Pharmacodynamic Outcomes Research Articles

IQ Survey Results on Current Industry Practices: Part 2-Quantitative Evaluations of Immunogenicity Assessment.

All biotherapeutics have the potential to induce an immunogenic response and generate anti-drug antibodies (ADAs), especially when administered as multiple doses over prolonged periods. However, a clinically meaningful effect of ADAs can be difficult to identify to communicate the impact of immunogenicity on drug exposure, safety and efficacy outcomes in product labels in a way that is useful for health care providers. The immunogenicity working Group, IQ Consortium (Clinical Pharmacology Leadership Group) has conducted a survey to understand the current practices in analyzing immunogenicity data generated during clinical development and its impact on pharmacokinetics, clinically relevant pharmacodynamic biomarkers, safety, and efficacy outcome measures. Information was collected for 93 drugs, spanning multiple drug classes and over the different phases of clinical development, including post-approval. The predominant drug classes reported included monoclonal antibodies or Fc-fusion proteins, endogenous protein replacement therapies, bispecific antibodies, and antibody-drug conjugates. The extent of quantitative evaluation varied and was influenced by several factors, including descriptive analyses, statistical approaches, and modeling. In addition to understanding current practices, this survey also highlights areas for future exploration in analyzing clinical relevance of ADAs which can facilitate the use for regulatory submissions and product labels.

In vitro colonic fermentation of fermented Radix Astragali by Poria cocos and anti-hyperuricemia mechanism based on network pharmacology and experiment verification

AimThis research aimed to probe the effects of fecal microbiota and Lactobacillus acidophilus on the metabolism of Radix Astragali (RA) and Poria cocos solid fermenting Radix Astragali (FRA). It further explores pharmacological effects of RA, Poria cocos, and FRA on HUA mouse model and the mechanisms in HUA treatment.MethodsFecal microbiota and Lactobacillus acidophilus were used to ferment FRA and RA in vitro to probe the impacts of microbiota on the metabolism of active compound. A HUA mouse model was used to carry out pharmacodynamic experiment of anti-hyperuricemia. Network pharmacology and molecular docking was utilized to elucidate the underlying mechanisms of RA and Poria cocos in the treatment of HUA.ResultsThe results indicated that astragaloside IV (AG IV), total saponins, and flavonoids continuously decreased in FRA and RA during 48 h fecal microbiota colonic fermentation. During Lactobacillus acidophilus fermentation, in FRA, the content of AG IV peaked at 12 h with a value of 1.14 ± 0.20 mg/g; total saponins and flavonoids reached the highest values of 136.34 ± 6.15 mg/g at 12 h and 6.35 ± 0.06 mg/g at 6 h; AG IV and total saponins reached the highest values 0.63 ± 0.05 mg/g and 115.12 ± 4.12 mg/g at 12 h and 24 h in RA, respectively; and total flavonoids consecutively decreased. The counts of Lactobacillus acidophilus increased significantly in FRA compared with RA. Pharmacodynamic outcomes revealed that FRA effectively reduced blood levels of uric acid (UA), triglycerides (TG), xanthine oxidase (XOD), alanine aminotransferase (ALT), and aspartate transaminase (AST) in HUA mice, exerting protective effects on the liver and kidney. Network pharmacology showed that there were 93 common targets for RA, Poria cocos, and HUA with the top five core targets tumor necrosis factor (TNF), signal transducer and activator of transcription 3 (STAT3), cysteinyl aspartate specific proteinase 3 (CASP3), jun proto-oncogene (JUN), and estrogen receptor 1 (ESR1). Molecular docking analysis revealed that AG IV, calycosin and formononetin bond well to the core targets.ConclusionThis research revealed the interaction of RA and FRA with fecal microbiota and Lactobacillus acidophilus, RA and Poria cocos were featured with multiple components, target points, and signaling pathways in HUA treatment, which provided fresh insights for further HUA therapeutics.

Personalized CZA-ATM dosing against an XDR E. coli in liver transplant patients; the application of the in vitro hollow fiber system.

A patient with an extensively drug-resistant (XDR) New Delhi metallo-β-lactamase (NDM) and oxacillinase (OXA-48) producing Escherichia coli (E. coli) infection was awaiting orthotopic liver transplant. There is no standardized antibiotic prophylaxis regimen; however, in line with the Infectious Diseases Society of America guidance, an antibiotic prophylactic regimen of ceftazidime-avibactam 2.5g TDS with aztreonam 2g three times a day (TDS) IV was proposed. The hollow fiber system (HFS) was applied to inform the individualized pharmacodynamic outcome likelihood prior to prophylaxis. A 4-log reduction in CFU/mL in the first 10 h of the regimen exposure was observed; however, the killing dynamics were slow and six 8-hourly infusions were required to reduce bacterial cells to below the limit of quantification. Thus, the HFS supported the use of the regimen for infection clearance; however, it highlighted the need for several infusions. Standard local practice is to administer prophylaxis antibiotics at induction of orthotopic liver transplantation (OLT); however, the HFS provided data to rationalize earlier dosing. Therefore, the patient was dosed at 24 h prior to their OLT induction and subsequently discharged 8 days after surgery. The HFS provides a dynamic culture solution for informing individualized medicine by testing antibiotic combinations and exposures against the bacterial isolates cultured from the patient's infection. .

A Phase 1 Assessment of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of (2R,6R)-Hydroxynorketamine in Healthy Volunteers.

(R,S)-Ketamine (ketamine) is a dissociative anesthetic that also possesses analgesic and antidepressant activity. Undesirable dissociative side effects and misuse potential limit expanded use of ketamine in several mental health disorders despite promising clinical activity and intensifying medical need. (2R,6R)-Hydroxynorketamine (RR-HNK) is a metabolite of ketamine that lacks anesthetic and dissociative activity but maintains antidepressant and analgesic activity in multiple preclinical models. To enable future assessments in selected human indications, we report the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of RR-HNK in a Phase 1 study in healthy volunteers (NCT04711005). A six-level single-ascending dose (SAD) (0.1-4 mg/kg) and a two-level multiple ascending dose (MAD) (1 and 2 mg/kg) study was performed using a 40-minute IV administration emulating the common practice for ketamine administration for depression. Safety assessments showed RR-HNK possessed a minimal adverse event profile and no serious adverse events at all doses examined. Evaluations of dissociation and sedation demonstrated that RR-HNK did not possess anesthetic or dissociative characteristics in the doses examined. RR-HNK PK parameters were measured in both the SAD and MAD studies and exhibited dose-proportional increases in exposure. Quantitative electroencephalography (EEG) measurements collected as a PD parameter based on preclinical findings and ketamine's established effect on gamma-power oscillations demonstrated increases of gamma power in some participants at the lower/mid-range doses examined. Cerebrospinal fluid examination confirmed RR-HNK exposure within the central nervous system (CNS). Collectively, these data demonstrate RR-HNK is well tolerated with an acceptable PK profile and promising PD outcomes to support the progression into Phase 2.

Adrenaline Auto-Injectors for Preventing Fatal Anaphylaxis.

Anaphylaxis affects up to 5% of people during their lifetime. Although anaphylaxis usually resolves without long-term physical consequences, it can result in anxiety and quality of life impairment. Rarely and unpredictably, community anaphylaxis can cause rapid physiological decompensation and death. Adrenaline (epinephrine) is the cornerstone of anaphylaxis treatment, and provision of adrenaline autoinjectors (AAI) has become a standard of care for people at risk of anaphylaxis in the community. In this article, we explore the effectiveness of AAIs for preventing fatal outcomes in anaphylaxis, using information drawn from animal and human invivo studies and epidemiology. We find that data support the effectiveness of intravenous adrenaline infusions for reversing physiological features of anaphylaxis, typically at doses from 0.05 to 0.5 μg/kg/min for 1-2 h, or ~ 10 μg/kg total dose. Intramuscular injection of doses approximating 10 μg/kg in humans can result in similar peak plasma adrenaline levels to intravenous infusions, at 100-500 pg/mL. However, these levels are typically short-lived following intramuscular adrenaline, and pharmacokinetic and pharmacodynamic outcomes can be unpredictable. Epidemiological data do not support an association between increasing AAI prescriptions and reduced fatal anaphylaxis, although carriage and activation rates remain low. Taken together, these data suggest that current AAIs have little impact on rates of fatal anaphylaxis, perhaps due to a lack of sustained and sufficient plasma adrenaline concentration. Effects of AAI prescription on quality of life may be variable. There is a need to consider alternatives, which can safely deliver a sustained adrenaline infusion via an appropriate route.

Safety and efficacy of apixaban versus warfarin in peritoneal dialysis patients with non-valvular atrial fibrillation: protocol for a prospective, randomised, open-label, blinded endpoint trial (APIDP2)

IntroductionSeveral randomised controlled trials have demonstrated that novel oral anticoagulants are safer compared with vitamin K antagonists for the management of non-valvular atrial fibrillation (NVAF) to prevent thromboembolic events in...

Cocrystal@protein-anchoring nanococktail for combinatorially treating multidrug-resistant cancer

Multidrug resistance (MDR), the major mechanism by which various cancers develop specific resistance to therapeutic agents, has set up enormous obstacles to many forms of tumor chemotherapy. Traditional cocktail therapy administration, based on the combination of multiple drugs for anti-MDR chemotherapy, often suffers from inconsistent in vivo pharmacokinetic behaviors that cannot act synchronously on the lesions, leading to limited pharmacodynamic outcomes. Despite the emergence of nanomedicines, which has improved chemotherapeutic drugs’ bioavailability and therapeutic effect on clinical application, these monotherapy-based nano-formulations still show poor progression in overcoming MDR. Herein, a “one stone and three birds” nanococktail integrated by a cocrystal@protein-anchoring strategy was purposed for triple-payload delivery, which paclitaxel-disulfiram cocrystal-like nanorods (NRs) were anchored with the basic protein drug Cytochrome c (Cyt C), followed by hyaluronic-acid modification. In particular, NRs were utilized as carrier-like particles to synchronously deliver biomacromolecule Cyt C into tumor cells and then promote cell apoptosis. Of note, on A549/Taxol drug-resistant tumor-bearing mice, the system with extraordinarily high encapsulation efficiency demonstrated prolonged in vivo circulation and increased tumor-targeting accumulation, significantly reversing tumor drug resistance and improving therapeutic efficacy. Our mechanistic study indicated that the system induced the apoptosis of Taxol-resistant tumor cells through the signal axis P-glycoprotein/Cyt C/caspase 3. Collectively, this nanococktail strategy offers a promising approach to improve the sensitivity of tumor cells to chemotherapeutic drugs and strengthen intractable drug-resistant oncotherapy.

What matters for drug delivery to tumor by nanoparticles: Gaining insights from PBPK/PD simulation of drug nanocrystals.

In our previous studies, drug nanocrystals were directly prepared by solution crystallization, possessing uniform particle size and morphology suitable for intravenous (IV) injection. These nanocrystals accumulated in a small percentage of their injected dose in tumor-bearing mice but showed similar anti-tumor effectiveness and much-reduced side effects compared with current commercial solubilized and encapsulated delivery systems. In this study, we aimed to delineate possible controlling factors for the pharmacokinetics (PK) and biodistribution behaviors of paclitaxel (PTX) nanocrystals tested in mice by applying physiologically based pharmacokinetics (PBPK) modeling, coupled with pharmacodynamics (PD) simulation, to the data. Our results show that clearance of the drug plays a significant, if not the most important, role in determining tissue distribution, including tumor accumulation of PTX nanocrystals. Surface treatment of drug nanocrystals with polymeric surfactants also appeared to affect PK profiles and PD outcomes. Importantly, when scaled to model human parameters, our PK/PD simulations suggest that drug distribution in humans, as opposed to animal models, was significantly influenced by tissue partitioning rather than drug clearance. This finding could facilitate the design and development of future drug delivery systems. Drug nanocrystals deposited in tissues, including tumors, could therefore act as depots, releasing the drug back into the circulation, possibly contributing to extended treatment, as well as any detrimental effects.

Double dosing ulipristal acetate emergency contraception for individuals with obesity: a randomised crossover trial

ObjectiveTo determine whether increasing the dose of ulipristal acetate (UPA)-containing emergency contraception (EC) improves pharmacodynamic outcomes in individuals with obesity.Study designWe enrolled healthy, regularly-cycling, confirmed ovulatory, reproductive-age individuals with body...

'Under pressure': The role of therapeutic drug monitoring in the treatment of hypertension.

Antihypertensive drugs do not qualify as optimal candidates for therapeutic drug monitoring (TDM), given their obvious physiological effect, the absence of a clear relationship between drug concentrations and pharmacodynamic outcomes and their wide therapeutic range. However, since non-adherence is a major challenge in hypertension management, using drug concentrations can be of value to identify non-adherence as a first step towards better blood pressure control. In this article we discuss the key challenges associated with measuring and interpreting antihypertensive drug concentrations that are important when TDM is used to improve non-adherence. Additionally, we elaborate on the role of TDM in optimizing antihypertensive drug treatment besides addressing non-adherence by highlighting its value in specific patient groups with altered pharmacokinetic parameters such as female vs. male or elderly patients.

Pharmacodynamic (PD) and immunophenotyping analyses of ATR inhibitor (ATRi) tuvusertib + ATM inhibitor (ATMi) lartesertib in a phase Ib study in patients with advanced unresectable solid tumors.

2612 Background: Ataxia telangiectasia-mutated (ATM) and Rad3-related (ATR) protein kinases orchestrate the DNA damage response. A synthetic lethal relationship between ATR and ATM genes in cancer has been described1 and ATMi synergistically potentiate the efficacy of ATRi in vitro and in vivo.2 The combination of tuvusertib + lartesertib was investigated in Part A1 of the open-label, multicenter study DDRiver Solid Tumors 320 in patients with advanced unresectable solid tumors. Here, we report results of the PD and immunophenotyping analyses. Methods: PD analysis comprised γ-H2AX in serial blood samples, stimulated ex vivowith 4-NQO, bleomycin, or controls. Flow cytometry was used to measure target inhibition via γ-H2AX modulation in the CD45+ lymphocytes fraction and to explore the effect of tuvusertib + lartesertib on the immunophenotype (myeloid-derived suppressor cells, T and B lymphocytes, monocytes, and natural killer cells subsets) in serial blood samples. Pharmacokinetic samples were analyzed by a validated bioanalytical liquid chromatography/mass spectrometry method. Time-matched blood samples were collected at baseline, 1, 3, 6, and 24 hours after first tuvusertib and lartesertib administration on days 1 and 8 of cycle 1 for the γ-H2AX analysis, and on days 1 and 15 of cycles 1 and 2 before treatment for immunophenotyping. Results: Immunophenotyping data and γ-H2AX levels were obtained from 41 and 34 patients, respectively. For tuvusertib, complete or almost complete target inhibition was seen at 1–6 hours after treatment, followed by a rebound above baseline after 24 hours, on both days 1 and 8 at doses of 130 and 180 mg once daily (QD). For lartesertib, a variable target inhibition of approximately 50 % on average was seen across all time points at doses of 100, 150 and 200 mg QD. No target inhibition was seen for tuvusertib at 90 mg QD and lartesertib at 50 mg QD (cohort 1). Tuvusertib + lartesertib induced a transient decrease of monocytes and natural killer (NK) cells, with partial or complete recovery to baseline levels during treatment breaks in schedules of 2 weeks on treatment followed by a treatment break of 1 or 2 weeks, respectively. Conclusions: Tuvusertib and lartesertib combination PD outcomes were in line with respective monotherapy observations.3,4 The combination did not cause any consistent change in the levels of immune cell subsets at all dose levels tested, except a mild, transient decrease in monocytes and NK cells, in line with the tuvusertib monotherapy observations. 1. Kantidze et al., Trends Cancer 2018;4(11):755–68. 2. Turchick et al., Mol Cancer Ther 2023;22(7):859–72. 3. Yap et al., Ann Oncol 2022;33(suppl_7):S197–S224. 4. Siu et al., Cancer Res 2023;83(8_Suppl):CT171. Clinical trial information: NCT05396833 .

Vaporized D-limonene selectively mitigates the acute anxiogenic effects of Δ9-tetrahydrocannabinol in healthy adults who intermittently use cannabis

BackgroundCannabis contains hundreds of chemical constituents beyond delta-9-tetrahydrocannabinol (THC), which is believed to drive most of its acute pharmacodynamic effects. The entourage effect theory asserts that non-THC constituents can impact acute cannabis effects, but few empirical studies have systematically evaluated this theory in humans. This study assessed whether the cannabis terpenoid d-limonene mitigates the acute anxiogenic effects of THC. MethodsTwenty healthy adults completed nine, double-blind outpatient sessions in which they inhaled vaporized THC alone (15mg or 30mg), d-limonene alone (1mg or 5mg), the same doses of THC and d-limonene together, or placebo; a subset of participants (n=12) completed a tenth session in which 30mg THC+15mg d-limonene was administered. Outcomes included subjective drug effects, cognitive/psychomotor performance, vital signs, and plasma THC and d-limonene concentrations. ResultsWhen d-limonene was administered alone, pharmacodynamic outcomes did not differ from placebo. Administration of 15mg and 30mg THC alone produced subjective, cognitive, and physiological effects typical of acute cannabis exposure. Ratings of anxiety-like subjective effects qualitatively decreased as d-limonene dose increased and concurrent administration of 30mg THC+15mg d-limonene significantly reduced ratings of “anxious/nervous” and “paranoid” compared with 30mg THC alone. Other pharmacodynamic effects were unchanged by d-limonene. D-limonene plasma concentrations were dose orderly, and concurrent administration of d-limonene did not alter THC pharmacokinetics. ConclusionsD-limonene selectively attenuated THC-induced anxiogenic effects, suggesting this terpenoid could increase the therapeutic index of THC. Future research should determine whether this effect extends to oral dose formulations and evaluate the interactions between other cannabis terpenoids or cannabinoids and THC.

A randomized, double-blind, single-dose, phase 1 study comparing the pharmacokinetics, pharmacodynamics, safety, and immunogenicity of denosumab biosimilar CT‑P41 and reference denosumab in healthy males

ABSTRACT Background This study’s objective was to demonstrate pharmacokinetic (PK) similarity and safety of denosumab biosimilar, CT‑P41, and United States–licensed reference denosumab (US-denosumab) in healthy male Asian adults, considering also pharmacodynamic (PD) outcomes. Research design and methods This double-blind, two-arm, parallel-group, Phase 1 study randomized (1:1) healthy males to a single (60-mg) subcutaneous dose of CT‑P41 or US-denosumab. Primary endpoints were area under the concentration – time curve (AUC) from time zero to infinity (AUC0–inf), AUC from time zero to the last quantifiable concentration (AUC0–last), and maximum serum concentration (Cmax). PK equivalence was determined if 90% confidence intervals (CIs) for ratios of geometric least-squares means (gLSMs) were within the predefined 80–125% equivalence margin. Secondary PK, PD, safety, and immunogenicity outcomes were also evaluated. Results Of 154 participants randomized (76 CT‑P41; 78 US-denosumab), 151 received study drug (74 CT‑P41; 77 US-denosumab). Primary and secondary PK results, PD results, safety, and immunogenicity were comparable between groups. Ninety percent CIs for ratios of gLSMs were within the predefined equivalence margin for AUC0–inf (100.4–114.7), AUC0–last (99.9–114.3), and Cmax (95.2–107.3). Conclusions Following a single dose in healthy males, CT‑P41 demonstrated PK equivalence with US-denosumab. Trial registration ClinicalTrials.gov: NCT06037395

Predicting pharmacodynamic effects through early drug discovery with artificial intelligence-physiologically based pharmacokinetic (AI-PBPK) modelling.

A mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model links the concentration-time profile of a drug with its therapeutic effects based on the underlying biological or physiological processes. Clinical endpoints play a pivotal role in drug development. Despite the substantial time and effort invested in screening drugs for favourable pharmacokinetic (PK) properties, they may not consistently yield optimal clinical outcomes. Furthermore, in the virtual compound screening phase, researchers cannot observe clinical outcomes in humans directly. These uncertainties prolong the process of drug development. As incorporation of Artificial Intelligence (AI) into the physiologically based pharmacokinetic/pharmacodynamic (PBPK) model can assist in forecasting pharmacodynamic (PD) effects within the human body, we introduce a methodology for utilizing the AI-PBPK platform to predict the PK and PD outcomes of target compounds in the early drug discovery stage. In this integrated platform, machine learning is used to predict the parameters for the model, and the mechanism-based PD model is used to predict the PD outcome through the PK results. This platform enables researchers to align the PK profile of a drug with desired PD effects at the early drug discovery stage. Case studies are presented to assess and compare five potassium-competitive acid blocker (P-CAB) compounds, after calibration and verification using vonoprazan and revaprazan.

Real-world experience on tolerability and safety of relugolix combined with androgen signaling inhibitors in patients with advanced prostate cancer.

85 Background: Relugolix is the first oral GNRH antagonist approved by the FDA in 2021 for the treatment of advanced prostate cancer (PCa). Approval was based on HERO study, which showed a rapid and sustained testosterone suppression superior to that of Leuprolide coupled with a significantly shorter time to eugonad state after discontinuation. Relugolix was associated with a 54% lower risk of major adverse cardiovascular events as compared with Leuprolide. There is very little data available regarding the tolerability safety of Relugolix in combination Enhanced Androgen Signaling Inhibitors (ASI). Here we provide real world experience on the combination of Relugolix and ASIs in patients(pts) with advanced PCa, focusing on safety, tolerability and pharmacodynamic outcome measures. Methods: Houston Methodist Genitourinary Oncology records were reviewed for identification of pts treated with combination Relugolix plus ASI for at least 1 month, from 09/21 to 07/23. Data collected included pts’ baseline and tumor characteristics, cardiovascular and metabolic comorbidities concomitant medication. We recorded Adverse Events, potential Drug Drug Interaction (DDI) and Testosterone (T) and PSA decline. Results: We report 152 advanced hormone-naive PCa pts with median age of 71 (range 48-96). 81% were White or/and Hispanic, 17 % black, 2 % Asian. Majority (90%) had at least 1 cardiovascular risk factor; hypertension (72%), hyperlipidemia (52%), obesity (41 %), diabetes mellitus (26%), coronary artery disease (30%) and atrial fibrillation (13%). ASIs combined with Relugolix included: Darolutamide (78%), Abiraterone (14%), Apalutamide (7%) and Enzalutamide (1%). All but one pt were compliant (99%). Median treatment exposure is 8 months (range 1 -21). All pts had baseline Testosterone >150ng/dL. All pts reached castrate T levels and 90% of patients achieved a T < 20 ng/dL. 55% pts reached PSA <0.1 at median of 4ms, 75% PSA decline > 90% and 91% PSA decline ≥50%. 7% pts discontinued Relugolix due to adverse events. Three pts (2%) had a major adverse cardiovascular event, including one sudden death, one with congestive heart failure, and one with myocardial infarction. Two pts (1%) reported grade 3 fatigue. G3 LFT elevations recorded in 2 pts (1%). No clinical signals of DDI reported. Conclusions: This is the first large original report of the combination of Relugolix with ASIs in real world practice. The combination has a favorable safety and tolerability profile with no new safety concerns. No new DDI concerns were raised. These findings in combination with pharmacodynamic outcome measures of T / PSA support the use of Relugolix in combination with ASIs as standard of care in advanced PCa.

Pharmacokinetics, pharmacodynamics and safety of 15mg-tolvaptan administered orally for 7 consecutive days to Chinese patients with child-Pugh B cirrhosis.

Background: Tolvaptan, a selective vasopressin V2-receptor antagonist, can elicit a diuretic effect without significant electrolyte loss. The aims were to evaluate multiple-dose pharmacokinetics, pharmacodynamics and safety of daily administration of 15mg tolvaptan in Chinese adult patients with confirmed Child-Pugh Class B cirrhosis accompanied by ascites. Methods: This was an open-label, single-center, single- and multiple-dose study. All patients received a daily 15mg dose of tolvaptan for 7 consecutive days. The plasma concentrations of tolvaptan and its two metabolites (DM-4103, DM-4107) were measured using high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). In addition, various pharmacokinetics parameters were calculated. The pharmacodynamic outcomes evaluated changes in serum sodium and potassium concentrations, daily urine volume, daily water consumption, fluid balance and body weight. Safety profiles, including the incidence of treatment-emergent adverse events (TEAEs), were carefully recorded. Results: Eleven patients with Child-Pugh B cirrhosis were eventually enrolled in the study. Plasma concentrations of tolvaptan and DM-4107 reached steady-states after 7 days of consecutive oral administration. No accumulation of tolvaptan or DM-4107 was found, but DM-4103 accumulated 18.2-fold after multiple-dosing. The daily urine volume and daily water consumption were statistically significantly increased after administration of tolvaptan from Day 1 to Day 7 (all p < 0.05), accompanied by an increased serum sodium concentration. Of 11 patients, 9 (81.8%) reported 20 TEAEs, with the majority being mild to moderate in severity. The most commonly occurring TEAEs were thirst (45.5%), pollakiuria (36.4%) and dry mouth (27.3%). Conclusion: Tolvaptan at a daily dose of 15mg had a diuretic effect but did not increase serum sodium excretion or lead to tolvaptan accumulation. It is therefore can be safely used for short-term treatment of Chinese adult patients with confirmed Child-Pugh B cirrhosis. Clinical Trial Registration: https://clinicaltrials.gov/search?term=NCT01359462, identifier NCT01359462.

Pharmacokinetics and pharmacodynamics of five distinct commercially available hemp-derived topical cannabidiol products.

Products containing cannabidiol (CBD) have proliferated after the 2018 Farm Bill legalized hemp (cannabis with ≤0.3% delta-9-tetrahydrocannabinol (Δ9-THC)). CBD-containing topical products have surged in popularity, but controlled clinical studies on them are limited. This study characterized the effects of five commercially available hemp-derived high CBD/low Δ9-THC topical products. Healthy adults (N = 46) received one of six study drugs: a CBD-containing cream (N = 8), lotion (N = 8), patch (N = 7), balm (N = 8), gel (N = 6) or placebo (N = 9; matched to an active formulation). The protocol included three phases conducted over 17 days: (i) an acute drug application laboratory session, (ii) a 9-day outpatient phase with twice daily product application (visits occurred on Days 2, 3, 7 and 10) (iii) a 1-week washout phase. In each phase, whole blood, oral fluid and urine specimens were collected and analyzed via liquid chromatography with tandem mass spectrometry (LC-MS-MS) for CBD, Δ9-THC and primary metabolites of each and pharmacodynamic outcomes (subjective, cognitive/psychomotor and physiological effects) were assessed. Transdermal absorption of CBD was observed for three active products. On average, CBD/metabolite concentrations peaked after 7-10 days of product use and were highest for the lotion, which contained the most CBD and a permeation enhancer (vitamin E). Δ9-THC/metabolites were below the limit of detection in blood for all products, and no urine samples tested "positive" for cannabis using current US federal workplace drug testing criteria (immunoassay cut-off of 50 ng/mL and confirmatory LC-MS-MS cut-off of 15 ng/mL). Unexpectedly, nine participants (seven lotions, one patch and one gel) exhibited Δ9-THC oral fluid concentrations ≥2 ng/mL (current US federal workplace threshold for a "positive" test). Products did not produce discernable pharmacodynamic effects and were well-tolerated. This study provides important initial data on the acute/chronic effects of hemp-derived topical CBD products, but more research is needed given the diversity of products in this market.

Clinical stage Alzheimer’s therapy, NNI‐362 promotes TH+ neurons associated with a reversal of motor deficits in AAV‐alpha synuclein model, leaving alpha synuclein unchanged

AbstractBackgroundNNI‐362 is a novel small molecule identified by phenotypic screening to discover compounds that promote new neurons from human neural progenitor cells and have neuroprotective capacity. A placebo‐controlled, double‐blind Phase 1a trial examined the safety and tolerability of NNI‐362, as well as a pharmacodynamic outcome ‐ the level of plasma p‐tau181, a blood‐based biomarker specific to Alzheimer’s disease (AD) pathology. Results in animal models of other age‐related disorders suggest NNI‐362 has the potential to halt or reverse AD and PD clinically.MethodAn AAV‐alpha synuclein rat model of Parkinson’s disease (PD) (MOTAC, France) was used to examine the effects of NNI‐362 treatment. This model results in anosmia and motor phenotypes, loss of TH+ neurons, and diminished adult‐born neurons triggered by alpha‐synuclein expression in the SNpc. NNI‐362 and placebo were formulated as a lipid suspension and administered orally once daily for up to 6 weeks post‐stabilization of AAV‐synuclein expression. At 8 weeks, brains were removed, and the SNpc sectioned and stained for TH+ neurons, alpha‐synuclein, and BrdU+ adult‐born neurons. Results were compared to AAV‐GFP‐injected, vehicle‐treated rats ‐ in groups of M or F and treatment or placebo (n = 14/group, 7F/7M).ResultBrain permeable therapy NNI‐362 did not alter alpha‐synuclein levels, but promoted BrdU+ neurons in the substantia nigra. Thus, generating and protecting TH+ neurons was associated with reversing motor deficits in females. No motor deficits and no BrdU+ neuron deficits were observed in AAV alpha‐synuclein treated males (twice run model), as such no amelioration by NNI‐362 treatment.ConclusionOral NNI‐362 may be a cause‐agnostic therapeutic ‐ promoting region‐specific new neurons, TH+ neuronal protection, and behavioral improvement when induced by dopaminergic deficit, including neurogenesis deficit. After AAV‐alpha‐synuclein induction of 2 weeks, and then followed by chronic NNI‐362 treatment, both behavior and neuron numbers were no different than AAV‐GFP control levels in this clinically‐relevant experimental model of PD.

Abstract 13840: Safety Outcomes From a First-in-Human Study of a Novel Investigational Monoclonal Antibody, REGN5381, an Agonist to the Natriuretic Peptide Receptor 1

Introduction: Natriuretic peptides (NPs) regulate vascular volume and tone via the membrane-bound guanylate cyclase, natriuretic peptide receptor 1 (NPR1). Activation of this pathway is known to lower systemic and venous blood pressure (BP) and effect natriuresis and diuresis. Previous recombinant NP infusions for heart failure were limited by their duration of effects. REGN5381, a novel investigational NPR1 agonist monoclonal antibody, showed sustained hemodynamic effects in animal models. Here, we report safety and pharmacodynamic (PD) outcomes from a phase 1, first-in-human study of REGN5381. Hypothesis: REGN5381 is sufficienty well tolerated in healthy humans to warrant continued clinical investigation. Aim: To assess the safety, tolerability, and REGN5381 PD in normotensive humans. Methods: This double-blind, single-ascending dose study (NCT04506645), randomized healthy adults aged 18-55 years (6:2) to receive a single intravenous dose of REGN5381 or placebo. Participants received a fixed-sodium and fluid diet and remained 4 days in the clinic for non-invasive hemodynamics monitoring and safety assessment. Results: A total of 48 participants were enrolled; 12 were randomized to placebo and 6 to each of 6 REGN5381 dose levels (total n=36). Eight (66.7%) participants in the placebo and 24 (66.7%) in the total REGN5381 group reported ≥1 treatment-emergent adverse event (TEAE), with no obvious relationship to dose level. Four (33.3%) participants in the placebo and 15 (41.7%) in the total REGN5381 group reported ≥1 study drug related TEAE, with no obvious relationship to dose level. Common TEAEs (experienced by &gt;10% of participants in the total group) were postural dizziness (placebo: 2 [16.7]%; total REGN5381: 6 [16.7]%) and headache (placebo: 5 [41.7%]; total REGN5381: 4 [11.1%]). Pyuria and orthostatic hypotension were reported in 4 (11.1%) participants in the total group, but none in the placebo group. No serious or severe TEAEs or deaths were reported in any dose groups. Participants treated with the highest dose saw a 7-11 mmHg reduction of systolic BP that was sustained over 72 hours (the full duration of inpatient monitoring). Conclusion: A single dose of REGN5381 is generally well-tolerated and provides sustained hemodynamic effects.

Combined translational pharmacometrics approach to support the design and conduct of the first-in-human study of DWP16001.

The objective of this study was to characterize the pharmacokinetics (PK)/pharmacodynamics (PD) of DWP16001, a novel sodium-glucose cotransporter 2 inhibitor, and predict efficacious doses for the first-in-human study using various translational approaches. A mechanistic PK/PD model was developed for DWP16001 using nonlinear mixed-effect modelling to describe animal PK/PD properties. Using allometry and in silico physiologically based equations, human PK parameters were predicted. Human PD parameters were scaled by applying interspecies difference and in vitro drug-specific factors. Human parameters were refined using early clinical data. Model-predicted PK and PD outcomes were compared to observations before and after parameter refinement. The PK/PD model of DWP16001 was developed using a 2-compartment model with first-order absorption and indirect response. Efficacious doses of 0.3 and 2 mg of DWP16001 were predicted using human half-maximal inhibitory concentration values translated from Zucker Diabetic Fatty rats and normal rats, respectively. After parameter refinement, doses of 0.2 and 1 mg were predicted to be efficacious for each disease model, which improved the prediction results to within a 1.2-fold difference between the model prediction and observation. This study predicted efficacious human doses of DWP16001 using population PK/PD modelling and a combined translational pharmacometrics approach. Early clinical data allowed the methods used to translate in vitro and in vivo findings to clinical PK/PD values for DWP16001 to be optimized. This study has shown that a refinement step can be readily applied to improve model prediction and further support the study design and conduct of a first-in-human study.