Clinical and Translational Science

Chronic wounds, such as diabetic and ischemic ulcers, involve impaired perfusion and delayed healing. TOP-N53 is a novel bifunctional molecule combining nitric oxide (NO) release with phosphodiesterase-5 (PDE5) inhibition to enhance local NO-cGMP signalling, resulting in vasodilation and angiogenesis. This first-in-human, randomized, double-blind, vehicle-controlled Phase I trial assessed the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single subcutaneous TOP-N53 doses in 29 healthy male volunteers. Each participant received injections of TOP-N53 and vehicle in the same forearm, but either at the proximal or at the distal site in an intra-individually blinded manner. Safety assessments included local and systemic parameters. PK and PD responses were evaluated by analysis of TOPN53 and its bioactivation metabolite TOP-52 in plasma, and by Laser Speckle Contrast Imaging (LSCI), a non-invasive method to measure skin perfusion, respectively. TOP-N53 was safe and well tolerated, with no serious adverse events or local or systemic adverse reactions. Plasma concentrations remained below the quantification limit and LSCI showed sustained dose-dependent increases in local skin perfusion at doses of 4.84 ug and 9.075 ug TOP-N53 SC for up to 24 h post injection when compared to vehicle. These findings support the favourable safety and tolerability profile of TOP-N53 associated with locally improved skin perfusion, encouraging its further clinical development as a topical treatment for chronic wounds with microvascular dysfunction.

BackgroundCompounded versions of tirzepatide are widely available in the U.S. in the form of fixed-dose combinations of tirzepatide and various analogs of vitamin B12. These combinations are mass marketed in the U.S. and other countries as comparable to FDA-approved tirzepatide products even though they undergo no evaluation of their potency or impurity profiles. Research Design and MethodsSamples of compounded tirzepatide combined with B12 obtained from various sources in the U.S. market were tested using various analytical methods. Samples were assessed for unacceptable levels of peptide-related impurities. ResultsOur testing identified a widespread and previously unidentified impurity in compounded tirzepatide-B12 products resulting from a chemical reaction between tirzepatide and certain analogs of B12. ConclusionDespite the presence of this impurity, these products continue to be mass marketed as "personalized" treatments. Our findings underscore the importance of testing and FDA approval before new drugs are marketed and highlights potential risks for patients associated with untested combinations. A novel impurity, present at substantial levels in compounded tirzepatide/B12 products, highlights risks inherent in marketing complex therapies outside the drug-approval framework. Although clinical effects of this impurity are unknown, the identification of a widespread impurity adds to the existing quality concerns presented by compounded tirzepatide.

BackgroundThe biosimilarity for erythropoietin (EPO) functionality of GBPD002 (test candidate) and Eprex(R) (comparator) has been evaluated by comparing the pharmacokinetic (PK) and pharmacodynamic (PD) properties following subcutaneous injection. MethodsThis was a randomized, double-blinded, two-sequence, crossover clinical trial. Subjects were randomly assigned and received a dose (4,000 IU) of either the test or comparator EPO, and received the alternative formulations after 4-weeks of washout period. ResultsThe PK parameters, viz., maximum observed concentration (Cmax) and area under the curve extrapolated to infinity (AUC0-inf), were calculated with the serum EPO concentrations from blood samples and were found comparable for both formulations. The geometric mean ratios (at 90% CI) of the Cmax and AUCinf were 0.89 and 1.16, respectively, which were within the regulatory range of 0.80 - 1.25. The time-matched serum EPO concentrations and PD markers (reticulocyte, hematocrit, hemoglobin, and red blood cell) denoted a counterclockwise hysteresis, suggesting a time delay between the observed concentration and the response. ANOVA-derived P-values (>0.05) for the effectors clearly revealed the similarity between effects on PD markers for the test and comparator drugs. Both formulations were found tolerated well, and anti-drug antibodies were not observed. ConclusionsThus, the two formulations are projected to be used interchangeably in clinical settings.

IntroductionTrans sodium crocetinate (TSC) is a synthetic carotenoid with a unique mechanism of action that improves the diffusion of oxygen by reducing oxygen transfer resistance within plasma, and it is currently being developed to enhance oxygen delivery to hypoxic tissues in multiple conditions. The goals of this study were to evaluate safety, pharmacokinetics, and pharmacodynamic properties of escalating doses of TSC on peripheral oxygenation utilizing transcutaneous oxygen measurements, when administered to healthy subjects breathing supplemental oxygen. MethodsThis was a dose-escalation, single-center, randomized, phase 1 study aimed at assessing the safety, pharmacokinetic and pharmacodynamic properties of TSC at doses of 0.5, 1.0, 1.5, 2.0, or 2.5 mg/kg as an intravenous bolus. Thirty healthy adult subjects of 18 to 55 years of age were enrolled and allocated to one of the five dose groups or placebo. Venous blood samples were collected for pharmacokinetic evaluations of TSC at 1, 10, 30 minutes, and 1.5 hours after the start of injection of the study drug. Pharmacodynamic assessment of tissue oxygenation was performed while the subjects breathed supplemental oxygen at 6 L/minute for 70 minutes prior to study drug administration: the first 10 minutes was to allow for equilibration, and the subsequent 60 minutes served as a baseline period (Period 1), followed by a time-matched 60-minute intervention period (Period 2). Tissue oxygenation readings were obtained by transcutaneous oximetry (TcpO2) measurement using four TcpO2 sensors placed on the lower limbs of subjects lying in a supine or semi-recumbent position. TcpO2 values were recorded over a 2-hour time period: 60 minutes prior to study drug administration (Period 1) and 60 minutes post administration of the study drug (Period 2). ResultsTSC was safe and well tolerated at all doses tested. The pharmacokinetic analyses demonstrated that clearance decreased at escalating doses of TSC. The results of the primary pharmacodynamic analysis revealed high levels of variability in the 60-minute baseline TcpO2 levels, however despite such variability, time-matched TcpO2 measurements demonstrated observed increases in median TcpO2 values in subjects who received TSC, relative to those who received a placebo. The high variability observed across the four sensors suggested that the data could not be pooled across all four sensors, therefore, additional supplemental analyses were performed. The results of the supplemental analyses indicated that the TcpO2 intra-subject slopes of the TSC treatment groups were consistently positive during the study intervention period, and therefore suggestive of an increase in TcpO2 levels. This was not observed in the placebo group. Based on this analysis, all TSC dose groups had a greater increase in TcpO2 levels than the placebo group, with the 2.5 mg/kg dose demonstrating the most notable increase over the 1-hour intervention period (Period 2). ConclusionsTSC administered as a single IV bolus dose ranging from 0.5 mg/kg to 2.5 mg/kg to healthy subjects breathing supplemental oxygen, was safe and well tolerated. Pharmacokinetic assessments demonstrated that TSC plasma concentrations increased with escalating dose and that increasing TSC dose was associated with a decrease in clearance. The high levels of variability in TcpO2 levels did not allow for pooling of sensor measurements for primary analysis; however, supplemental analysis of individual sensor measurements demonstrated an observed dose effect of TSC on peripheral tissue oxygenation relative to placebo.

ObjectiveYouth with type 2 diabetes have higher metformin treatment failure rates when compared with adults. Our objectives were to develop a population pharmacokinetic (PK) model for metformin in youth to examine current dosing strategies and to quantify the relationship between metformin PK and obesity in youth with type 2 diabetes. Research Design and MethodsWe performed semi-intensive PK sampling in 50 youth less than 18 years with T2D on metformin. We measured metformin levels at pre-dose and at 1-2 and 3-6-hours after a supervised 1000 mg dose of immediate-release metformin. We used non-linear mixed effects modeling to develop a population PK model. Simulations were performed to estimate area under the 24-hour metformin concentration-time curve (AUC) values. ResultsMean age was 15.0 (standard deviation (SD) 1.6) years, 66% were male, mean body mass index (BMI), 35.9 (SD 6.8) kg/m2, and mean estimated glomerular filtration rate (eGFR), 114.7 (SD 22.6) mL/min/1.73m2. Estimated clearance increased by 3% (21.4% relative standard error (RSE)) for every 1 kg/m2 increase in body mass index (BMI), and by 6% (53.8% RSE) for every 10 mL/min/1.73m2 increase in eGFR. When comparing AUC estimates from our model with data from 236 adults on metformin, median AUC for youth was lower than for adults on 2,000 mg of metformin (18.47 mg*h/L vs. 27.49 mg*h/L). Simulations showed that in youth, higher doses of at least 2,550 mg and up to 3,000 mg daily were needed to achieve exposures similar to adults. ConclusionsObesity is associated with increased metformin clearance and reduced AUC in youth and higher doses are needed to achieve comparable drug exposure to adults.

The safety, tolerability, pharmacokinetics, age-related effects of single (SD) and repeat (RD) doses of CMS121, a novel small molecule fisetin derivative, were evaluated in healthy adult volunteers. The effects of food were also evaluated in healthy young adult subjects. SD of up to 1800 mg or RD up to 900 mg/day for 7 days was generally well tolerated, with the majority of TEAEs mild in severity. Generally, the pharmacokinetics of CMS121 and its metabolites were well characterized and increased in a dose-proportional or slightly greater than dose-proportional manner across the range of doses assessed. CMS121-C2 metabolite appears to contribute the most to the presence of the molar-equivalent CMS121 in plasma than the parent compound or the other metabolites (i.e. CMS121-C1 and CMS121-C3). Urinary excretion of CMS121 metabolites was minimal, implying urinary excretion may not be a major clearance route by which CMS121 is eliminated after oral dosing. There is a significant effect of age on the pharmacokinetics of CMS121 and its metabolites, with higher systemic exposures to CMS121 and its metabolites and longer terminal elimination half-lives in elderly subjects. Systemic exposures to CMS121 were higher in the fed state by approximately 50%.

IntroductionHealth information exchanges (HIEs) provide the capability to electronically move health care information among different health care information systems and store these data for downstream use cases. However, use of data from HIEs for postmarketing surveillance of medical products is not previously explored. ObjectivesTo conduct a pilot descriptive study characterizing data from MyHealth Access Network - a statewide HIE for Oklahoma, to understand its utility for conducting pharmacoepidemiology studies. Materials and methodsMyHealth Access Network connects 95% of all hospital activity, 100% of federally qualified health center activity, and most community behavioral health clinics, tribal health systems, and independent providers in the state. As a use case to understand data in MyHealth Access Network, we characterized patients with Type 2 Diabetes Mellitus (T2DM), aged 18 years or older and treated with one of two common antidiabetic drug classes: Sodium-Glucose Co-Transporter 2 inhibitors (SGLT-2i) and Dipeptidyl Peptidase 4 inhibitors (DPP-4i) in a new user cohort design. A cohort entry date was defined based on records of medication initiation for either of the two drug classes, using dispensing data from insurance claims (when available) or prescribing data from electronic health records (EHRs) when claims were not available. Patient characteristics including demographics, comorbidities, comedications, clinical and lifestyle related factors, and healthcare utilization factors were summarized for the two exposure groups. ResultsA total of 76,018 DPP-4i initiators and 101,599 SGLT-2i initiators met our inclusion criteria. The mean age was 59 years and nearly half were women in both the groups. While there was a large proportion of those with missing race information (32% DPP-4i, 24% SGLT-2i), a majority were White (47% DPP-4i, 57% SGLT-2i). The second most reported race category was American Indian or Alaskan Natives (13% DPP-4i, 9.9% SGLT-2i), which is in line with their representation in the 2024 US Census for Oklahoma. Hemoglobin A1c (HbA1c) results were available for 63% and 66% of the DPP-4i and SGLT-2i groups with mean + SD of 8.1+ 1.9% and 8.2 + 1.9%, respectively. Serum creatinine was recorded for 67% DPP-4i and 70% SGLT-2i initiators with mean + SD of 1.30 + 1.01 mg/dL and 1.14 + 0.64 mg/dL, respectively. DiscussionHIEs may offer a promising resource for population-based postmarketing surveillance of medical products owing to their comprehensive capture of information across various healthcare settings.

Background Plasma gelsolin (pGSN) is a non-immunosuppressive anti-inflammatory immunomodulator with demonstrated efficacy in animal models of acute lung injury. Its potential role in moderate-to-severe acute respiratory distress syndrome (ARDS) is currently under investigation. Methods We conducted a phase 1, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics of recombinant human pGSN (rhu-pGSN) following intravenous (IV) administration to healthy volunteers. Thirty-two participants were assigned to 4 sequentially ascending dose cohorts (6, 12, 18, 24 mg/kg of body weight) to receive five IV infusions of rhu-pGSN or saline placebo. Each cohort includes 8 subjects randomized 3:1 with rhu-pGSN or placebo. Doses were administered at 0 hours, 12 hours, 36 hours, 60 hours, and 84 hours. The primary outcome is the incidence and severity of clinical and laboratory AEs regardless of causality. Secondary outcomes include the pharmacokinetics of IV rhu-pGSN and the presence of anti-rhu-pGSN antibodies at Day 28. Results Overall, 10 subjects (41.7%) who received rhu-pGSN reported a total of 13 adverse events (AEs), and 1 subject (12.5%) who received placebo reported an AE. All AEs were mild or moderate. AEs in system organ classes that were reported by 2 or more subjects in either arm were skin and subcutaneous tissue disorders (12.5% rhu-pGSN; 0% placebo), gastrointestinal disorders (8.3% rhu-pGSN; 0% placebo), and nervous system disorders (12.5% rhu-pGSN; 12.5% placebo). No AEs by preferred term were reported by more than 1 subject in either arm. Three subjects (12.5%) experienced an AE assessed as related to study drug. No serious AEs occurred, and no AEs led to study discontinuation, dose interruption/reduction, or death. There were no apparent between-treatment differences in laboratory abnormalities, vital signs, or electrocardiogram findings. Conclusions Overall, in this study, IV rhu-pGSN (up to 24 mg/kg daily) appeared safe and well tolerated compared to placebo. The median half-life of rhu-pGSN exceeded 14 h across all dosing regimens, supporting once daily IV dosing in healthy subjects. Trial registration This study was registered with ClinicalTrials.gov on 2023-03-29 under the registration identifier NCT05789745.

Reports of metformin drug products contaminated with unacceptable levels of the probable human carcinogen N-Nitrosodimethylamine (NDMA) prompted a national sampling of post-market metformin drug products in early 2020. To broadly sample the United States market and minimize supply chain bias, metformin medication samples were crowdsourced directly from individuals across many states. 155 samples were received, and liquid chromatography-high resolution mass spectrometry tests for a panel of nitrosamines and N,N-Dimethylformamide (DMF) revealed significant levels of NDMA and DMF that relate to formulation. 49% of all medication samples contained detectable levels of NDMA and, when scaled to maximum daily tablet dose, 16% of all medication samples contained NDMA levels exceeding the United States Food and Drug Administration acceptable daily intake (ADI) limit. The highest NDMA detection from the tested samples was 748 ng per 500 mg tablet, which, when scaled to a common 2000 mg per day dosage regimen, is 31 times the ADI limit. The presence of N,N-Dimethylformamide (DMF) across 74% of the sampled metformin products is concerning given its same carcinogenicity categorization as NDMA and proposed role in formation of NDMA. Results underscore the need for continued surveillance of product quality, recalls of tainted medications, and investigation of metformin manufacturing practices.

Glucagon-like peptide-1 receptor agonists (GLP1RAs) are transformative therapies for diabetes and obesity, yet their long-term clinical effects are incompletely understood. To address this, we conducted a phenome-wide association study (PheWAS) to assess potential therapeutic and adverse effects of GLP1RAs using genetic drug proxies near the GLP1R locus. Fifteen variants associated with GLP1R expression in the Genotype-Tissue Expression (GTEx) project were tested against 1,204 phecodes in the Million Veteran Program (MVP, n = 464,626), with replication and meta-analysis within the UK Biobank (n = 449,349) and the Vanderbilt BioVU (n = 118,130). In the MVP, GLP1RA proxies showed expected metabolic benefits, including lower risk of type 2 diabetes (OR = 0.966, 95% CI [0.957-0.974], p = 4.55 x 10-14] and obesity (OR = 0.978, 95% CI [0.969-0.986], p = 6.94x10-7). Protective effects were also found for chronic venous insufficiency, obstructive sleep apnea, cancer of the esophagus, orthopnea, and diabetes complications (retinopathy, nephropathy, retinopathy). However, associations with mental health disorders were cohort-dependent (anxiety disorders in MVP OR = 1.02, 95% CI [1.012-1.0316], p = 1.07 x 10-5, BioVU OR = 0.960, 95% CI [0.938-0.981], p = 3.12 x 10-4). The results reinforce the therapeutic promise of GLP1RAs for metabolic diseases while underscoring the need for cautious monitoring of potential mental health effects.

Glucagon receptor-like peptide receptor agonists, GLP-1 RAs, are one of the most commonly used drugs for type-2 diabetes mellitus. The clinical guidelines recommend GLP-1 RAs as adjunct to diabetes therapy in patients with chronic kidney disease, presence or risk of atherosclerotic cardiovascular disease, obesity, and other cardiometabolic conditions. The weight loss seen in clinical trials has been explored further in healthy individuals, putting GLP-1 RAs on track to be the next weight loss treatment. Although the adverse event profile is relatively safe, most GLP-1 RAs come with a labeled black boxed warning of the risk of thyroid cancers, based on animal models and some postmarketing case reports in humans. Considering the increasing popularity of this drug class and its expansion into a new popular indication, a further review of most recent postmarketing safety data is warranted to quantify thyroid hyperplasia and neoplasms instances. In this study we analyzed over eighteen million reports from United States Food and Drug Administration Adverse Event Reporting System and identified 17,653 relevant GLP-1 RA monotherapy reports to provide the evidence of significantly increased propensity for thyroid hyperplasias and neoplasms in patients taking GLP-1 RA as monotherapy when compared to patients taking sodium-glucose cotransporter-2 inhibitor monotherapy.

Guideline-based combination therapy (GBT) achieves sputum culture conversion rates in 23-34% of patients with Mycobacterium abscessus complex (MAB) lung disease (LD). Thus, new therapies are needed. We performed a systematic review to validate and benchmark the hollow fiber system model of MAB-LD (HFS-MAB) for drug development. We performed a literature search to identify all published HFS-MAB pharmacokinetics (PK)-pharmacodynamics (PD) studies. Preferred Reporting Items for Systematic Reviews and Meta-Analyses was used for bias minimization. A total of 12 studies were identified. The average quality score was 13.7 out of 21. Eight were monotherapy (exposure-effect and dose-fractionation), one-double {beta}-lactam, and three GBT studies. For omadacycline and imipenem, HFS-MAB data was accompanied by clinical real-world evidence confirming HFS-MAB findings. Monotherapy or combination therapy microbial kill was always terminated by antimicrobial resistance. We used quantitative analyses to rank drugs efficacy. The three highest-ranked drugs based cfu/mL fold-kill compared to multi-drug GBT, were sulbactam-durlobactam (177-fold), epetraborole (15-fold), and omadacycline (7-fold). We used the PK/PD target exposures identified by studies in the systematic analysis in Monte Carlo experiments (MCE) to identify optimal doses for inhaled formulations. The optimal inhalational dose of imipenem/cilastatin was 250 mg/day, for tigecycline 4 mg/day, for cefoxitin 50 mg/day, and for amikacin liposome inhalation suspension 590mg once weekly. The HFS-MAB is tractable for exposure-effect, dose-fractionation, and factorial design combination studies. It can be used to rank drugs and inform on which drugs to test in novel combinations. The HFS-MAB fulfills the US Food and Drug Administration Roadmap definition of non-animal New Approach Methodologies.

Tacrolimus is the cornerstone of immunosuppressive therapy after pediatric liver transplantation. However, reliance on the physicians experience for dose titration, coupled with tacrolimuss narrow therapeutic window and inter and intra-patient variability, often results in frequent under or over-dosing with detrimental patient outcomes. Existing predictive dose personalization models are not readily feasible for clinical implementation, as they require multiple measurements each day while the standard frequency is once daily. We developed CURATE.AI, a small-data artificial intelligence-derived platform, as a clinical decision support system to personalize doses using the patients own data obtained once a day. Retrospective dose personalization with CURATE.AI on 16 patients data demonstrated potential to enable patients to stay in the therapeutic range longer and reach the therapeutic range significantly earlier. Our findings support the testing of CURATE.AI in a prospective controlled trial as an aid for the physicians decision on tacrolimus dose personalization after pediatric liver transplantation.

BackgroundSickle Cell Disease (SCD) remains a globally important disorder with limited therapeutic options. This study utilizes the advanced capabilities of the DeepNEU(C) platform v8.2 and aiHumanoid (Pat. Pend.) simulations to evaluate potential drug combinations for treating SCD, focusing on vaso-occlusive events (VOE) and associated secondary outcomes. MethodsUsing data from 25 virtual patients in each of six treatment groups, therapeutic responses to each treatment were investigated. The study evaluated the primary outcome of VOE and secondary outcomes, including HbA, HbF, Quality of Life (QoL), RBC hemolysis, and Pain. Treatment toxicities were also assessed across all dosage levels. ResultsThe combination of Endari (L-glutamine powder) plus Crizanlizumab (a P-selectin antibody) demonstrated superior efficacy, with significant improvements in primary and secondary endpoints. This regimen, along with Voxelotor (a hemoglobin S polymerization inhibitor) plus Crizanlizumab, showed promising reductions in VOE, RBC hemolysis, and enhanced QoL scores. Notably, these results align with existing literature emphasizing the benefits of combination therapies in SCD management. Furthermore, aiHumanoid simulations indicated that these treatment combinations present lower cumulative multi-organoid toxicity, potentially translating to better patient outcomes and reduced healthcare costs. ConclusionAI-driven virtual clinical trials offer an innovative approach in evaluating drug combinations, presenting a robust case for the efficacy of Endari plus Crizanlizumab in managing SCD. The results warrant further research and real-world trials, potentially reshaping clinical guidelines for SCD treatment.

PurposeUp to 80% of patients undergoing taxanes or platinum-based chemotherapy (CT) develop a disturbing peripheral polyneuropathy referred to as CIPN, that affects their treatment compliance to CT and long-term quality of life (QoL). Cumulative evidence shows that taxanes and platinum agents sensitize epidermal nociceptive terminals by potentiating the activity of nociceptor thermosensitive channels. Our aim was to evaluate the efficacy and safety of a non-pharmacological nociceutical formulation acting on epidermal nociceptive endings preventing, delaying and/or lessening CIPN sensory symptoms during CT. MethodsWe designed a proof-of-concept, double-blind, randomized, two-arms multicenter clinical study (NCT06733545). Participants started a daily topical application of the assigned formulation in hands (moisturizing or nociceutical). Upon appearance of neuropathic symptoms in hands and/or feet, they applied the creams twice daily in hands and feet. Diagnosis and follow up of CIPN grade and adverse effects were conducted by study investigators, as well as a QoL questionnaire. ResultsA cohort of 142 patients treated with taxanes and/or platinum agents were randomly assigned to the two groups. Withdrawals were similar in both arms (9 and 14), leading to a balanced number of patients per group (61 moisturizing vs 58 nociceutical). Overall, a similar number of participants developed a peripheral neuropathy in both arms (73% moisturizing vs 67% nociceutical, p=0.1). A lower CIPN incidence in hands was observed in the nociceutical arm (32% vs 13%, p=0.03). Furthermore, the nociceutical formulation delayed the appearance of neuropathic symptoms as compared to the moisturizing cream (6 vs 8 cycle, p=0.009). The Leonard scale questionnaire revealed that the nociceutical formulation attenuated the severity of patients neuropathic symptoms from extremely to hardly any (58% vs. 35%, p<0.0017), increasing patient QoL. ConclusionThis pilot study suggests that topical protection of nociceptive epidermal terminals with a topical nociceutical formulation reduced the incidence of CIPN in hands, delayed its onset and increased the QoL of patients. These findings provide solid evidence for a larger, confirmatory clinical study.

Metabolomics is an emerging and powerful molecular profiling method supporting clinical investigations. For clinical metabolomics studies, serum is commonly used. Serum is collected after blood coagulation, a complex biochemical process involving active platelet metabolism. This may proof relevant as platelet counts and function may vary substantially in individuals. Applying a multi-omics analysis strategy comprising proteins and metabolites with a focus on lipid mediators, we systematically investigated serum and plasma obtained from the same healthy donors. While Biocrates MxP Quant 500 results correlated well (n=461, R2=0.991), lipid mediators (n=77, R2=0.906) and proteins (n=322, R2=0.860) differed substantially between serum and plasma. Actually, secretome analysis of activated platelets identified all proteins and most lipid mediators significantly enriched in serum when compared to plasma. Furthermore, a prospective, randomized, controlled parallel group metabolomics trial was performed, monitored by serum and plasma analyses. Healthy individuals received either acetylsalicylic acid, affecting platelets, or omega-3 fatty acids, hardly affecting platelets, for a period of seven days. In the acetylsalicylic acid group, serum analysis apparently demonstrated a significant drug-induced downregulation of the lipid mediators TXB2 and 12-HETE. The absence of these observation in plasma analyses suggested that these drug effects took place only during blood coagulation. Other effects of acetylsalicylic acid on alpha-linolenic acid and the fatty acid composition of triglycerides were detected both in serum and plasma. In the omega-3 fatty acid group, serum and plasma analysis results did not differ. These data strongly support the hypothesis that the serum metabolome is substantially confounded by platelets. Key pointsO_LISerum metabolomics data are confounded by platelets C_LIO_LIClinical evaluation of drug effects should be based on plasma metabolomics C_LI

In the management of atrial fibrillation, the most frequently prescribed oral anticoagulant is apixaban, given at a fixed dose of 5mg BID. Apixaban is predominantly metabolized by cytochrome P4503A4 (CYP3A4) and is also a substrate for the drug efflux transporter P-glycoprotein (P-gp). In nearly 300,000 Medicare patients with AF receiving apixaban, we previously showed that concomitant therapy with drugs that inhibit both CYP3A4 and P-gp, specifically amiodarone or diltiazem, significantly increased serious bleeding that caused hospitalization and/or death. We hypothesized that this adverse effect was mediated by an increase in apixaban plasma concentrations caused by concomitant therapy that reduced drug elimination. Utilizing left-over samples obtained from clinically indicated blood draws that would typically be discarded, the Vanderbilt University Medical Center biobank BioVU contains >353,000 samples linked to de-identified electronic medical records (EMRs), with both DNA and plasma harvested. Of 35 samples drawn from patients taking apixaban 5mg BID, 5 were identified to be drawn from patients concomitantly taking drugs inhibiting both CYP3A4 and P-gp. Using a chromogenic anti-Xa assay, we found that plasma concentrations of apixaban were significantly higher (347{+/-}64 ng/mL; mean{+/-}SEM) for patients receiving concomitant CYP3A4/P-gp-inhibiting drugs compared to those not treated with these drugs (166{+/-}67 ng/mL; P=0.025, Mann Whitney). There were no differences between the 2 patient groups with respect to age, weight, or serum creatinine. The results of this pilot study provide preliminary data to support our hypothesis, and they demonstrate the practicality of obtaining pharmacokinetic data from a large cohort of plasma samples linked to deidentified EMRs. This approach could be used to define the role of apixaban levels in high-risk clinical scenarios and to better understand the relationship between drug levels and bleeding risk.

ObjectiveTo establish an optimized sotalol dosing strategy for fetal tachycardia by using a pregnancy computational model for dose simulations. MethodsA physiologically-based computational model, including pregnancy-related changes and placental transfer values, was established and verified. Simulations of the current dosing advises and prospective dosing scenarios were performed. To avoid maternal dose-related toxicity (QT-prolongation) we aimed for maternal concentrations <2.5 mg/L. Based on neonatal concentration-effect data, we aimed for a fetal Ctrough concentrations of 0.4 - 1.0 mg/L. ResultsThe pregnancy physiologically-based pharmacokinetic model accurately predicted maternal and fetal exposures. Predictions indicate that almost 16% of maternal plasma concentrations exceed the toxic level of 2.5 mg/L at the maximum oral daily dose of 480 milligram, while 90% of fetuses have a Ctrough concentration within the therapeutic window. When lowering the maximum daily dose to 400 mg, 0.1% of maternal plasma concentrations exceed 2.5 mg/L, while 87% of the fetal plasma concentrations remain in the therapeutic window. Additionally dosing 480 mg in three times daily reduces the risk of high maternal plasma exposure to 0.3%, while maintaining effective fetal Ctrough concentrations in 95% of fetuses. ConclusionPregnancy computational modeling can be used to adequately predict maternal and fetal sotalol exposures. Our simulations suggest that daily doses should not exceed 400 milligram and that dividing the oral daily dose over three doses improves the balance between high maternal plasma exposure and effective fetal concentrations. FundingThis publication is based on research funded by the Bill & Melinda Gates Foundation (INV-023795).

Glucagon/glucagon-like peptide-1 (GLP-1) receptor co-agonists may provide greater weight loss than agonists targeting the GLP-1 receptor alone. We report results from three phase 1 trials investigating the glucagon/GLP-1 receptor co-agonist NNC9204-1177 (NN1177) for once-weekly subcutaneous use in adults with overweight or obesity. Our focus was a 12-week multiple ascending dose (MAD), placebo-controlled, double-blind trial in which adults (N=99) received NN1177 (dose-escalated to treatment doses of 200, 600, 1,300, 1,900, 2,800, 4,200, and 6,000 g) or placebo. Two other trials also contribute to the findings in this report: a first human dose (FHD) / single ascending dose (SAD), placebo-controlled, double-blind trial in which adults (N=49) received NN1177 (treatment doses of 10, 40, 120, 350, 700 and 1,100 g) or placebo, and a drug-drug interaction (DDI), open-label, single-sequence trial in which adults (N=45) received a 4,200 g dose of NN1177. Pharmacokinetic, safety and tolerability, and pharmacodynamic endpoints were assessed. For the MAD and FHD/SAD trials, baseline characteristics were generally balanced across groups. The half-life of NN1177 was estimated at between 77.3 and 111 hours. NN1177 appeared tolerable across trials; however, a number of safety concerns were observed, including an increase in heart rate (range 5-22 beats per minute) and decrease in reticulocyte count, which were both dose dependent, and increased markers of inflammation (fibrinogen and C-reactive protein), hepatic disturbances (increased aspartate aminotransferase and alanine aminotransferase), impaired glucose tolerance (dose groups 2,800-6,000 ug) and reduced blood levels of some amino acids. Clinically relevant weight loss was achieved (up to 12.6% at week 12; 4,200 ug in the MAD trial), but this was not accompanied by cardiometabolic improvements. In conclusion, although treatment with NN1177 was associated with dose-dependent and clinically relevant weight loss, unacceptable safety concerns precluded further clinical development.

ObjectiveTo investigate the effects of sodium fructose diphosphate (FDP) on blood coagulation parameters, including reaction time and plasma coagulation factor activity, in both in vitro and in vivo models. MethodsThree thromboelastography systems (Maiketian, Lepu, Dingrun) were used to assess coagulation parameters (reaction time [R], clotting time [K], -angle, maximal amplitude [MA]) in blood samples spiked with varying FDP concentrations. An automatic coagulation analyzer quantified the activities of coagulation factors II, V, VII, VIII, IX, X, XI, and XII in FDP-treated plasma.Differences between FDP-treated and control groups were statistically compared. Linear regression analyzed correlations between FDP concentrations and coagulation parameters. For in vivo studies, New Zealand white rabbits received intravenous FDP (0.5, 1, 2, or 4 g/kg), and thromboelastography parameters were monitored at multiple time points post-administration (0.5-2 hours). ResultsThromboelastography demonstrated a strong positive correlation between FDP concentration and R values across all systems (P < 0.001; r = 0.988 [Maiketian], 0.999 [Lepu], 0.996 [Dingrun]). No significant associations were observed between FDP and K, -angle, or MA (P > 0.05). In vitro experiments revealed significant negative correlations between FDP concentration and activities of factors V (r = -0.995), VII (r = -0.990), IX (r = -0.989), XI (r = -0.997), and XII (r = -0.995) (P < 0.001), while factors II, VIII, and X remained unaffected (P > 0.05). In vivo administration demonstrated dose-dependent prolongation of R-time, reaching statistical significance (p < 0.05) at:0.5 g/kg: 0.5 hr post-dose,1 g/kg: 0.5-1.5 hr,2 g/kg: 0.5-1.5 hr,4 g/kg: 0.5-2 hr. ConclusionFDP significantly impacts coagulation testing outcomes both in vitro and in vivo, potentially through modulation of intrinsic pathway factors (V, VII, IX, XI, XII) and direct interference with clot initiation. These findings suggest clinically relevant anticoagulant properties that warrant further investigation.