharmacokinetic in special populations, such as the elderly. We aimed to mechanistically describe amantadine pharmacokinetics in healthy subjects and shed some light on the differences in drug behavior between healthy volunteers (18-65 years) and an elderly/geriatric population (65-98 years) using PBPK modeling and simulation. The middle-out PBPK model includes mechanistic description of drug renal elimination, specifically an organic cation transporter (OCT)2-mediated electrogenic bidirectional transport (basolateral) and multidrug and toxic compound extrusion (MATE)1-mediated efflux (apical). The model performance was verified against plasma and urine data reported after single and multiple dose administration in healthy volunteers and elderly patients from 18 independent studies. The ratios of predicted vs. observed maximal plasma concentration and area under the concentration-time curve values were within 1.25-fold. The model illustrates that renal transporter activity is expected to decrease in healthy elderly compared to healthy volunteers, which is in line with literature proteomic data for OCT2. The model was applied to assess the potential of reaching toxicity-related plasma concentrations in different age groups of geriatric subjects.

Advanced Model-based Approach to Evaluate Human Plasma, Cerebrospinal Fluid, and Neuronal mTORC1 Activation Biomarkers After NV-5138 Administration in Healthy Volunteers

NV-5138 ([S]-2-amino-5,5-difluoro-4,4-dimethylpentanoic acid) is an orally bioavailable, small-molecule activator of the mechanistic target of rapamycin complex 1 (mTORC1) pathway in development for treatment-resistant depression. The authors established a model to describe the relationship between plasma and cerebrospinal fluid (CSF) concentrations of NV-5138 and between CSF concentrations and potential biomarkers thought to be associated with mTORC1 activity (ie, orotic acid, N-acetylmethionine, and N-formylmethionine). Data were collected from a randomized, double-blind, placebo-controlled, tolerability, and pharmacokinetic (PK) parameter study of 5 ascending (400, 800, 1600, 2400, and 3000 mg), once-daily oral doses of NV-5138 in healthy subjects. NV-5138 plasma PK parameter samples were collected at 15 time points over 24 hours on days 1 and 7, and at pre dose on days 2-6 for all doses. NV-5138 CSF PK parameter and CSF biomarker samples were collected on days 1 and 7 at pre dose and 4, 8, and 12 hours post dose for all doses except 3000 mg. A model-based approach was used to develop and validate a model that describes the relationship between NV-5138 in CSF and biomarker concentrations. Twenty-four of the 42 enrolled subjects had simultaneous plasma and CSF measurements of NV-5138 and CSF biomarker concentrations and were included in the PK parameter and pharmacodynamic (PD) analyses. A 2-compartment plasma and CSF PK parameter, with indirect PD effects, model was developed and validated. NV-5138 plasma concentrations were positively correlated with those in CSF, although CSF concentrations lagged slightly behind those in plasma, as indicated by a counterclockwise hysteresis effect. Similarly, the relationship between the PD measures of mTORC1 activation and NV-5138 was also characterized by counterclockwise hysteresis, when the increase in CSF biomarker concentrations lagged behind those of NV-5138, consistent with a signaling intermediary/cascade, such as mTORC1. Maximal biomarker activation was achieved at NV-5138 CSF concentrations of approximately 3 µg/mL, which were associated with daily doses of 1600 mg NV-5138. The safety profile analysis (n = 42) found that most of the reported adverse events were mild in severity, with no severe, serious, unusual, or unexpected adverse events or any dissociative effects; 2 subjects (400-mg cohort) discontinued due to adverse events that were judged to be unrelated to study medication. The model will be used for designing future efficacy and tolerability studies. Consecutive daily doses of NV-5138 were well tolerated in this healthy volunteer study.

Population pharmacokinetic modeling of oral brepocitinib in healthy volunteers and patients with immuno-inflammatory diseases.

The objective of this population pharmacokinetic (PK) analysis was to characterize the concentration-time profile of brepocitinib plasma concentration after single- and multiple-oral administration in healthy volunteers (HVs) and patients with immuno-inflammatory diseases. Blood samples from phase I HV and phase II clinical studies of patients with alopecia areata, psoriasis, psoriatic arthritis, ulcerative colitis (UC), vitiligo, and hidradenitis suppurativa were analyzed using a nonlinear mixed-effects modeling approach. Effects of patients' characteristics on brepocitinib exposure were investigated. Overall, 8552 brepocitinib plasma concentrations from 775 individuals were included in the analysis. The PKs of brepocitinib were adequately described by a two-compartment model with first-order absorption and a lag time for tablet formulation, dose-dependent bioavailability, and Box-Cox transformed interindividual variabilities on apparent clearance (CL/F) and apparent central volume of distribution (Vc/F). For a typical 70-kg non-Asian female patient with baseline aspartate aminotransferase of 22 unit/liter, CL/F and Vc/F estimates were 17.5 L/h and 88.5 L, respectively. Asians had a higher exposure (independent of body weight), caused by a 10% lower CL/F when compared to other individuals. Independent of baseline body weight, the male population showed 13% higher Vc/F compared to the female population. Patients with UC were predicted to have 46% slower absorption rate compared to other individuals. The PKs of brepocitinib were well-characterized by a two-compartment model with first-order absorption and dose-dependent bioavailability. Several covariates, such as race and sex, were identified to have statistically significant, but not clinically meaningful, effects on the estimated PK parameters.

Population Pharmacokinetics of Fasinumab in Healthy Volunteers and Patients With Pain Due to Osteoarthritis of the Knee or Hip.

Osteoarthritis (OA) pain management options are currently limited. Fasinumab, an anti-nerve growth factor monoclonal antibody, has been investigated in healthy volunteers and patients with OA-related pain, among other conditions. Data from 12 Phase I-III clinical trials of 92 healthy volunteers and 7430 patients with OA were used to develop a population pharmacokinetic model to characterize fasinumab concentration-time profiles and assess the covariates' effect on fasinumab pharmacokinetic parameters. Participants received single or repeated fasinumab doses intravenously (IV)/subcutaneously (SC), based on body weight (0.03-1mg/kg IV or 0.1-0.3mg/kg SC)/fixed dose (9-12mg IV or 1-12mg SC). Fasinumab concentration-time data following IV and SC administration in healthy volunteers and patients with OA-related pain were adequately described by a 2-compartment model. Bioavailability increased with higher doses; estimated at 55.1% with 1mg SCdose, increasing in a greater-than-proportional manner above this. Body weight had the largest predicted impact on fasinumab steady-state exposures, participants at the 5th and 95th percentiles had a 43%-45% higher/22%-23% lower exposure versus reference, respectively. Other covariates had small but clinically irrelevant impacts.

Comparative bioavailability and bioequivalence of two 400 mg moxifloxacin tablet products after single dose administration in healthy volunteers under fasting conditions

The aim of this study was to assess whether the pharmacokinetic profiles of two Moxifloxacin formulations were similar. Moxifloxacin is a fluoroquinolone antibacterial agent with a broad spectrum of activity, encompassing Gram-negative and Gram-positive bacteria. This was a randomized, 2 sequences and 2 periods, crossover comparative study of two medications: Avalox® 400mg coated tablet, manufactured by Bayer S.A (reference), and Moxifloxacin 400mg coated tablet, manufactured by Eurofarma Laboratórios S.A (test). Plasma samples obtained from 36 eligible subjects were analyzed for Moxifloxacin using LC-MS/MS as analytical method and Moxifloxacin-d4 as internal standard. The statistical analysis showed no significant differences for AUC0-t (Avalox® vs. Moxifloxacin Eurofarma test CI [94.25 – 99.28]) and Cmax (Avalox® vs. Moxifloxacin Eurofarma test CI [90.70 – 106.45]). The current pharmacokinetic study demonstrated bioequivalence between the single agents and provided evidence of bioequivalence between Avalox® and Moxifloxacin Eurofarma.

Comparison of pharmacokinetics and safety between CE-fosphenytoin sodium, fosphenytoin sodium, and phenytoin sodium after intravenous and intramuscular administration in healthy volunteers.

Background: Captisol®-enabled-fosphenytoin sodium (CE-fosphenytoin sodium) injection is a modified formulation of fosphenytoin sodium. Objective: We aim to compare the intravenous and intramuscular bioavailability and safety between CE-fosphenytoin sodium, fosphenytoin sodium (Cerebyx®), and phenytoin sodium (intravenous injection only). Methods: In pivotal study 1, 54 subjects were divided into three sequence groups that receive intravenous injection of 250mg of phenytoin sodium equivalent (PE), CE-fosphenytoin sodium (T), or fosphenytoin sodium (R1) and 250mg of phenytoin sodium (R2) in period 1. After a 14-day washout period, 36 subjects were randomized to two treatment sequence groups (T-R1 or R1-T, n = 18 per group) in period 2, in which the subjects who received R2 in period 1 were removed, those who received T in period 1 used R1 (T-R1), while those who previously received R1 used T (R1-T). In pivotal study 2, a single intramuscular dose of T (400mg PE) or R1 (400mg PE) was administered according to the individual sequential treatment assignment in each period. There was a washout (14days) period before receiving the next period study drug. Results: T and R1 have similar pharmacokinetic characteristics regarding total and free phenytoin, showing bioequivalence of both drugs in the intravenous and intramuscular administration. The geometric mean ratio was close to 1 (0.98-1.06). The AUC of total and free phenytoin in subjects who intravenously received T and R1 was very similar to those who received R2, although their Cmax was lower than that of the subjects who received R2. Overall, treatment with T and R1 was safe and well-tolerated, without serious adverse events (SAEs) or grade III adverse events (AEs). With intravenous (i.v.) or intramuscular (i.m.) treatment, the incidence of drug-related AEs using T was similar to that using R1. Treatment with T and R1 had clearly superior tolerability than that with R2. Conclusion: CE-fosphenytoin sodium is a promising substitute for fosphenytoin sodium. Clinical Trial Registration: http://www.chinadrugtrials.org.cn/, CTR20202154 (11 November 2020).

Effects of Chios Mastiha essential oil on cholesterol levels of healthy volunteers: A prospective, randomized, placebo-controlled study (MASTIHA-OIL)

IntroductionChios Mastiha essential oil (CMO) is a natural product extracted from the resin of Mastiha, possessing antioxidant, anti-microbial, anti-ulcer, anti-neoplastic, and cholesterol-lowering capabilities in vitro, and its hypolipidemic effect was confirmed in animal studies. Yet, there are no randomized, placebo-controlled clinical studies in the literature regarding CMO's hypolipidemic effects in humans. A prospective, randomized, placebo-controlled study was designed to study the hypolipidemic effect of CMO capsules on healthy volunteers with elevated cholesterol. Methods192 healthy volunteers were screened and 160 of them with total cholesterol> 200 mg/dl participated in the study. They were randomized with a 2:1 ratio of receiving CMO capsules (200 mg mastiha-oil/capsule) and placebo for 8 weeks respectively. 113 patients received CMO and 47 were randomized in the control group, and all of them completed the follow-up period. ResultsAfter 8 weeks of CMO administration, total and LDL cholesterol were significantly lower in the CMO compared to the placebo group 215.2 ± 27.5 vs 237.0 ± 27.9 mg/dl (p < 0.001) and 135.0 ± 26.1 vs 153.0 ± 23.3 mg/dl (p < 0.001) respectively. No gastrointestinal adverse events or liver or renal toxicity were reported. Additionally, in the CMO group total cholesterol was significantly decreased by 20.6 mg/dl (9%), LDL by 18.1 mg/dl (12%), triglycerides by 21.8 mg/dl (15%), and glucose by 4.6 mg/dl (5%) and HDL was increased by 2.4 mg/dl (5%), compared to their baseline values. ConclusionThe MASTIHA-OIL study showed the efficacy and safety of CMO in reduction of total and LDL cholesterol after 8 weeks of administration in healthy volunteers with elevated cholesterol levels.

Pharmacokinetic Variables of Dapagliflozin/Metformin Extended-release Fixed-dose Combination in Healthy Chinese Volunteers and Regional Comparison

A fixed-dose combination (FDC) product combining dapagliflozin and metformin may increase medication adherence in patients with type 2 diabetes mellitus (T2DM) by minimizing pill burden associated with co-administration of individual component (IC) formulations and, consequently, improve cost-efficiency and compliance. This study evaluated the bioequivalence of the dapagliflozin/metformin FDC product versus IC administration in healthy volunteers from a Chinese population and assessed the safety profile of the FDC product. In addition, pharmacokinetic (PK) and safety comparisons of dapagliflozin and metformin across different regions were conducted to evaluate regional differences. This single-center, open-label, parallel-cohort, randomized, 2-period, crossover study enrolled Chinese adults (aged 18-55 years). Volunteers in cohort 1 received either a single FDC tablet of dapagliflozin/metformin extended release (XR) (5/500 mg) or IC tablets (dapagliflozin [5 mg] and metformin XR [500 mg]). Volunteers in cohort 2 received a higher dosage in a similar manner (dapagliflozin [10 mg] and metformin XR [1000 mg]). Volunteers in each cohort were subsequently crossed over to receive the alternate cohort treatment. Plasma concentrations of dapagliflozin and metformin were determined, and bioequivalence analyses were performed under standard fed conditions. Eighty healthy Chinese volunteers (89.9% male; mean age, 28.7 years) were randomized into cohort 1 (n=40) and cohort 2 (n=39; 1 volunteer withdrew before receiving study treatment). The mean plasma concentration-time profiles of the dapagliflozin and metformin FDC and IC formulations for both doses were found to be nearly superimposable. Dapagliflozin and metformin XR FDC were bioequivalent to the IC tablets, with 90% CIs for each pairwise comparison contained within the 80% to 125% bioequivalence limits. Both the FDC and IC formulations were well tolerated, with no serious adverse events/death. PK parameters for dapagliflozin in the Chinese volunteers were slightly to moderately higher than those from studies conducted in Brazil, Russia, and the United States, and the safety profile of the dapagliflozin/metformin FDC product was consistent with that of other studies. The difference in PK parameters among the 4 regions was not clinically meaningful. The bioequivalence of the dapagliflozin/metformin FDC and IC formulations in healthy Chinese adults was established without any new safety concerns. Notably, the observed bioequivalence may be extrapolated to patients with T2DM as the PK parameters of dapagliflozin and metformin in healthy adults are similar to those reported in patients with T2DM. gov identifier: NCT04856007.

Measurement of renal congestion and compliance following intravenous fluid administration using shear wave elastography

ObjectiveUltrasound shear wave elastography (SWE) is a novel technique that may provide non-invasive measurements of renal compliance. We aimed to investigate the relationship between intravenous (IV) fluid administration and change in SWE measurements. We hypothesised that following IV fluid administration in healthy volunteers, global kidney stiffness would increase and that this increase in stiffness could be quantified using SWE. Our second hypothesis was that graduated doses of IV fluids would result in a dose-dependent increase in global kidney stiffness measured by SWE. DesignRandomised prospective study. SettingIntensive Care Unit. ParticipantsHealthy volunteers aged 18–40 years. InterventionsParticipants were randomised to receive 20 ml/kg, 30 ml/kg, or 40 ml/kg of normal saline. The volume of fluid infused was based on the actual body weight recorded. Main outcome measuresWe recorded average SWE stiffness (kPa with standard deviation of the mean), median SWE stiffness (kPa), and the interquartile range. ResultsNinety-eight percent of participants (44/45) demonstrated an increase in global kidney stiffness following administration of IV fluids. The average SWE pre fluid administration was 7.572 kPa ± 2.38 versus 14.9 kPa ± 4.81 post fluid administration (p < 0.001). In subgroup analysis, there were significant changes in global kidney stiffness pre and post fluid administration with each volume (ml/kg) of fluid administered. Average percentage change in global kidney stiffness from baseline was compared between the three groups. There was no significant difference when comparing groups 1 and 2 (197.1% increase ± 49.5 vs 216.1% ± 72.0, p ¼ 0.398), groups 2 and 3 (216.1% increase ± 72.0 vs 197.8% ± 59.9, p ¼ 0.455), or groups 1 and 3 (197.1% increase ± 49.5 vs 197.8% ± 59.9, p ¼ 0.972). ConclusionsFluid administration results in immediately visible and quantifiable changes in global kidney stiffness across all infused volumes of fluid.

Safety, Tolerability, and Pharmacokinetics of the Novel Adenosine A2A Antagonist/Inverse Agonist KW-6356 Following Single and Multiple Oral Administration in Healthy Volunteers.

KW-6356 is an adenosine A2A receptor-selective antagonist and inverse agonist. We conducted 2 studies: study 6356-001 (no NCT number), a randomized, double-blind, placebo-controlled phase 1 trial of single ascending (1, 3, 10mg) and multiple (6mg once daily) oral doses of KW-6356 in healthy Japanese subjects; and study 6356-004 (NCT03830528), including a randomized, double-blind, placebo-controlled phase 1 trial of single ascending (21, 42, 60mg) and multiple (24mg once daily) oral doses of KW-6356, and a phase 1 open-label trial of multiple oral doses (6mg once daily) of KW-6356 in healthy Japanese and White subjects, to evaluate the safety, tolerability, and pharmacokinetics of KW-6356. KW-6356 was well tolerated after administration of single doses of up to 60mg and multiple doses of up to 24mg once daily for 14days. The pharmacokinetics of KW-6356 were linear after a single dose of up to 60mg KW-6356. The mean terminal elimination half-life of KW-6356 ranged from 18.4 to 43.1hours following administration of single doses of 1-60mg. There was no clear difference in the safety or pharmacokinetics of KW-6356 between healthy Japanese and White subjects.

The impact of ADRB2 polymorphisms on immune responses and norepinephrine-induced immunosuppression.

To evaluate whether common nonsynonymous variants [single-nucleotide polymorphisms (SNPs) or SNP haplotypes] in the β2-adrenergic receptor render subjects more susceptible to norepinephrine-induced immunosuppression and whether they are associated with dysregulated ex vivo and in vivo inflammatory responses. Peripheral blood mononuclear cells from healthy volunteers (main cohort: n = 106, secondary cohort: n = 408) were ex vivo stimulated with various stimuli and production of cytokines was assessed. Additionally, ex vivo modulation of cytokine production by norepinephrine was evaluated in the main cohort. Volunteers from the main cohort also underwent experimental endotoxemia (administration of 1 ng/kg lipopolysaccharide), during which in vivo plasma cytokine concentrations and clinical inflammatory parameters were measured. Subjects were genotyped, common SNPs in the ADRB2 gene were extracted (rs1042711, rs1042713, and rs1042714), and the presence of haplotypes was identified (CysGlyGln, CysArgGln, and ArgGlyGlu). In both cohorts, presence of ADRB2 SNPs or haplotypes was not associated with altered ex vivo cytokine responses. Norepinephrine attenuated production of the proinflammatory cytokines TNF and IL-6 [-26% (-22% to -30%) and -14% (-9% to -18%), respectively, both P < 0.0001] and enhanced release of the anti-inflammatory IL-10 [+9% (+3% to +15%), P = 0.003]. These effects were not modulated by the presence of ADRB2 SNPs or haplotypes (all P values >0.37). In addition, no influence of SNPs or haplotypes on in vivo cytokine concentrations or clinical inflammatory parameters was observed (P values >0.14). Common nonsynonymous variants in the ADRB2 gene influence neither ex vivo cytokine production or norepinephrine-mediated immunosuppression nor the systemic in vivo inflammatory response induced by lipopolysaccharide administration in healthy volunteers.

PSUN304 CRN04777 an Oral, Nonpeptide SST5-selective Somatostatin Agonist Dose Dependently Suppresses Basal and Stimulated Insulin Secretion

Abstract Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in neonates, infants, and children, and is caused by genetic mutations in the insulin secretion pathway in pancreatic beta-cells. Current medical and surgical treatments are often highly burdensome, only partially effective, and associated with significant morbidity. CRN04777 is a potent orally bioavailable SST5 agonist (EC50=0.41 nM) that is &amp;gt;1300 fold selective over other SST receptor subtypes. CRN04777 has been shown to suppress both glucose- and sulfonylurea (SU)-induced insulin secretion in rats. The latter is a model for the most common known monogenic form of human congenital HI. We report initial results from a randomized, double-blinded, placebo-controlled single ascending dose study evaluating the safety, pharmacokinetics and pharmacodynamics of CRN04777 in 74 healthy volunteers. Endogenous insulin secretion was stimulated using intravenous glucose tolerance tests (IVGTT) or SU challenges in separate cohorts of volunteers. In the IVGTT cohorts, single doses of CRN04777 (0.5-120 mg) were administered after an overnight fast and 1 hour prior to an IV bolus of 300 mg/kg glucose, followed by serial measurements of blood glucose and insulin over 180 minutes. The SU-challenge cohorts received single doses of CRN04777 (30 and 60 mg) one hour after SU administration (5 mg of glibenclamide/glyburide), followed by measurement of the IV glucose infusion rate (GIR) over 8 hours under automated euglycemic clamp conditions (ClampArt®). CRN04777 was orally absorbed (Tmax 1-3 hours) and demonstrated a dose dependent increase in systemic exposures with an apparent terminal elimination t1/2 of approximately 40 hours. Basal insulin secretion was reduced dose-dependently, with a 73% reduction following 120 mg of CRN04777. Likewise, glucose stimulated insulin secretion during the IVGTT (plasma insulin AUC) was reduced dose-dependently by approximately 50% with a parallel doubling of plasma glucose AUC following 120 mg of CRN04777. CRN04777 resulted in dose-dependent reversal of SU-induced insulin secretion, with 79% and 90% reductions in insulin AUC5-180min, respectively, at 30 and 60 mg doses. At the 60 mg dose of CRN04777, no exogenous glucose infusion was needed to prevent SU-induced hypoglycemia. CRN04777 was well tolerated across the dose range evaluated. All adverse events (AEs) were considered mild or moderate and there were no serious AEs. The data from this single-dose, proof-of-concept study show that the selective SST5 agonist CRN04777 is well tolerated after oral administration in healthy volunteers, is suitable for once daily dosing and suppresses insulin secretion under basal and stimulated conditions, including in a pharmacologic model of congenital HI. Multiple ascending dose evaluations in healthy volunteers are underway to support future studies in congenital HI patients. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Pharmacokinetics and Safety of Sodium Benzoate, a d-Amino Acid Oxidase (DAAO) Inhibitor, in Healthy Subjects: A Phase I, Open-label Study

PurposeN-methyl-d-aspartate receptor (NMDAR)-mediated neurotransmission plays a critical role in cognition and memory, and d-serine is a co-agonist of the receptor. d-serine is metabolized by d-amino acid oxidase (DAAO). Sodium benzoate is a DAAO inhibitor that leads to the elevation of d-serine levels and enhances NMDAR functions as a therapeutic for wide-spectrum central nervous system (CNS) disorders, including schizophrenia and dementia. For therapeutic application of sodium benzoate in CNS disorders, we conducted a Phase I study to evaluate its safety, tolerability, and pharmacokinetic profile after single-dose oral administration in healthy volunteers. In contrast to the accumulation in the CNS, sodium benzoate has a rapid pharmacokinetic profile when measured peripherally. MethodsIn this Phase I study, subjects were randomized into 4 different dose groups after a single oral administration. The pharmacokinetic parameters of sodium benzoate were assessed after exposure to 250, 500, 1000, and 2000 mg of sodium benzoate. All adverse events were investigated and recorded. FindingsThe Cmax and AUC of sodium benzoate exhibited a higher than dose-proportional increase within the dose range from 250 to 2000 mg under fasting conditions. The slopes were 1.78 and 2.61 and the 90% CIs were 1.41 to 2.15 and 2.20 to 3.03 for Cmax and AUC, respectively. Sodium benzoate was absorbed and converted to benzoic acid rapidly, reaching Cmax after ∼0.5 hour and elimination t1/2 after ∼0.3 hour. No subjects reported adverse events that were sodium benzoate related. ImplicationsThe nonlinear pharmacokinetic response was observed within the dose range up to 2000 mg. Sodium benzoate treatment exhibited a favorable safety profile and was well tolerated at all dose levels. The study results serve as a foundation that should be useful for investigating efficacy and safety in the drug's subsequent clinical development. Trial registration: TFDA-103607047.

Clinical, Cellular, and Molecular Effects of Corticosteroids on the Response to Intradermal Lipopolysaccharide Administration in Healthy Volunteers.

The intradermal lipopolysaccharide (LPS) challenge in healthy volunteers has proven to be a valuable tool to study local inflammation in vivo. In the current study the inhibitory effects of oral and topical corticosteroid treatment on intradermal LPS responses were evaluated to benchmark the challenge for future investigational drugs. Twenty‐four healthy male volunteers received a two‐and‐a‐half‐day twice daily (b.i.d.) pretreatment with topical clobetasol propionate 0.05% and six healthy volunteers received a two‐and‐a‐half‐day b.i.d. pretreatment with oral prednisolone at 0.25 mg/kg body weight per administration. Participants received one injection regimen of either 0, 2, or 4 intradermal LPS injections (5 ng LPS in 50 µL 0.9% sodium chloride solution). The LPS response was evaluated by noninvasive (perfusion, skin temperature, and erythema) and invasive assessments (cellular and cytokine responses) in suction blister exudate. Both corticosteroids significantly suppressed the clinical inflammatory response (erythema P = 0.0001 for clobetasol and P = 0.0016 for prednisolone; heat P = 0.0245 for clobetasol, perfusion P < 0.0001 for clobetasol and P = 0.0036 for prednisolone). Clobetasol also significantly reduced the number of monocytes subsets, dendritic cells, natural killer cells, and T cells in blister exudate. A similar effect was observed for prednisolone. No relevant corticosteroid effects were observed on the cytokine response to LPS. We successfully demonstrated that the anti‐inflammatory effects of corticosteroids can be detected using our intradermal LPS challenge model, validating it for evaluation of future investigational drugs, as an initial assessment of the anti‐inflammatory effects of such compounds in a minimally invasive manner.

Acute change in functional brain entropy following psilocybin administration in healthy volunteers

Acute change in functional brain entropy following psilocybin administration in healthy volunteers

Population Pharmacokinetics of Rezafungin in Patients with Fungal Infections.

ABSTRACTRezafungin is a novel antifungal agent of the echinocandin class with potent activity against species of Candida and Aspergillus, including subsets of resistant strains, and Pneumocystis jirovecii. The objective of this analysis was to develop a population pharmacokinetic (PK) model to characterize the disposition of rezafungin in plasma following intravenous (IV) administration in healthy volunteers and in patients with candidemia and/or invasive candidiasis. The population PK model was based on a previous model from phase 1 data; formal covariate analyses were conducted to identify any relationships between subject characteristics and rezafungin PK variability. A four-compartment model with linear elimination and zero-order drug input provided a robust fit to the pooled data. Several statistically significant relationships between subject descriptors (sex, infection status, serum albumin, and body surface area [BSA]) and rezafungin PK parameters were identified, but none were deemed clinically relevant. Previous dose justification analyses conducted using data from phase 1 subjects alone are expected to remain appropriate. The final model provided a precise and unbiased fit to the observed concentrations and can be used to reliably predict rezafungin PK in infected patients.

Physiologically based pharmacokinetic modelling of treprostinil after intravenous injection and extended-release oral tablet administration in healthy volunteers: An extrapolation to other patient populations including patients with hepatic impairment.

AimsPulmonary arterial hypertension (PAH) is characterized by increased pulmonary arterial pressure, resulting in right ventricular overload, right heart failure and eventually death. Treprostinil is a prostacyclin analogue that is used in the treatment of PAH. As an orphan drug, limited information is available regarding its disposition and its use in special populations such as elderly, paediatric and pregnant patients. The objective of the current study was to develop a robust physiologically based pharmacokinetic (PBPK) model for treprostinil intravenous injection and extended‐release tablet as the first step to optimize treprostinil pharmacotherapy in patients.MethodsPBPK model was built using Simcyp simulator which integrated physicochemical properties, observed or predicted parameters for drug absorption, distribution and elimination for treprostinil, and population specific physiological characteristics. Three clinical trials after intravenous infusion and nine studies after oral administration of treprostinil extended‐release tablet in healthy volunteers were used to develop and validate the model. The simulated PK profiles were compared with the observed data. Extrapolation of the model to patient populations including patients with hepatic impairment was conducted to validate the predictions.ResultsMost of the observed data were within the 5th and 95th percentile interval of the prediction. Most of the percentage error in the PK parameters were within ±50% of the corresponding observed parameters. The developed model predicted the lung exposure of treprostinil to be approximately 0.17 times of concentration in plasma.ConclusionPredicted absorption, distribution, and metabolic enzyme kinetics gave an insight into the disposition of treprostinil in humans. Extrapolation of the established model to patient populations with hepatic impairment successfully documented the model reliability. The developed model has the potential to be used in the PK predictions in other special patient populations with different demographic, physiological and pathological characteristics.

Physiologically based modelling of tranexamic acid pharmacokinetics following intravenous, intramuscular, sub-cutaneous and oral administration in healthy volunteers

Background: Tranexamic acid (TXA) is an antifibrinolytic drug that reduces surgical blood loss and death due to bleeding after trauma and post-partum haemorrhage. Treatment success is dependant on early intervention and rapid systemic exposure to TXA. The requirement for intravenous (IV) administration can in some situations limit accessibility to TXA therapy. Here we employ physiologically based pharmacokinetic modelling (PBPK) to evaluate if adequate TXA exposure maybe achieved when given via different routes of administration. Methods: A commercially available PBPK software (GastroPlus®) was used to model published TXA pharmacokinetics. IV, oral and intramuscular (IM) models were developed using healthy volunteer PK data from twelve different single dose regimens (n = 48 participants). The model was verified using separate IV and oral validation datasets (n = 26 participants). Oral, IM and sub-cutaneous (SQ) dose finding simulations were performed. Results: Across the different TXA regimens evaluated TXA plasma concentrations varied from 0.1 to 94.0 µg/mL. Estimates of the total plasma clearance of TXA ranged from 0.091 to 0.104 L/h/kg, oral bioavailability from 36 to 67% and Tmax from 2.6 to 3.2 and 0.4 to 1.0 h following oral and intramuscular administration respectively. Variability in the observed TXA PK could be captured through predictable demographic effects on clearance, combined with intestinal permeability and stomach transit time following oral administration and muscle blood flow and muscle/plasma partition coefficients following intra-muscular dosing. Conclusions: This study indicates that intramuscular administration is the non-intravenous route of administration with the most potential for achieving targeted TXA exposures. Plasma levels following an IM dose of 1000 mg TXA are predicted to exceed 15 mg/mL in < 15 min and be maintained above this level for approximately 3 h, achieving systemic exposure (AUC0–6) of 99 to 105 µg*hr/mL after a single dose. Well-designed clinical trials to verify these predictions and confirm the utility of intramuscular TXA are recommended.

New Drugs on the Horizon for Functional and Motility Gastrointestinal Disorders

New Drugs on the Horizon for Functional and Motility Gastrointestinal Disorders