Total AUC Research Articles

Pharmacokinetics, disposition, and biotransformation of the cardiac myosin inhibitor aficamten in humans.

Aficamten, a cardiac myosin inhibitor, is being developed for the treatment of patients with symptomatic hypertrophic cardiomyopathy (HCM). The purpose of this study was to determine the absorption, metabolism, and excretion of aficamten. Eight healthy male participants received a single oral dose of 20 mg aficamten (containing approximately 100 μCi of radiocarbon). Blood, urine, and feces samples were collected up to a maximum of Day 26. The pharmacokinetics of aficamten were characterized by moderate absorption, with a median tmax of 2.0 h postdose. The median t1/2 of aficamten was 99.6 h with similar t1/2 observed for metabolites and total radioactivity in plasma and whole blood. The overall total recovery of administered total radioactivity was 89.7% with 57.7% of the dose recovered in feces and 32.0% in urine. The main circulating metabolites in plasma included monohydroxylated metabolites M1a (CK-3834282) and M1b (CK-3834283) accounting for 10.5% and 36.4% of the total radioactivity AUC both with a median tmax of 5 h. The other major plasma metabolite was M5 (an oxygen-linked glucuronide conjugate of M1a), which accounted for 10.3% of the total plasma radioactivity exposure, with a tmax of 24 h. In urine, M5 was the most abundant metabolite with 8.02% total radioactive dose (TRD), followed by M1a and M1b with 6.16% and 2.85% TRD, respectively; however, there were no metabolites in urine observed at >10% of dose. The major metabolite in feces was M18 representing 44.1% of the radioactive dose. These findings indicated that aficamten was eliminated by metabolism, and to a minor extent, by fecal excretion of unchanged aficamten with renal excretion playing a minor role. Feces were the principal route of excretion of the radioactive dose.

PBPK modeling of recombinant factor IX Fc fusion protein (rFIXFc) and rFIX to characterize the binding to type 4 collagen in the extravascular space.

Patients with severe and sometimes moderate hemophilia B are prophylactically treated with factor IX concentrates to prevent bleeding. For some time now, various extended terminal half-life (EHL) recombinant factor IX concentrates are available allowing less frequent administration during prophylaxis in comparison to standard half-life recombinant FIX (rFIX). Especially, recombinant FIX-Fc fusion protein (rFIXFc; Alprolix®) exhibits a rapid distribution phase, potentially due to binding to type IV collagen (Col4) in the extravascular space. Studies suggest that the presence of extravascular rFIXFc is protective against bleeding as without measurable FIX activity in plasma, and no extra bleeding seems to occur. The physiologically based pharmacokinetic (PBPK) model for rFIXFc which we describe in this study, is able to accurately predict the observed concentration-time profiles of rFIXFc in plasma and is able to quantify the binding of rFIXFc to Col4 in the extravascular space after an intravenous dose of 50 IU/kg rFIXFc in a male population. Our model predicts that the total AUC of rFIXFc bound to Col4 in the extravascular space is approximately 19 times higher compared to the AUC of rFIXFc in plasma. This suggests that rFIXFc present in the extravascular compartment may play an important role in achieving hemostasis after rFIXFc administration. Further studies on extravascular distribution of rFIXFc and the distribution profile of other EHL-FIX concentrates are needed to evaluate the predictions of our PBPK model and to investigate its clinical relevance.

Bioequivalence of Elagolix/Estradiol/Norethindrone Acetate Fixed-Dose Combination Product: Phase 1 Results in Healthy Pre- and Postmenopausal Women.

Fixed-dose combination (FDC) therapies can enhance patient convenience and adherence to prescribed treatment regimens. Elagolix is a novel oral gonadotropin-releasing hormone receptor antagonist approved for management of moderate to severe pain associated with endometriosis and heavy menstrual bleeding associated with uterine fibroids. Hormonal add-back therapy can attenuate the reversible hypoestrogenic effects of elagolix. An FDC formulation containing elagolix/estradiol (E2)/norethindrone acetate (NETA) 300/1/0.5mg as the morning dose and an elagolix 300mg capsule as the evening dose, were evaluated in 2 bioequivalence studies including the effects of food. Study 1 in premenopausal women assessed the bioavailability of the elagolix 300-mg capsule relative to the commercially available elagolix 300-mg tablet. Study 2 in postmenopausal women, elagolix/E2/NETA (300mg/1mg/0.5mg) FDC capsule was assessed relative to the elagolix 300-mg tablet coadministered with E2/NETA 1-mg/0.5-mg tablet, the regimen that was studied in Phase 3 uterine fibroid studies. Under fasting conditions, the test elagolix 300-mg capsule was bioequivalent to the reference elagolix 300-mg tablet. Under fasting conditions, the elagolix/E2/NETA FDC capsule was bioequivalent to the coadministered elagolix 300-mg tablet and E2/NETA 1/0.5-mg tablet. Following administration of elagolix/E2/NETA FDC capsule after a high-fat breakfast, elagolix mean maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) were 38% and 28% lower, relative to fasting conditions. NETA mean Cmax was 51% lower and AUC from time 0 to infinity was 20% higher, while baseline-adjusted total estrone mean Cmax and AUC were 46% and 14% lower, respectively. No safety concerns were identified. These results enabled bridging the elagolix/E2/NETA FDC capsule.

Insulin Secretion Defect in Children and Adolescents with Obesity: Clinical and Molecular Genetic Characterization.

Childhood obesity is increasing worldwide and presents as a global health issue due to multiple metabolic comorbidities. About 1% of adolescents with obesity develop type 2 diabetes (T2D); however, little is known about the genetic and pathophysiological background at young age. The objective of this study was to assess the prevalence of impaired glucose regulation (IGR) in a large cohort of children and adolescents with obesity and to characterize insulin sensitivity and insulin secretion. We also wanted to investigate adolescents with insulin secretion disorder more closely and analyze possible candidate genes of diabetes in a subcohort. We included children and adolescents with obesity who completed an oral glucose tolerance test (OGTT, glucose + insulin) in the outpatient clinic. We calculated Matsuda index, the area under the curve (AUC (Ins/Glu)), and an oral disposition index (ISSI-2) to estimate insulin resistance and beta-cell function. We identified patients with IGR and low insulin secretion (maximum insulin during OGTT < 200 mU/l) and tested a subgroup using next generation sequencing to identify possible mutations in 103 candidate genes. The total group consisted of 903 children and adolescents with obesity. 4.5% showed impaired fasting glucose, 9.4% impaired glucose tolerance, and 1.2% T2D. Matsuda index and Total AUC (Ins/Glu) showed a hyperbolic relationship. Out of 39 patients with low insulin secretion, we performed genetic testing on 12 patients. We found five monogenetic defects (ABCC8 (n = 3), GCK (n = 1), and GLI2/PTF1A (n = 1)). Using surrogate parameters of beta-cell function and insulin resistance can help identify patients with insulin secretion disorder. A prevalence of 40% mutations of known diabetes genes in the subgroup with low insulin secretion suggests that at least 1.7% of patients with adolescent obesity have monogenic diabetes. A successful molecular genetic diagnosis can help to improve individual therapy.

A composite entropy-based uncertainty measure guided attribute reduction for imbalanced mixed-type data

In real-world scenarios, datasets generally exhibit containing mixed-type of attributes and imbalanced classes distribution, and the minority classes in the data are the primary research focus. Attribute reduction is a key step in the data preprocessing process, but traditional attribute reduction methods commonly overlook the significance of minority class samples, causing the critical information possessed in minority class samples to damage and decrease the performance of classification. In order to address this issue, we develop an attribute reduction algorithm based on a composite entropy-based uncertainty measure to handle imbalanced mixed-type data. To begin with, we design a novel oversampling method based on the three-way decisions boundary region to synthesize the samples of minority class, for the boundary region to contain more high-quality samples. Then, we propose an attribute measure to select candidate attributes, which considers the boundary entropy, degree of dependency and weight of classes. On this basis, a composite entropy-based uncertainty measure guided attribute reduction algorithm is developed to select the attribute subset for the imbalanced mixed-type data. Experimental on UCI imbalanced datasets, as well as the results indicate that the developed attribute reduction algorithm is significantly outperforms compared to other attribute reduction algorithms, especially in total AUC, F1-Score and G-Mean.

Association of GLP-1 secretion with parameters of glycemic control in women after gestational diabetes mellitus

IntroductionWomen with a history of gestational diabetes mellitus (GDM) are at high risk of developing type 2 diabetes, while the exact mechanisms underlying its pathophysiology are still unclear. We investigated...

Cross-species drug metabolism and impact of metabolic stability testing under anaerobic condition on predicting pharmacokinetics of keto-enol containing compound in humans

After oral administration of [14C]-S-1360 in rats and dogs, [14C]-S-1360 was absorbed rapidly and the bioavailability was 93.7% in rats and 75.1% in dogs. Based on the results in animals, good systemic exposure would be expected in humans. In contrast to the expectation, the exposure was low in healthy volunteers compared to the exposure expected. In addition, human mass balance study using [14C]-S1360 revealed that a large amount of metabolites existed in human plasma. The major metabolites in human plasma were reduced metabolite (HP1) and S-1360 N-glucuronide, and they respectively accounted for approximately 30% of total AUC. Unchanged S-1360 accounted for only 14% of total AUC. The results showed that a significant difference between humans and animals were observed in metabolism of S-1360. Although S-1360 was stable in human hepatocytes under aerobic condition (approximately 84% remaining at 1 h), S-1360 was labile under anaerobic condition (approximately 55% remaining at 1 h). The present study revealed that the reductive metabolism pathways are the key metabolic pathway of S-1360, especially the metabolic stability test under anaerobic condition is important to predict pharmacokinetics of keto-enol containing compound, such as S-1360.

Preclinical safety, toxicokinetics and metabolism of BIIB131, a novel prothrombolytic agent for acute stroke

BIIB131, a small molecule, is currently in Phase 2 for the treatment of acute ischemic stroke. Safety and metabolism of BIIB131 were evaluated following intravenous administration to rats and monkeys. Exposure increased dose-proportionally in rats up to 60 mg/kg and more than dose-proportionally in monkeys at greater than 10 mg/kg accompanied by prolonged half-life and safety findings. The BIIB131 was poorly metabolized in microsomes with no inhibition of CYPs. BIIB131-glucuronide, formed by UGT1A1, accounted for 21.5% metabolism in human hepatocytes and 28–40% in rat bile. In rats, excretion was primarily via the bile. BIIB131 inhibited the hERG and Nav1.5 cardiac channels by 39% but showed no effect on cardiovascular parameters in monkeys. Toxicology findings were limited to reversable hematuria, changes in urinary parameters and local effects. A MTD of 30 mg/kg was established in monkeys, the most sensitive species, at total plasma Cmax and AUC of 6- and 14-fold, respectively, greater than the NOAEL. The Phase 1 study started with intravenous 0.05 mg/kg and ascended to 6.0 mg/kg which corresponded to safety margins of 147- to 0.9-fold (for Cmax) within the linear drug exposure. Thus, the preclinical profile of BIIB131 has been appropriately characterized and supports its further clinical development.

Higher energy flux may improve short-term appetite control in adolescents with obesity: the NEXT study.

Recent evidence suggests better appetite control in states of high-energy flux (HEF) in adults and lean children. Nevertheless, it is unknown whether this extends to youth with obesity. This study compares the effects of low, moderate or HEF on short-term appetitive control in adolescents with obesity. Sixteen adolescents with obesity (12-16 years, Tanner stages 3-5, 11 females) randomly completed three conditions: (i) low-energy flux (LEF); (ii) moderate energy flux (MEF; + 250 kcal) and (iii) HEF (HEF; + 500 kcal). Energy flux was achieved in MEF and HEF through elevated energy intake (EI) and concomitant increase in energy expenditure using cycling exercise (65 % VO2peak). Ad libitum EI, macronutrient intake and relative EI were assessed at dinner, subjective appetite sensations taken at regular intervals and food reward measured before dinner. Ad libitum EI at dinner was greater in LEF compared with HEF (P = 0·008), and relative EI (REI) was higher in LEF compared with MEF (P = 0·003) and HEF (P < 0·001). The absolute consumption of carbohydrates was lower in LEF compared with MEF (P = 0·047) and HEF (P < 0·001). Total AUC for hunger and desire to eat was lower in HEF compared with LEF (P < 0·001) and MEF (P = 0·038). Total AUC for prospective food consumption was lower on HEF compared with LEF (P = 0·004). Food choice sweet bias was higher in HEF (P = 0·005) compared with LEF. To conclude, increasing energy flux may improve short-term appetite control in adolescents with obesity.

Relationship between Pharmacokinetic Profile and Clinical Efficacy Data of Three Different Forms of Locally Applied Flurbiprofen in the Mouth/Throat.

This study aimed to link pharmacokinetic (PK) data from different flurbiprofen preparations for the treatment of sore throat with published data to elucidate whether early efficacy is due to the local action of flurbiprofen or a systemic effect after absorption of the swallowed drug. Three comparative bioavailability studies conducted in healthy subjects provided data from flurbiprofen 8.75 mg formulations, including spray solution, spray gel, lozenges, and granules. A parallel interstudy comparison was made of PK parameters, including partial AUCs (pAUCs), using an ANOVA model with the calculation of 90% confidence intervals (CI) for the differences between least squares (LS) means for each of the test groups versus the respective reference groups. All three studies showed bioequivalence for the respective product comparisons. The interstudy comparison showed a slower rate of absorption for granules compared to spray solution (reference) based on Tmax, Cmax, and pAUCs for 1 h and 2 h. When AUC0.25h and AUC0.5h were considered, slower rates of absorption were also seen for lozenges and spray gel. The differences correlated with the reported time of onset of action, which is faster for the spray solution (20 min) compared to lozenges (26 min) and granules (30 min). These pAUCs provide useful data that allow for the discrimination between formulations. Moreover, the pAUC values represent <5% of the total AUC, suggesting that the early onset of pain relief is a response to immediate local absorption at the site of action rather than a systemic effect.

Metabolism and Disposition of the Novel Oral Factor XIa Inhibitor Asundexian in Rats and in Humans.

Current anticoagulants pose an increased risk of bleeding. The development of drugs targeting factor XIa, like asundexian, may provide a safer treatment option. A human mass‑balance study was conducted to gain a deeper understanding of the absorption, distribution, metabolism, excretion, and potential for drug-drug interaction of asundexian. Additionally, an overview of the biotransformation and clearance pathways for asundexian in humans and bile-duct cannulated (BDC) rats in vivo, as well as in vitro in hepatocytes of both species, is reported. The mass balance, biotransformation, and excretion pathways of asundexian were investigated in six healthy volunteers (single oral dose of 25 mg [14C]asundexian) and in BDC rats (intravenous [14C]asundexian 1 mg/kg). Overall recovery of radioactivity was 101% for humans (samples collected up to 14 days after dosing), and 97.9% for BDC rats (samples collected in the 24 h after dosing). Radioactivity was mainly excreted into feces in humans (80.3%) and into bile/feces in BDC rats (> 94%). The predominant clearance pathways in humans were amide hydrolysis to metabolite M1 (47%) and non-labeled M9 with subsequent N-acetylation to M10; oxidative biotransformation was a minor pathway (13%). In rats, hydrolysis of the terminal amide to M2 was the predominant pathway. In human plasma, asundexian accounted for 61.0% of total drug-related area under the plasma concentration-time curve (AUC); M10 was the major metabolite (16.4% of the total drug-related AUC). Excretion of unmetabolized drug was a significant clearance pathway in both species (human, ~ 37%; BDC rat, ~ 24%). The near-complete bioavailability of asundexian suggests negligible limitations on absorption and first-pass metabolism. Comparison with radiochromatograms from incubations with human or rat hepatocytes indicated consistency across species and a good overall in vitro/in vivo correlation. Similar to preclinical experiments, total asundexian-derived radioactivity is cleared quantitatively predominantly via feces. Excretion occurs mainly via amide hydrolysis and as the unchanged drug.

190-LB: Differences in Postprandial and Counterregulatory Glucagon Excursions in Healthy Relatives to Type 1 Diabetes with Different Number of Islet Autoantibodies

Background and aims: Early changes in glucagon during the progression to type 1 diabetes (T1D) are not well understood. We investigate whether the glucagon responses to a mixed meal and hypoglycemia depend on the number of islet autoantibodies (Ab) in individuals at risk for T1D. Methods: Sixty healthy relatives of T1D with mean±SD age of 23.7±10.7 years, HbA1c of 5.3±0.3%, and BMI of 23.8±5.6 kg/m2 and zero (N=21), one (N=18), and ≥2 (N=21) Ab, were enrolled in an ancillary study from the NIH-funded TrialNet Pathway to Prevention study. Participants underwent a clinical test consisting of a mixed meal tolerance test (MMTT) followed by insulin-induced hypoglycemia. Glucagon was measured from -30 to 120 min around the MMTT and 0 to 40 min during hypoglycemia to estimate the Ab group differences in the meal and counter-regulatory glucagon responses assessed via the glucagon incremental area under the curve (iAUC). Results: There were significant differences in the net iAUC of the glucagon responses to the MMTT (p=0.024), while the group difference in the glucagon counter-regulation estimated via the total AUC approached significance (p=0.08). Conclusion: The study suggests that the glucagon responses to a meal and possibly, hypoglycemia, may be altered during the very early stages of the progression to T1D. Disclosure T. Igbe: None. E. Montaser: None. M. D. Breton: Consultant; Dexcom, Inc. Research Support; Dexcom, Inc. Consultant; Tandem Diabetes Care, Inc. Research Support; Tandem Diabetes Care, Inc., Novo Nordisk. Consultant; Roche Diabetes Care, Sanofi, Arecor. S. A. Brown: Research Support; Dexcom, Inc., Insulet Corporation, Tandem Diabetes Care, Inc. M. D. DeBoer: Research Support; Dexcom, Inc., Tandem Diabetes Care, Inc. A. L. McCall: None. B. Kovatchev: Speaker's Bureau; Tandem Diabetes Care, Inc. Research Support; Dexcom, Inc., Novo Nordisk, Tandem Diabetes Care, Inc. Other Relationship; Dexcom, Inc., Johnson &amp; Johnson Medical Devices Companies, Novo Nordisk, Sanofi. L. Farhy: Research Support; Dexcom, Inc., Novo Nordisk. Funding National Institute of Diabetes and Digestive and Kidney Diseases (DP3DK106907); Commonwealth Research Commercialization Fund (MF20-007-LS); The Leona M. and Harry B. Helmsley Charitable Trust (2204-05134); JDRF (2-SRA-2022-1260-S-B)

Busulfan, melphalan, and carfilzomib (BuMelCar) conditioning for autologous stem cell transplant (ASCT) in multiple myeloma: Phase I/II data.

8021 Background: Melphalan-200 high dose chemotherapy for ASCT has been the standard of care for multiple myeloma (MM) for over 30 years. Newer combination regimens such as Busulfan and Melphalan (BuMel) have demonstrated improved progression free survival (PFS) but with increased transplant related morbidity including mucositis and infections. Our group previously demonstrated that adding a proteasome inhibitor (bortezomib) to BuMel further increased PFS with mucositis ameliorated by Palifermin. Building on this effectiveness, we added carfilzomib to the BuMel backbone in a Phase I/II manner focused on safety and initial effectiveness of this novel regimen. Methods: This phase I/II open-label dose-escalation/expansion study (NCT03795597) enrolled patients with relapsed or high risk first remission MM. Patients received Busulfan over 4 days at a target total AUC of 20,000 mM-min followed by melphalan at 140mg/m2. Patients received 4 total doses of IV carfilzomib, 2 before melphalan and 2 after, with the final 2 doses escalated based on toxicity. Palifermin was given on days -11,-10, 0, and +1. Once MTD was determined, 10 more patients were treated at that level. Primary objective was safety and secondary outcomes were response to treatment at day 100 including MRD, engraftment kinetics, PFS, and OS. Results: Patients were predominantly male (79%) with median age 60.95 years. Median KPS was 80 and median HCT-CI was 2. The carfilzomib MTD was 36 mg/m2. One SAE of grade V ischemic colitis was seen at the 45 mg/m2 dose level. Toxicity at 36 mg/m2 yielded a similar pattern to our prior bortezemib containing regimen with grade 1 NSVT in 2 patients and hypertension in another. With a median follow up of 22 months, only 1 of the 13 MTD patients has progressed at 33mo. 2-year PFS and OS are both 100%. Analysis at D+100 showed 69% of MTD patients were MRD negative regardless of genetics. Conclusions: This novel BuMelCar ASCT regimen is safe and tolerable and appears to lead to a high % of MRD negative disease at D+100, which other studies correlate to a high PFS at 2 years. A comparison study with mel 200 is warranted to test whether BuMelCar can improve transplant outcomes especially in high-risk patients. Clinical trial information: NCT03795597 . [Table: see text]

Effects of combined test dose and therapeutic drug monitoring strategy in exposure-directed busulfan.

Although exposure-directed busulfan (BU) dosing can improve allogeneic hematopoietic stem cell transplantation outcomes, there is still large variability in BU exposure with test dose alone due to changes in BU clearance caused by drug interactions. We conducted a single-arm phase II trial using the combined test dose and therapeutic drug monitoring strategy (PK-guided group) and compared the outcomes with an external historical cohort receiving a fixed-dose (fixed-dose group). The first eight and second eight doses were adjusted based on the area under the blood concentration-time curve (AUC) of the test and first doses, respectively, targeting a total AUC of 82.1mg·h/L. All patients received either BU and cyclophosphamide conditioning (BU/CY) or fludarabine (FLU)-containing conditioning. The BU clearance at the first dose decreased more in patients receiving FLU than in those receiving BU/CY; however, BU clearance also declined over time in patients who received BU/CY. The simulated total AUC (sAUC) with test dose only was significantly higher in patients who received FLU than in those who received BU/CY, but sAUC with the combined strategy was comparable. The 100-day progression-free survival was 85.5% (95% confidence interval [CI]: 71.9-92.8%), and was not inferior to that in the fixed-dose group. For the FLU-containing regimens, the PK-guided group showed decreased relapse (0.0% vs. 26.9%, p = 0.03), and favorable overall survival (75.1% vs. 57.0%, p = 0.07) at 1year. The combined strategy effectively controlled the BU exposure close to the target levels, potentially improving efficacy, especially in patients receiving the FLU-containing regimen. Clinical evaluation of efficacy of dose-modified intravenous busulfan in allogeneic hematopoietic stem cell transplantation for hematological malignancy (#UMIN000014077, June 15th, 2014).

Individual Components of Polymyxin B Modeled via Population Pharmacokinetics to Design Humanized Dosage Regimens for a Bloodstream and Lung Infection Model in Immune-Competent Mice.

Polymyxin B is a "last-line-of-defense" antibiotic approved in the 1960s. However, the population pharmacokinetics (PK) of its four main components has not been reported in infected mice. We aimed to determine the PK of polymyxin B1, B1-Ile, B2, and B3 in a murine bloodstream and lung infection model of Acinetobacter baumannii and develop humanized dosage regimens. A linear 1-compartment model, plus an epithelial lining fluid (ELF) compartment for the lung model, best described the PK. Clearance and volume of distribution were similar among the four components. The bioavailability fractions were 72.6% for polymyxin B1, 12.0% for B1-Ile, 11.5% for B2, and 3.81% for B3 for the lung model and were similar for the bloodstream model. While the volume of distribution was comparable between both models (17.3 mL for the lung and ~27 mL for the bloodstream model), clearance was considerably smaller for the lung (2.85 mL/h) compared to that of the bloodstream model (5.59 mL/h). The total drug exposure (AUC) in ELF was high due to the saturable binding of polymyxin B presumably to bacterial lipopolysaccharides. However, the modeled unbound AUC in ELF was ~16.7% compared to the total drug AUC in plasma. The long elimination half-life (~4 h) of polymyxin B enabled humanized dosage regimens with every 12 h dosing in mice. Daily doses that optimally matched the range of drug concentrations observed in patients were 21 mg/kg for the bloodstream and 13 mg/kg for the lung model. These dosage regimens and population PK models support translational studies for polymyxin B at clinically relevant drug exposures.

Fasting and diurnal blood ketonemia and glycemia responses to a six-week, energy-controlled ketogenic diet, supplemented with racemic R/S-BHB salts

Single doses of exogenous ketone salts (KS) transiently increase circulating beta-hydroxybutyrate (BHB) (∼1mM; 1-2h) regardless of starting levels of ketosis; however, no studies have explored how sustained use of KS influences measures of ketonemia and glycemia. To determine the response to a hypocaloric, well-formulated ketogenic diet (KD), with and without the inclusion of two daily racemic KS doses (6g R-BHB+6g S-BHB per serving) on 1) daily fasting capillary R-BHB and glucose (R-BHB/GLUfast), 2) bi-weekly 13h diurnal BHB and glucose (R-BHB/GLUdiur), 3) three-hours post-KS ingestion kinetics (R-BHBKS), and 4) bi-weekly fasting plasma enantiomer-specific BHB (R/S-BHBplasma). Non-diabetic adults with overweight and obesity were randomized to receive a precisely measured hypocaloric KD (∼75 %en of maintenance) for six weeks, supplemented twice-daily with KS or placebo (PL). A non-randomized comparison group was provided an isonitrogenous/isoenergetic low-fat diet (LFD). All meals were provided to subjects. Capillary blood was collected daily to measure R-BHB/GLUfast and hourly for R-BHB/GLUdiur. Plasma was collected to measure R/S-BHBplasma, insulin, fasting glucose, and insulin resistance (HOMA-IR). Total AUC was calculated using the trapezoidal method. Mean R-BHBfast increased significantly during KD+PL (1.0mM BHB), an effect enhanced 26% during KD+KS. GLUfast AUC was-6% lower during KD+KS versus LFD. Mean R-BHBdiur increased 40% in KD+KS versus KD+PL, whereas GLUdiur decreased 13% during both KDs versus LFD. R-BHBKS peaked (Δ: ∼1mM) 1h after the morning KS dose, but not following the afternoon dose. Both R/S-BHBplasma increased during KD independent of KS inclusion. R-BHBplasma was 50-times greater compared to S-BHBplasma, and the KS augmented S-BHBplasma 50% more than PL. Fasting insulin and HOMA-IR decreased after 14 days independent of diet. A hypocaloric KD was effective at reducing diurnal glucose compared to a LFD independent of weight loss, but twice-daily racemic KS ingestion during KD augmented ketonemia, both as R- and S-BHB, and decreased mean fasting glucose beyond a KD alone. The hypoglycemic effects of KD in combination with exogenous ketones merit further investigation.

EEG in the Global Brain Consortium, aiming to strengthen linkages between neuroscientists across borders and disciplines to advance equitable solutions to priority health challenges worldwide

AbstractBackgroundThe Global Brain Consortium https://globalbrainconsortium.org/ promotes the goals of open science and serves as a clearinghouse to interface synergistically with other initiatives.MethodTwo interacting projects are of interest here: 1) The Harmonized Multinational quantitative EEG norms (HarMNqEEG) project provides open data and software (www.biorxiv.org/content/10.1101/2022.01.12.476128v1) for the first batch‐free Developmental Equations obtained from 1564 EEG cross‐spectral from 9 countries, 12 devices, 14 studies. 2) The Biomarkers of Dementia for Global Health supports Electrophysiology PIA efforts.ResultAs a result of the two projects, we evaluated qEEG discrimination on samples from the Medellin Study. The groups to be distinguished were those without the Preseninin‐1 mutation sample, asymptomatic carriers, and symptomatic carriers. We show that Hermitian Riemannian qEEG descriptive parameters and the HarMNqEEG norms allow the elastic‐net robust classifier to accurate classification (Figure 1) with total AUC in the range of .91‐,93, and acceptable accuracies between groups (Figure 2).ConclusionTo our knowledge, this is the first report on the use of harmonized Riemannaian norms in the age‐adjusted classification of EEGs from this condition.

The correlation between total deceleration and acceleration surface areas on electronic fetal monitoring and neonatal cord blood pH in postdate pregnancies.

To assess the correlation between the total decelerations area in the final 120 min before delivery and neonatal cord blood pH in postdate pregnancies. This cross-sectional study included women with gestational age greater than 41 weeks, singleton pregnancy, and a category II electronic fetal monitoring (EFM) of at least 30 min during the final 120 min before delivery. We included postdate deliveries of an otherwise low-risk parturient population. Each area was calculated as duration × depth × 1/2. Correlations were tested using the Spearman correlation coefficient. A total of 100 EFMs were included in the analysis. Median pH was significantly lower in neonates above the median total deceleration area under the curve (AUC; 7.26 vs. 7.32, P=0.002). Gestational age at delivery was independently associated with total deceleration AUC above median (adjusted odds ratio 1.21, 95% confidence interval 1.09-1.37) controlling for history of previous cesarean delivery and duration of second stage of labor. A significant correlation was found between cord blood pH and total deceleration area (P < 0.001, Spearman correlation coefficient -0.37). Among women with postdate pregnancies, the total deceleration area and the mean maximum duration of decelerations were negatively correlated with cord blood pH. Further studies are needed to incorporate deceleration area as a method in predicting fetal acidemia.

Efficacy and Safety of Biosimilar Candidate ABP 959 As Compared with Eculizumab Reference Product in Paroxysmal Nocturnal Hemoglobinuria

Introduction: ABP 959 is a biosimilar candidate to eculizumab reference product (RP). Eculizumab is a humanized recombinant immunoglobulin antibody that binds to the human complement component 5 protein to inhibit progression of complement cascades and is approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome, generalized myasthenia gravis, and neuromyelitis optica spectrum disorder. Methods: This multicenter, randomized, double-blind, active-controlled, 2-period crossover study compared the efficacy and safety of ABP 959 and eculizumab RP in adult patients with PNH who were stable on eculizumab 900 mg IV every 14 ± 2 days. The primary objective of this study was to evaluate the efficacy of ABP 959 compared to eculizumab RP based on control of intravascular hemolysis, with a secondary objective to compare their safety, pharmacokinetics (PK), and immunogenicity. Results from Period 1 of the crossover study are presented here. Patients were randomized 1:1 to receive either ABP 959 at 900 mg IV for 52 weeks in Period 1 followed by eculizumab RP 900 mg IV for 26 weeks in Period 2 (ABP 959/RP) or eculizumab RP 900 mg IV for 52 weeks followed by ABP 959 at 900 mg IV for 26 weeks (RP/ABP 959) (Figure). The primary efficacy endpoint for the parallel comparisons was hemolysis, measured by lactate dehydrogenase (LDH) at week 27; clinical similarity between treatments was assessed by comparing the 1-sided 97.5% upper confidence interval (CI) limit for the geometric least squares (LS) mean ratio between ABP 959 and eculizumab RP, with a non-inferiority (NI) margin of 2.873. To assess the robustness of the primary analysis result, a sensitivity analysis was conducted using a subset of randomized patients who did not experience any important protocol deviation affecting their primary efficacy evaluation. Secondary endpoints included total complement (50% total hemolytic complement activity [CH50]), LDH-time profile, number of units of packed red blood cells (pRBCs) transfused, safety, immunogenicity, and PK area under the serum concentration-time curve (PK AUC) of ABP 959 and eculizumab RP. Results: Forty-two patients (20 in the ABP 959/RP group; 22 in the RP/ABP 959 group) were randomized and treated in Period 1 across 25 centers. Forty-one (97.6%) patients (20 [100%] in ABP 959/RP and 21 [95.5%] in RP/ABP 959) completed Period 1 dosing. Baseline demographic and disease characteristics were comparable between the 2 treatment groups - mean (SD) age: 50.2 (16.6) years; time since original PNH diagnosis: 128.3 (116.1) months; duration of pre-study treatment: 68.4 (39.8) months. Results for week 27 LDH geometric LS means are presented below (Table). The ratio of the geometric LS means of LDH (ABP 959/RP) was 1.0628, with a 1-sided 97.5% upper CI of 1.1576 contained within the prespecified NI margin of 2.873, establishing similarity in clinical efficacy between ABP 959 and eculizumab RP in the parallel comparison; 95% CI was 0.9758 to 1.1576. Results from the sensitivity analysis were identical with results from the primary efficacy analysis. Total complement (CH50), total hemoglobin, serum-free hemoglobin, haptoglobin, bilirubin, and type III erythrocytes values were generally stable over time and results were comparable between the 2 treatment groups. The overall LDH profile and the mean number of units of pRBCs transfused during the study period were also comparable. Total PK AUC from week 13 to week 15 were similar between the 2 treatment groups. A comparable safety profile was observed in Period 1 between treatment groups, with only a single patient (4.5%) in the eculizumab RP group discontinuing the study due to any adverse event (grade 2 non-serious asthenia and grade 2 non-serious fatigue). The nominal difference in serious adverse event incidence was determined to be not clinically meaningful. Additionally, immunogenicity results through Period 1 were similar between ABP 959 and eculizumab RP groups. No patients in either treatment group tested positive for binding antidrug antibodies (ADAs), neutralizing ADAs, or treatment-boosted ADAs. Conclusions: Similarity in clinical efficacy was established between ABP 959 and eculizumab RP in the primary endpoint of hemolysis, measured by LDH at week 27. Additionally, comparable safety, PK, and immunogenicity results support the conclusion of clinical similarity between ABP 959 and eculizumab RP. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Model-Informed Precision Busulfan Dosing in Pediatric Patients Undergoing Hematopoietic Cell Transplantation- Real-World Data

Targeted i.v. busulfan dosing in pediatric non-malignant and malignant disorders undergoing HCT has been challenging due to the unpredictable PK of busulfan in young children. In 59 children with b-thalassemia undergoing HCT, we have previously reported that Bu TDM is feasible, and targeted IV Bu resulted in better EFS than untargeted oral bu in these patients (Balasubramanian et al., TCT 2019). However, the incidence of graft rejection was still high, probably due to age-related clearance of busulfan in very young children (Gaziev J et al. Blood. 2010). Precision dosing models result in less inter-patient variability in systemic exposure and better treatment outcomes (Shukla P et al. Front Pharmacol. 2020). We carried out a pilot study of precision busulfan dosing in pediatric patients in collaboration with InsightRX(California, USA). We aimed to evaluate the performance of the InsightRX precision dosing model for busulfan in young patients undergoing HCT and compare with the incidence of mixed chimerism on days 30, 60, and 90 post HCT [> 5% recipient cells], the time to neutrophil and platelet engraftment and the incidence of regimen related toxicities. Thirteen patients were enrolled in the study from June 2021 to May 2022, and the demographics are listed in Table 1. Initial Bu dosing was based on EMA guidelines (Body weight-based dosing, Palmer J et al. BBMT. 2016). Busulfan levels were monitored after doses 1, 5, 9, and 13 using a validated LC-MS/MS method (Desire et al., 2013). The values were entered in the InsightRX TDM algorithm, and a cumulative AUC of 80-90mg.hr/L was targeted. The mean Bu dose per EMA guideline and the actual dose received after precision dosing was compared. Based on InsightRX prediction, ten patients received higher cumulative Bu dosing, and 3 received lower cumulative Bu dosing compared to fixed weight-based dosing (Fig 1A). All patients had lower Bu AUC (<4.6 mg*hr/L) after the 1st dose, while at the end of the 13th dose, most patients achieved therapeutic Bu AUC (Median: 4.8 (3.6-5.8 mg*hr/L, Fig 1B). The interpatient variability in systemic exposure was only 12% with precision dosing, compared to 33% with the trapezoidal rule-based method (Balasubramanian et al., TCT 2019). Irrespective of the busulfan formulation, GST genotype, and underlying disease, the total cumulative target AUC was achieved in all the patients; two patients rejected the graft (one rejected within day+90 and the other rejected late after day+90, both had unrelated donor source and lowered cumulative Bu AUC compared to the other patients), and one developed Sinusoidal obstruction syndrome (despite lower cumulative Bu AUC, therefore cannot be attributed to Bu exposure). Targeting higher cumulative Bu exposure using a model-informed precision dosing software resulted in better HCT outcomes. Our study suggests the feasibility of improved precision of dosing of busulfan in young children undergoing HCT resulting in improved outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal