Mean Half-life Research Articles

Phase 1 studies of the safety, tolerability, pharmacokinetics, and pharmacodynamics of BI690517 (vicadrostat), a novel aldosterone synthase inhibitor, in healthy male volunteers.

In chronic kidney disease (CKD), raised plasma aldosterone levels are strongly associated with adverse cardiorenal outcomes. Current standard of care may improve outcomes; however, elevated aldosterone levels often persist. We report safety results for BI690517 (vicadrostat), a potent, selective aldosterone synthase inhibitor under investigation for CKD. Four phase 1 studies of BI690517 conducted in healthy European/Chinese/Japanese men: two single rising dose (SRD) and two multiple rising dose (MRD) studies. proportion of participants with investigator-defined drug-related adverse events (AEs). Single and multiple doses of BI690517 ≤ 80mg (0.7-80mg [European SRD]; 3-80mg [Chinese/Japanese SRD and MRD]) were well tolerated. Proportions of participants with drug-related AEs: European SRD, 8.3% (4/48); Chinese/Japanese SRD, 21.4% (12/56); European MRD, 13.9% (10/72); Japanese MRD, 2.8% (1/36). No serious AEs, deaths, or AEs leading to treatment discontinuation were reported; one AE of severe orthostatic hypotension occurred (European SRD). Plasma exposure to BI690517 increased dose dependently; median time to maximum concentration was 0.50-1.75h and mean half-life was 4.4-6.3h. Exposure was slightly higher in Asians versus Europeans and may relate to lower body weight in Asian participants. A standardized high-fat/high-calorie meal reduced the rate, but not extent, of BI690517 absorption. Plasma aldosterone concentrations decreased markedly 1-2h after BI690517 administration; decreases were more pronounced with increasing BI690517 doses. BI690517 was well tolerated and demonstrated dose-dependent inhibition of aldosterone synthesis. Larger studies are warranted to confirm these findings.

Phase 1 Mass Balance Study of Pizuglanstat: An Investigational Hematopoietic Prostaglandin D Synthase Inhibitor.

Pizuglanstat is a novel hematopoietic prostaglandin D synthase inhibitor and investigational treatment for Duchenne muscular dystrophy. This Phase 1 mass balance study aimed to characterize the absorption, metabolism, and excretion of carbon-14 (14C)-labeled pizuglanstat in healthy adults (ClinicalTrials.gov, NCT04825431). After administering a single oral dose of [14C]pizuglanstat solution containing 400mg of pizuglanstat and 1 megabecquerel of radioactivity to 6 healthy men (median age, 26years), pizuglanstat in plasma reached a maximal concentration after a median of 0.5hour and declined with a geometric mean half-life of 7.7hours. Pizuglanstat and its metabolites were primarily excreted via the fecal route; on average, 66.1% of administered radioactivity was excreted in feces after 168hours, compared with 32.2% excreted in urine. Pizuglanstat was mostly present as the unchanged parent molecule in plasma, urine, and feces, while the sulfate conjugate of hydroxyl pizuglanstat was the major metabolite in each sample type. Two adverse drug reactions of urticaria were reported in 2 participants (33.3%); both events were nonsevere and manageable with treatment, and no other clinically significant safety events were observed. Overall, this study provides important pharmacokinetic, mass balance, and safety data to support the development of pizuglanstat as a new treatment for Duchenne muscular dystrophy.

First-in-human study on tolerability, pharmacokinetics and pharmacodynamics of single and multiple escalating doses of XKH001, a recombinant humanized monoclonal antibody against IL-25 in healthy Chinese volunteers

Background: XKH001 is a recombinant humanized IgG1 monoclonal antibody against IL-25 for the treatment of type 2 inflammatory diseases. This study aimed to evaluate the tolerability, pharmacokinetics, and pharmacodynamics of XKH001 in humans for the first time. Research design and methods: This clinical investigation adopted a randomized, double-blind, and placebo-controlled single ascending dose (SAD) and multiple ascending dose (MAD) design. Results: XKH001 was well tolerated in healthy Chinese subjects. Following repeated administration, XKH001 showed a slow absorption with a median Tmax of 4–7 days and a mean half-life (t1/2) of 22–25 days. The accumulation ratio ranged from 1.34 to 1.99. The exposure was mostly dose proportional, with a mean slope of 0.85–1.06. All subjects tested negative for ADA (except three subjects tested positive). The subjects who received 600 mg XKH001 in the MAD study showed a 78.2 ng/mL decrease in the total immunoglobulin E (IgE) level 85 days after the first administration, while the subjects who received matched placebo exhibited only a 8.6 ng/mL decrease.Conclusions: XKH001 showed favorable safety and pharmacokinetics profiles and a low immunogenicity in its first-in-human study. The data support its further clinical evaluation in patients with type 2 inflammatory diseases.

A humanized anti-MSLN×4-1BB bispecific antibody exhibits potent antitumour activity through 4-1BB signaling activation and fc function without systemic toxicity

BackgroundAgonistic monoclonal antibodies targeting 4-1BB/CD137 have shown preclinical promise, but their clinical development has been limited by severe liver toxicity or limited efficacy. Therefore, a safe and efficient immunostimulatory molecule is urgently needed for cancer immunotherapy.MethodsA novel anti-MSLN×4-1BB bispecific antibody (bsAb) was generated via antibody engineering, and its affinity and activity were detected via enzyme-linked immunosorbent assay (ELISA), flow cytometry, and T-cell activation and luciferase reporter assays. In vivo antitumour activity was assessed by establishing humanized mice bearing human MSLN-expressing MC38 (MC38/hMSLN) or CT26 (CT26/hMSLN) cells, and safety was further evaluated in cynomolgus monkeys.ResultsWe generated two humanized anti-MSLN×4-1BB bsAbs (HK013-G1/G4) by fusing an anti-4-1BB scFv to the C-terminus of an anti-MSLN VHH with an intact Fc fragment from human IgG1 or IgG4. The two bsAbs were able to block the binding of CA125 to MSLN and stimulate 4-1BB signaling pathway, which was strictly dependent on MSLN expression. In particular, HK013-G1 retained Fc function and induced ADCC effect in tumour cells, whereas HK013-G4 did not. Strikingly, HK013-G1 showed superior antitumour activity to HK013-G4 both in vitro and in vivo and remained effective even in the presence of soluble MSLN. HK013-G1 enhanced antitumour immunity and induced durable antigen-specific immune memory to prevent rechallenged tumour growth, even at a dose as low as 1 mg/kg. Furthermore, HK013-G1 did not induce nonspecific production of proinflammatory cytokines and showed good tolerability up to the highest tested dose (30 mg/kg weekly) for 5 weeks, with no HK013-G1-related adverse effects observed in cynomolgus monkeys. In addition, the mean half-life of HK013-G1 was approximately 61 and 97 h at single doses of 3 and 30 mg/kg, respectively.ConclusionThe optimal anti-MSLN×4-1BB bsAb HK013-G1 exhibited synergistic antitumour effects by inducing an ADCC effect (innate immunity) and stimulating the 4-1BB signaling pathway (adaptive immunity) upon cross-bridging with MSLN with no systemic toxicity, which may offer the promise of an improved therapeutic window relative to that of 4-1BB agonists.

Scp776, A Novel IGF-1 Fusion Protein for Acute Therapy to Promote Escape From Apoptosis in Tissues Affected by Ischemic Injury: 2 Randomized Placebo-Controlled Phase 1 Studies in Healthy Adults.

Apoptosis is a major driver of cell loss and infarct expansion in ischemic injuries such as acute ischemic stroke (AIS) and acute myocardial infarction (AMI). Insulin-like growth factor-1 (IGF-1) can mitigate cell death and potentiate recovery following acute ischemic injury, but short half-life and nonspecificity limit its therapeutic potential. Scp776 is an IGF-1 fusion protein designed to target damaged tissue and promote apoptosis escape and is in clinical development as an acute therapy for AIS and AMI. Two phase 1 placebo-controlled studies in healthy volunteers evaluated safety, tolerability, pharmacokinetic profile, and pharmacodynamics under single (1, 2, or 4mg/kg) or multiple (6, 6.2, or 7.25mg/kg total doses) dosing regimens. In addition, a blood glucose management plan was developed and implemented to mitigate hypoglycemia that may develop following scp776 injection. Scp776 was well tolerated in healthy volunteers (n=51) without serious adverse events. Exposure increased in a near dose-proportional manner with a mean half-life across all doses of 8hours. Adaptive dextrose infusions maintained normal blood glucose levels with occasional mild hypoglycemic events. These results informed scp776 dose selection and the design of blood glucose monitoring protocols for phase 2 studies.

Obicetrapib exhibits favorable physiochemical and pharmacokinetic properties compared to previous cholesteryl ester transfer protein inhibitors: An integrated summary of results from non-human primate studies and clinical trials.

Anacetrapib, a cholesteryl ester transfer protein (CETP) inhibitor previously under development, exhibited an usually extended terminal half-life and large food effect and accumulated in adipose tissue. Other CETP inhibitors have not shown such effects. Obicetrapib, a potent selective CETP inhibitor, is undergoing Phase III clinical development. Dedicated assessments were conducted in pre-clinical and Phase I and II clinical studies of obicetrapib to examine the pharmacokinetic issues observed with anacetrapib. After 9 months of dosing up to 50 mg/kg/day in cynomolgus monkeys, obicetrapib was completely eliminated from systemic circulation and not detected in adipose tissue after a 13-week recovery period. In healthy humans receiving 1-25 mg of obicetrapib, the mean terminal half-life of obicetrapib was 148, 131, and 121 h at 5, 10, and 25 mg, respectively, and food increased plasma levels by ~1.6-fold with a 10 mg dose. At the end of treatment in Phase II trials, mean plasma levels of obicetrapib ranged from 194.5 ng/mL with 2.5 mg to 506.3 ng/mL with 10 mg. Plasma levels of obicetrapib decreased by 92.2% and 98.5% at four and 15 weeks post-treatment, respectively. Obicetrapib shows no clinically relevant accumulation, is minimally affected by food, and has a mean terminal half-life of 131 h for the 10 mg dose. These data support once daily, chronic dosing of obicetrapib in Phase III trials for dyslipidemia management.

First-in-Human Phase I Clinical Trial of the Adenosine A1R/A3R Agonist AST-004 in Healthy Subjects.

AST-004 is a small-molecule adenosine A1/A3 receptor agonist that has exhibited significant cerebroprotective efficacy in preclinical models of acute ischemic stroke and traumatic brain injury. The primary objectives of this clinical phase I first-in-human study were to evaluate the safety and tolerability profile of single ascending intravenous doses in healthy subjects. The secondary objectives were to characterize the single-dose pharmacokinetic profiles in plasma, cerebrospinal fluid (CSF), and urine. In part 1 of the study, AST-004 was administered in ascending dose cohorts of 5, 25, 50, 75, and 100 mg, with 6 subjects in each cohort receiving the study drug and 2 receiving placebo. In part 2, all 12 subjects received a 100 mg IV infusion of the study drug followed by a single CSF collection per subject via lumbar puncture at 20, 40, or 60 minutes after infusion. A total of 42 subjects received AST-004, with no severe or serious adverse events observed. Twelve of these subjects experienced a treatment-emergent adverse event, the most frequent across groups being headache. In part 2, pharmacokinetic analyses confirmed that AST-004 was distributed in the CSF, with the CSF-to-plasma ratio increasing over the 3 timepoints sampled. The mean half-life was 1.1 to 1.4 hours for doses of 25 to 100 mg, and the geometric mean maximum plasma concentration obtained in the highest dosing cohort (100 mg) was 2232±428 ng/mL. AST-004 was safe and well-tolerated at plasma concentrations 3 to 8× higher than those associated with significant efficacy in astrocyte's preclinical primate stroke efficacy studies, with CSF concentrations highest at the 60-minute collection timepoint, the last timepoint tested. This study supports additional clinical investigations, including evaluation of an extended infusion to support the phase 2 program in stroke and traumatic brain injury.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of the oral allosteric TYK2 inhibitorESK-001 using a randomized, double-blind, placebo-controlled study design.

ESK-001 is a highly selective allosteric inhibitor of tyrosine kinase 2 (TYK2), which plays an essential role in mediating cytokine signaling in multiple immune-mediated diseases. In 2 phase I studies, a first-in-human single ascending dose (SAD) and multiple ascending dose (MAD) study and a multiple-dose (MD) study, we evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of orally administered ESK-001 in healthy participants using a randomized, double-blind, placebo-controlled study design. ESK-001 was rapidly absorbed with systemic exposures generally increasing dose-proportionally across all cohorts. The mean terminal half-life ranged from 8 to 13 h with no to minimal accumulation of ESK-001 following q.d. doses and ~2-fold accumulation following Q12 doses. Less than 1% of unchanged ESK-001 was eliminated in urine. ESK-001 inhibited the downstream TYK2 pathway as shown by inhibition of pSTAT1 expression. Transcriptomic analysis of unstimulated whole blood samples confirmed dose-dependent inhibition of Type I IFN-induced genes and SIGLEC1, a novel TYK2-responsive biomarker. By correlating PK exposure data with PD readouts, a strong PK/PD relationship was demonstrated. There were no deaths, serious treatment-emergent adverse events (TEAEs), nor severe TEAEs, and most TEAEs were mild in severity. In conclusion, ESK-001 was generally safe and well-tolerated in healthy participants, showed linear dose-dependent PK characteristics, and maximally inhibited TYK2-dependent pathways with a predictable concentration-dependent PK/PD relationship. These findings were used to select the dose range of ESK-001 for the STRIDE phase II trial in plaque psoriasis and to support further clinical development of ESK-001 in other TYK2-mediated diseases.

A Phase 1 Study in Healthy Subjects to Evaluate the Safety and Pharmacokinetics of a Human Monoclonal Antibody (S315) Against Diphtheria Toxin.

Diphtheria is a recurrent threat with endemic still occurs in many parts of the world. The standard of care is horse serum-derived diphtheria antitoxin (eDAT), which is in critical short supply globally. S315 is a fully human, monoclonal immunoglobulin G1 neutralizing antibody, specific to the receptor-binding domain of diphtheria toxin. S315 is intended to be a safer, more readily available alternative to replace eDAT. This first-in-human, randomized, double-blind, dose escalation study evaluated the safety, tolerability, and pharmacokinetics of S315 in healthy adults. Cohorts of study subjects received single intravenous infusions of S315 (480 mg, 960 mg, 1920 mg, 3840 mg, and 7680 mg) or matched placebo. Safety was assessed by standard clinical and laboratory evaluations. Serum S315 concentrations were measured by enzyme-linked immunosorbent assay (ELISA) and an in vitro diphtheria toxin neutralization assay, followed by pharmacokinetic analyses. Forty-one subjects were enrolled. S315 was safe and well tolerated. Most adverse events were mild or moderate. Peak mean serum concentrations ranged from 199 µg/mL to 2872 µg/mL (ELISA) and from 234 AU/mL to 1147 AU/mL (neutralization assay), with low variability. Mean serum half-life ranged from 12 to 27 days (ELISA) and from 17 to 22 days (neutralization assay). S315 was generally safe and well tolerated by healthy subjects. Pharmacokinetic data suggest that S315 serum neutralizing activity is an order of magnitude greater than that attained by eDAT. The results of this study support continued development of S315 as a replacement for eDAT to address critical global supply issues. Clinical Trials Registration. NCT04075175.

Pharmacokinetics and Pharmacodynamics of Rusfertide, a Hepcidin Mimetic, Following Subcutaneous Administration of a Lyophilized Powder Formulation in Healthy Volunteers.

Hepcidin, an endogenous peptide hormone, binds to ferroportin and is the master regulator of iron trafficking. Rusfertide, a synthetic peptide, is a potent hepcidin mimetic. Clinical studies suggest rusfertide may be effective in the treatment of polycythemia vera. This study investigated the dose-ranging pharmacokinetics, pharmacodynamics, and safety of a lyophilized formulation of rusfertide. A randomized open-label crossover study was conducted in two groups of healthy adult subjects to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of subcutaneous rusfertide doses that ranged from 10 to 60 mg of a lyophilized formulation and 20 mg of an aqueous prefilled syringe formulation that were used in clinical trials. Rusfertide showed a rapid initial absorption. Median time to peak plasma concentrations for the lyophilized formulation was 24h for doses of 10-30 mg and 2-4 h for doses of 45 and 60 mg. Mean terminal half-life ranged from 19.6 to 57.1 h. Rusfertide peak concentration and area under the concentration-time curve increased with an increasing dose, but in a less than dose-proportional manner. Metabolites M4 and M9 were identified as major metabolites. At the rusfertide 20-mg dose, the lyophilized formulation had an area under the concentration-time curve from time zero to infinity approximately 1.5-fold higher than the aqueous formulation. The elimination half-life was comparable for the two formulations. Dose-related decreases in serum iron and transferrin-iron saturation were seen following rusfertide treatment. The majority of treatment-emergent adverse events were mild; treatment-related treatment-emergent adverse events seen in ≥10% of subjects were injection-site erythema and injection-site pruritus. Rusfertide was well tolerated; the pharmacokinetic and pharmacodynamic results indicate that lyophilized rusfertide is suitable for once-weekly or twice-weekly administration.

Safety, pharmacokinetics, and pharmacodynamics of sofnobrutinib, a novel non-covalent BTK inhibitor, in healthy subjects: First-in-human phase I study.

Bruton's tyrosine kinase (BTK) is a potential therapeutic target for allergic and autoimmune diseases. This first-in-human phase I study evaluated safety, pharmacokinetic, and pharmacodynamic profiles of sofnobrutinib (formerly AS-0871), a highly selective, orally available, non-covalent BTK inhibitor, in healthy adult subjects. Single ascending doses (SAD; 5-900 mg) and multiple ascending doses (MAD; 50-300 mg twice daily [b.i.d.] for 14 days [morning dose only on Day 14]) of sofnobrutinib were tested. In the entire study, all adverse events (AEs) were mild or moderate, and no apparent dose-proportional trend in severity or frequency was observed. No serious treatment-emergent AEs, cardiac arrythmias, or bleeding-related AEs were reported. In the SAD part, sofnobrutinib exhibited approximately dose-dependent systemic exposures up to 900 mg with rapid absorption (median time to maximum concentration of 2.50-4.00 h) and gradual decline (mean half-lives of 3.7-9.0 h). In the MAD part, sofnobrutinib showed low accumulation after multiple dosing (mean accumulation ratios of ≤1.54) and reached a steady state on ≤Day 7. Single dosing of sofnobrutinib rapidly and dose-dependently suppressed basophil and B-cell activations in exvivo whole blood assays. Multiple dosing of sofnobrutinib achieved 50.8%-79.4%, 67.6%-93.6%, and 90.1%-98.0% inhibition of basophil activation during the dosing interval of 50, 150, and 300 mg b.i.d., respectively. Based on pharmacokinetic-pharmacodynamic analysis, half-maximal inhibitory concentration (IC50) of sofnobrutinib for basophil activation was 54.06 and 57.01 ng/mL in the SAD and MAD parts, respectively. Similarly, IC50 for B-cell activation was 187.21 ng/mL. These data support further investigation of sofnobrutinib in allergic and autoimmune diseases.

A randomized, placebo-controlled first-in-human study of oral TQS-168 in healthy volunteers: Assessment of safety, tolerability, pharmacokinetics, pharmacodynamics, and food effect.

TQS-168, a first-in-class small-molecule inducer of peroxisome proliferator-activated receptor gamma coactivator 1-alpha gene expression, is in development for the treatment of amyotrophic lateral sclerosis. A single-ascending-dose (SAD) and multiple-ascending-dose (MAD) study of TQS-168 was carried out in healthy male subjects to investigate safety, tolerability, pharmacokinetics (PK), food effect, and preliminary pharmacodynamic effects (PD). Since solubility enhancement could be beneficial, assessment of three formulations was incorporated into the study using an integrated rapid manufacturing and clinical testing approach. Dosing in the SAD part was initiated with a crystalline methylcellulose (MC) suspension, and then spray-dried dispersion (SDD) and hot-melt extrusion (HME) suspensions were evaluated. The HME and SDD formulations showed two and fourfold higher exposure than the MC suspension, respectively, and the SDD formulation was selected for progression to subsequent SAD and MAD cohorts, in which there was further investigation of the food effect on exposure in addition to assessments of safety, tolerability, PK, and PD. Cmax and AUC plasma exposures of TQS-168 were supra-proportional at higher doses, irrespective of formulation. Median Tmax for TQS-168 occurred between 0.5 and 4.0 h post-dose and occurred later with higher doses. Geometric mean half-lives (T1/2) for TQS-168 were independent of formulation and food, ranging from 3.2 to 10.5 h following single doses and 4.1 to 7.3 h following multiple doses. Food blunted TQS-168 Cmax but had minimal impact on AUC. TQS-168 was considered to be safe and generally well tolerated following single and multiple oral doses. The SDD formulation was selected for future patient studies.

Prolonging the circulatory half-life of C1 esterase inhibitor via albumin fusion.

Hereditary Angioedema (HAE) is an autosomal dominant disease characterized by episodic swelling, arising from genetic deficiency in C1-esterase inhibitor (C1INH), a regulator of several proteases including activated Plasma kallikrein (Pka). Many existing C1INH treatments exhibit short circulatory half-lives, precluding prophylactic use. Hexahistidine-tagged truncated C1INH (trC1INH lacking residues 1-97) with Mutated N-linked Glycosylation Sites N216Q/N231Q/N330Q (H6-trC1INH(MGS)), its murine serum albumin (MSA) fusion variant (H6-trC1INH(MGS)-MSA), and H6-MSA were expressed in Pichia pastoris and purified via nickel-chelate chromatography. Following intravenous injection in mice, the mean terminal half-life of H6-trC1INH(MGS)-MSA was significantly increased versus that of H6-trC1INH(MGS), by 3-fold, while remaining ~35% less than that of H6-MSA. The extended half-life was achieved with minimal, but significant, reduction in the mean second order rate constant of Pka inhibition of H6-trC1INH(MGS)-MSA by 33% relative to that of H6-trC1INH(MGS). Our results validate albumin fusion as a viable strategy for half-life extension of a natural inhibitor and suggest that H6-trC1INH(MGS)-MSA is worthy of investigation in a murine model of HAE.

Assessing the Best Cryptocurrencies for Long-Term Investment Using Mean Reversion and Half-Life Volatility Models

Assessing the Best Cryptocurrencies for Long-Term Investment Using Mean Reversion and Half-Life Volatility Models

The First Triple Agonist for Antiobesity: Retatrutide.

The prevalence of individuals with overweight and obesity has increased by 18% since 1990 and it is projected that by 2030, nearly 50% of US adults will have obesity. Lifestyle modifications, such as diet and exercise, typically lead to approximately 3-5% weight loss, whereas 5-15% weight loss is necessary to significantly impact obesity-associated comorbidities and improve overall health outcomes. In addition to lifestyle modifications, pharmacotherapy has been utilized as an adjunctive treatment to increase weight loss and improve health outcomes. The Food and Drug Administration has currently approved 6 drugs to treat overweight and obesity, with the recently approved drugs surging in popularity after demonstrating superior weight loss outcomes. Additionally, a number of agents are in the pipeline, offering promise of unprecedented degrees of weight loss. One such drug is retatrutide, which is a triple agonist targeting the glucagon-like peptide-1 receptor (GLP-1R), glucose-dependent insulinotropic polypeptide receptor, and glucagon receptor. Phase 1 and 2 clinical trials have demonstrated the safety, tolerability, and pharmacokinetics of retatrutide in patients with obesity and/or type 2 diabetes. The pharmacokinetics of retatrutide were dose proportional and its mean half-life of approximately 6 days supported a once-weekly dosing. The safety profile was similar to GLP-1R agonists and glucose-dependent insulinotropic polypeptide receptor/GLP-1R co-agonists, with gastrointestinal disorders being the most common adverse effects reported. Each trial demonstrated greater weight loss with retatrutide treatment in comparison to placebo, with greatest efficacy at higher doses. Overall, these clinical trials have demonstrated the superior efficacy of retatrutide as a weight loss medication in patients with overweight and obesity.

Development, physico-chemical characterization, and in vivo stability of a novel aglycosylated monoclonal antibody targeting FAM19A5

Introducing aglycosylation into therapeutic monoclonal antibodies (mAbs) can prevent side effects associated with fragment crystallizable (Fc)-mediated effector functions. This modification induces structural changes in the heavy chain constant domain 2-constant domain 3 within Fc regions, which decreases antibody stability at acidic pH and high temperature. In this study, NS101, a novel aglycosylated mAb targeting family with sequence similarity 19, A5 (FAM19A5) for neurological diseases was evaluated with respect to its developability and in vivo stability as therapeutics. When recombinant CHO cells producing NS101 were cultivated using a fed-batch mode in a 500 L bioreactor, cell growth and mAb production profiles were consistent across three consecutive runs. NS101, thus produced, features an additional intra-disulfide bond in the heavy chain complementarity-determining region 3, contributing strong and sophisticated binding to the cryptic epitope. The melting temperature (Tm) of NS101 was lower than that of commercial glycosylated therapeutic mAbs, but NS101 showed better stability at 4 °C for 36 months. The binding affinity of NS101 to FAM19A5 and neonatal Fc receptor were comparable to those of glycosylated NS101. In addition, in three human cohort groups receiving 6, 12, and 24 mg/kg of NS101, the mean half-life was 22 days, and NS101 exhibited in vivo stability, considering that the half-lives of commercialized therapeutic mAbs and endogenous IgGs are 2–4 weeks and 21 days, respectively. Taken together, the results obtained here demonstrate that NS101, a novel aglycosylated mAb, has potential as a therapeutic agent for neurological diseases.

Clinical Pharmacokinetics of Atropine Administered Ocularly Using an Ultrasensitive Bioanalytical Assay.

Purpose: Previous pharmacokinetic studies conducted on atropine sulfate ophthalmical solution have utilized bioanalytical assays that lacked sufficient sensitivity to fully characterize the complete pharmacokinetic profile. To address these limitations, Pharma Medica Research Inc. has developed and validated an ultrasensitive bioanalytical method capable of accurately quantifying the active enantiomer, L-hyoscyamine, with a very low limit of quantitation of 0.500 pg/mL. The objective of this study was to evaluate the pharmacokinetics of L-hyoscyamine in healthy subjects using a highly sensitive bioanalytical assay. Methods: Ten subjects were administered 0.3 mg of Isopto Atropine solution into the conjunctival sac of the eye. Blood samples were taken as early as 2 min and up to 24 h following administration. The plasma samples were assayed for L-hyoscyamine using a chiral method with an analytical range of 0.500-500 pg/mL. The pharmacokinetic parameters were estimated using both a noncompartmental and compartmental approach. Results: The pharmacokinetics of L-hyoscyamine were fully characterized as there were no samples that were below the limit of quantitation following dosing. Using noncompartmental analysis, the mean Cmax was 467.9 ± 159.4 pg/mL with a median (range) Tmax of 0.5 (0.08-1) h. The mean area under the concentration-time curve was 1668.96 ± 436.02 h·pg/mL and the mean half-life was 3.91 ± 1.16 h. Overall, the study drug was well tolerated and no serious adverse events were reported. Conclusion: Through the utilization of a proprietary ultrasensitive bioanalytical method, a comprehensive investigation into the pharmacokinetics of L-hyoscyamine has been successfully conducted. This advanced method offers significant potential for optimizing study designs and facilitating in-depth examinations of the pharmacokinetics of ocularly administered atropine formulations.

Safety and Pharmacokinetics of Single-Dose Mirikizumab in Chinese Healthy Participants: Results From a Phase 1 Study.

The objective of this phase 1 single-dose study was to evaluate the safety, tolerability, and pharmacokinetics of mirikizumab in Chinese healthy adults. Sixty participants were randomized within 5 planned dose cohorts: intravenous (IV) 300mg, IV 600mg, IV 1200mg, subcutaneous (SC) 200mg, and SC 400mg to receive mirikizumab (10 participants in each cohort) or placebo (2 participants in each cohort). No death or serious adverse events occurred. Twenty-eight (56.0%) participants who received mirikizumab reported 49 treatment-emergent adverse events (TEAEs)and 8 (80.0%) participants who received placebo reported 18 TEAEs. The majority of TEAEs were mild in severity. Following IV 300-1200mg mirikizumab, the arithmetic mean of both area under the concentration versus time curve from time 0 to infinity (AUC0-∞) and maximum observed drug concentration (Cmax) increased by approximately 3.5-fold, and the arithmetic mean half-life(t1/2) ranged from 9.64 to 12.0 days. Following SC 200 and 400mg mirikizumab, the arithmetic mean of both AUC0-∞ and Cmax increased by approximately 1.6-fold, the median time to Cmax(tmax) was 2.98 days for both, and the arithmetic mean t1/2 was 10.6 and 10.5 days, respectively. Absolute bioavailability based on pooled SC and IV dose data was 38.2%. In this study, the safety and pharmacokinetic profile of mirikizumab were consistent with what has been reported in other studies.

First-in-Human Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of BMS-986308: A Renal Outer Medullary Potassium Channel Inhibitor.

In patients with heart failure (HF) who respond inadequately to loop diuretic therapy, BMS-986308, an oral, selective, reversible renal outer medullary potassium channel (ROMK) inhibitor may represent an effective diuretic with a novel mechanism of action. We present data from the first-in-human study aimed to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) following single ascending doses of BMS-986308 in healthy adult participants. Forty healthy participants, aged from 20 to 55 years, and body mass index (BMI) from 19.8 to 31.6 kg/m2 were assigned to 1 of 5 dose cohorts (1, 3, 10, 30, and 100 mg) and randomized (6:2) to receive BMS-986308 oral solution or matching placebo. Following administration, BMS-986308 was rapidly absorbed with a median time to maximum concentration (Tmax) of 1.00 to 1.75 h and exhibiting a mean terminal half-life (t1/2) of approximately 13 h. Dose proportionality was evident in BMS-986308 area under the concentration-time curve (AUC), while maximum concentration (Cmax) was slightly greater than dose-proportional. We observed that urine output (or diuresis; mL) and urinary sodium excretion (or natriuresis; mmol) increased in a dose-dependent manner, starting at a minimum pharmacologically active dose of 30 mg. The largest mean changes from baseline in diuresis and natriuresis occurred in both the 6- and -24 h post-dose period following administration of 100 mg (1683.0 mL and 2055.3 mL, and 231.7 mmol and 213.7 mmol, respectively; ***P < 0.001). Overall, single-dose BMS-986308 was found to be safe, well-tolerated, with an excellent PK profile, and substantial diuretic and natriuretic activity.

Randomized, double-blind, phase 1a single-ascending dose and food effect studies assessing safety and pharmacokinetics of EC5026 in healthy volunteers.

Chronic pain represents a significant unmet medical need, affecting one-fifth of the U.S. population. EC5026 is a small molecule inhibitor of the enzyme soluble epoxide hydrolase (sEH) which is being developed as a novel non-opioid, non-NSAID analgesic. EC5026 prolongs the action of epoxy fatty acids, endogenous analgesic lipid mediators that are rapidly metabolized by sEH. We evaluated the safety and pharmacokinetic profile of EC5026 in two phase I trials, a single-ascending dose (SAD) study and a fed-fasted study. The SAD study evaluated EC5026 doses ranging from 0.5 to 24 mg in healthy volunteers. EC5026 was well tolerated. No treatment-emergent adverse events were considered related to EC5026. No apparent treatment- or dose-related trends in laboratory results, vital signs, physical examinations, or electrocardiograms were observed. A linear, near-dose-proportional increase in exposure was observed with progressive doses in the SAD study; plasma exposure was below or near the lower limit of quantification after 0.5-2 mg doses. Mean half-lives ranged from 41.8 to 59.1 h. for doses of 8-24 mg, supporting a once-daily dosing regimen. In the fed-fasted study using 8 mg EC5026 tablets, higher peak concentrations (66%) and total exposures (53%) were observed under the fed condition. Plasma concentrations declined in a monoexponential manner with mean half-lives of 59.5 h. in the fed state and 66.9 h. in the fasted state. Future clinical trials using EC5026 for the treatment of pain are justified based on the favorable outcomes from both clinical trials along with preclinical evidence of analgesic activity.