AUC Ratio Research Articles

External delay and dispersion correction of automatically sampled arterial blood with dual flow rates.

Arterial sampling for PET imaging often involves continuously measuring the radiotracer activity concentration in blood using an automatic blood sampling system (ABSS). We proposed and validated an external delay and dispersion correction procedure needed when a change in flow rate occurs during data acquisition. We also measured the external dispersion constant of [11C]CURB, [18F]FDG, [18F]FEPPA, and [18F]SynVesT-1. External delay and dispersion constants were measured for the flow rates of 350, 300, 180, and 150 mL/h, using 1-minute-long rectangular inputs (n = 10; 18F-fluoride in saline). Resulting constants were used to validate the external delay and dispersion corrections (n = 6; 18F-fluoride in saline; flow rate change: 350 to 150 mL/h and 300 to 180 mL/h); constants were modelled to transition linearly between flow rates. Corrected curves were assessed using the percent area-under-the-curve (AUC) ratio and a modified model selection criterion (MSC). External delay and dispersion constants were measured for various radiotracers using a blood analog (i.e., similar viscoelastic properties). ABSS outputs were successfully corrected for external delay and dispersion using our proposed method accounting for a change in flow rate. AUC ratio reduced from ~10% for the uncorrected 350-150 mL/h output (~6% for the 300-180 mL/h) to < 1% after correction when compared to true input (511 keV energy window); approx. 5-fold increase in MSC. Assuming an internal dispersion constant of 5 seconds, the dispersion constant (internal + external) for [11C]CURB, [18F]FDG, [18F]FEPPA, and [18F]SynVesT-1 was 13, 9, 16, and 10 s, respectively. This study presented an external delay and dispersion correction procedure needed when a change in flow rate occurs during ABSS data acquisition. Additionally, this is the first study to measure the external delay and dispersion constants using a blood analog solution, a suitable alternative to blood when estimating external dispersion.

Effect of Food Intake or Coadministration With an Acid-Reducing Agent on Lenacapavir Pharmacokinetics Following Oral Administration.

Lenacapavir is a potent, long-acting HIV-1 capsid inhibitor used in combination with other antiretrovirals to treat HIV-1 infection. The pharmacokinetics of orally administered drugs may be affected by food intake or coadministration of acid-reducing agents (ARA). Two Phase 1 studies were conducted on healthy participants to evaluate the effect of food and the impact of the histamine H2-receptor antagonist famotidine in parallel cohorts. In Study 1, oral lenacapavir (300mg) was administered under fasting conditions, after a standardized high-fat meal, and after a low-fat meal (n=8/cohort). In Study 2, lenacapavir 300mg was administered alone (n=27) and 2 hours after famotidine (40mg; n=25), each under fasting conditions. For the high-fat meal versus fasted comparison, the percentage geometric least-squares mean (%GLSM) ratios for the lenacapavir area under the curve to infinity (AUCinf) and maximum concentration (Cmax) were 115.2 and 145.2, respectively. For the low-fat meal, the %GLSM ratios for lenacapavir AUCinfand Cmax were 98.6 and 115.8, respectively, versus the fasted state. In the famotidine study, the %GLSM ratio for lenacapavir AUC from time zero to the last quantifiable concentration was 137.4, and for Cmax was 100.6. Based on available clinical safety data, the exposure increases observed in these studies were not expected to be clinically relevant. Overall, these data support the dosing of oral lenacapavir without regard to food intake or coadministration with ARAs.

Examining the Impact of Diet-and-Exercise-Induced Weight Loss on Drug Metabolism and Gastric Emptying in Patients with Obesity.

Obesity significantly influences drug pharmacokinetics (PK), which challenges optimal dosing. This study examines the effects of diet-and-exercise-induced weight loss on key drug-metabolizing enzymes and gastric emptying in patients with obesity, who frequently require medications for comorbidities. Participants followed a structured weight management program promoting weight loss over 3-6 months and were not concomitantly on potential CYP inducers or inhibitors. Using a drug cocktail of acetaminophen, caffeine, omeprazole, and midazolam, we assessed UGT1A1, CYP1A2, CYP2C19, and CYP3A4 enzyme activities before and after weight loss, respectively, by measuring parent and metabolite concentrations. The time to maximum acetaminophen plasma concentrations reflected the gastric emptying time. PK profiles were compared across two phases: baseline (Phase 1) and post-weight loss (Phase 2). Twenty-four participants enrolled, 21 completed Phase 1 and 12 completed both phases. Statistically significant (N = 12, P <.05) gains in CYP2C19 and CYP3A4 activity were observed after weight loss of 7.6% to 26.2%, with a median [25th, 75th percentile] increase in activity of 90.5 [15.0, 194.3] % and 43.0 [7.5, 68.0] %, respectively. A 2- or 3-h single plasma sample-based ratio of the metabolite to parent concentration strongly correlated with the respective AUC ratio for the drug metabolism phenotype (N = 21). Our findings provide provisional data for evaluation of the effects of non-pharmacologically and non-surgically induced weight loss on gastric emptying and drug metabolism for future physiologically based PK models. Development of mechanistic models to optimize drug dosing in obesity are necessary since weight and body composition shifts are expected with emerging new treatments.

Cytokine Dynamics in Action: A Mechanistic Approach to Assess Interleukin 6 Related Therapeutic Protein-Drug-Disease Interactions.

Understanding cytokine-related therapeutic protein-drug interactions (TP-DI) is crucial for effective medication management in conditions characterized by elevated inflammatory responses. Recent FDA and ICH guidelines highlight a systematic, risk-based approach for evaluating these interactions, emphasizing the need for a thorough mechanistic understanding of TP-DIs. This study integrates the physiologically based pharmacokinetic (PBPK) model for TP (specifically interleukin-6, IL-6) with small-molecule drug PBPK models to elucidate cytokine-related TP-DI mechanistically. The integrated model successfully predicted TP-DIs across a broad range of both constant and fluctuating IL-6 levels, as observed in patients with rheumatoid arthritis, Crohn's disease, HIV-infection, and those undergoing hip-surgery or bone marrow transplantation (all simulated AUC and Cmax ratios were within a twofold error of the observed data). Constant IL-6 levels that would be associated with mild, moderate, and strong inhibitory interactions were estimated. The time-course and extent of TP-DI potential were also assessed in cytokine storm triggered by SARS-CoV-2 infection (COVID-19) and T-cell engager therapies (blinatumomab, mosunetuzumab, and epcoritamab). Additionally, scenarios involving concurrent CYP enzyme suppression by IL-6 and induction by rifampicin were assessed for the magnitude of drug interaction. By providing a robust mechanistic framework for understanding cytokine-drug interactions and establishing reliable exposure-response relationships, this study enhances predictive accuracy and informs human dosing strategies. It demonstrates the potential of PBPK models to improve therapeutic decision making and patient care, particularly in inflammatory conditions.

New Insights Into Hepatic Impairment (HI) Trials.

Hepatic impairment (HI) trials are traditionally part of the clinical pharmacology development to assess the need for dose adaptation in people with impaired metabolic capacity due to their diseased liver. This review aimed at looking into the data from dedicated HI studies, cluster these data into various categories and connect the effect by HI with reported pharmacokinetics (PK) properties in order to identify patterns that may allow waiver, extrapolations, or adapted HI study designs. Based on a ratio ≥ 2 or ≤ 0.5 in AUC or Cmax between hepatically impaired participants/healthy controls these were considered "positive" or "negative". In case of more than one HI severity stratum per compound included in the HI trial, the comparison of the AUC ratios for mild, moderate, or severe HI were used to investigate the increase across HI categories. For the in total 436 hits, relevant PK information could be retrieved for 273 compounds of which 199 were categorized negative, 69 positive ups and 5 positive downs. Fourteen out of 69 compounds demonstrated a steep increase in the AUC ratios from mild to severe HI. Compounds demonstrating a steep increase typically had a high plasma protein binding of > 95%, high volume of distribution, lower absolute bioavailability, minor elimination via the kidneys, were predominantly metabolized by CYP3A4 or CYP2D6 and the majority of these compounds were substrates of OATP1B1. While for compounds with steep increase studies in all severity strata may be warranted they may also offer the potential to estimate the appropriate doses in an HI trial. On the other hand, for compounds with slow or no increase across HI severity strata, reduced HI trials may be justified, e.g. only testing PK in moderate HI.

In Vitro Dynamic Model Evaluation of Meropenem Alone and in Combination with Avibactam Against Carbapenemase-Producing Klebsiella pneumoniae.

Background: A potential strategy to maintain the efficacy of carbapenems against carbapenemase-producing Klebsiella pneumoniae (CPKP) is their combination with carbapenemase inhibitors. To address these issues, the effectiveness of a novel combination of meropenem with avibactam against CPKP was studied. Additionally, the applicability of a pharmacokinetically-based approach to antibiotic/inhibitor minimum inhibitory concentration (MIC) determinations to better predict efficacy was examined. Methods: CPKP strains were exposed to meropenem alone or in combination with avibactam in an in vitro hollow-fiber infection model. Treatment effects were correlated with simulated antibiotic and antibiotic/inhibitor combination ratios of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC). All MICs were determined at standard and at high inocula; combination MICs were determined using the conventional approach with fixed avibactam concentration or using the pharmacokinetic (PK)-based approach with a fixed meropenem-to-avibactam concentration ratio, equal to the respective drug therapeutic AUC ratios. Results: Meropenem alone was not effective even against a "susceptible" CPKP strain. The addition of avibactam significantly improved both meropenem MICs and its effectiveness. The effects of meropenem alone and in combination with avibactam (merged data) correlated well with AUC/MIC ratios only when MICs were determined at high inocula and using the PK-based approach (r2 0.97); the correlation was worse with the conventional approach (r2 0.73). Conclusions: The effectiveness of meropenem/avibactam against CPKP is promising. A single "effect-AUC/MIC" relationship useful for predicting meropenem efficacy (alone or in combination with avibactam) was obtained using MICs at high inocula and combination MICs determined using a PK-based approach.

Pharmacokinetic Interaction Between Olaparib and Regorafenib in an Animal Model.

Olaparib (OLA) and regorafenib (REG) are metabolized by the CYP3A4 isoenzyme of cytochrome P450. Both drugs are also substrates and inhibitors of the membrane transporters P-glycoprotein and BCRP. Therefore, the potential concomitant use of OLA and REG may result in clinically relevant drug-drug interactions. Knowledge of the influence of membrane transporters and cytochrome P450 enzymes on the pharmacokinetics of drugs makes it possible to assess their impact on the efficacy and safety of therapy. The study aimed to evaluate the bilateral pharmacokinetic interactions of OLA and REG and its active metabolites after a single administration in healthy rats. The study was performed in male Wistar rats (n = 24) randomly divided into three groups: one study group, IREG+OLA (n = 8), received REG with OLA, and two control groups, IIREG (n = 8) and IIIOLA (n = 8), received REG and OLA, respectively. The concentrations of OLA, REG, REG-N-oxide (M-2), and N-desmethyl-REG-N-oxide (M-5) were determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The values of the pharmacokinetic parameters of OLA, REG, M-2, and M-5 were determined by non-compartmental analysis with linear interpolation. After OLA administration, the pharmacokinetic parameters of REG (AUC0-∞, tmax, and t0.5) increased significantly by 3.38-, 2.66-, and 1.82-fold, respectively. On the other hand, REG elimination parameters, i.e., kel and Cl/F, were significantly reduced in the study group by 1.77- and 1.70-fold, respectively. In the study group, Cmax and AUC0-t values were also 7.22- and 8.86-fold higher for M-2 and 16.32- and 17.83-fold higher for M-5, respectively. The Metabolite M-2/Parent and Metabolite M-5/Parent ratios for Cmax and AUC0-t increased by 6.52-, 10.74-, 28-, and 13-fold, respectively. After administration of OLA with REG, the Cmax, AUC0-t, and AUC0-∞ of OLA increased by 2.0-, 3.4-, and 3.4-fold, respectively, compared to the control group. Meanwhile, Cl/F and Vd/F of OLA were significantly decreased in the presence of REG. OLA was shown to significantly affect the pharmacokinetics of REG and its active metabolites M-2 and M-5 in rats after co-administration of both drugs. There was also a significant effect of REG on the pharmacokinetics of OLA, which may have clinical relevance. The AUC ratios (study group/control group) were 3.41 and 3.39 for REG and OLA, respectively, indicating that REG and OLA were moderate inhibitors in this preclinical study. The results obtained need to be confirmed in clinical studies. This study may provide guidance on the safety of using both drugs in clinical practice.

Comparison of busulfan pharmacokinetics between four-times-daily and once-daily administration in pediatric patients: a preliminary prospective observational trial.

Therapeutic drug monitoring (TDM) of busulfan (BU) is useful for achieving the target area under the curve (AUC) because its effective plasma-concentration range is narrow. This preliminary observational study evaluated the pharmacokinetic (PK) parameters of BU administered four times daily or once daily to pediatric patients. The plasma concentrations were measured at both the test dose and first dose, and the doses on day 1 and days 2-4 were determined based on each TDM. A comparison of PK parameters between four-times-daily and once-daily administration was performed for both the test dose and first dose of BU. Of the 11 patients, five received four-times-daily BU and six received once-daily BU. The Vd for once-daily administration was higher than that for four-times-daily administration for the first dose but not for the test dose. The ratio of actual AUC for the first dose to estimated AUC guided by the test dose was lower with once-daily administration than with four-times-daily administration. These results indicate that the PK parameters of BU administered once daily are challenging to predict based on the TDM of the test dose. TDM should be considered on day 1 to achieve the target AUC, especially with once-daily administration.

Limited sampling approach for model-informed precision dosing of daptomycin to rapidly achieving the target area under the concentration-time curve: A simulation study.

Daptomycin, an anti-methicillin-resistant Staphylococcus aureus drug, causes exposure-dependent muscle toxicity and eosinophilic pneumonia. Although the area under the concentration-time curve (AUC)-guided dosing is crucial, an optimal blood sampling strategy is lacking. This study aimed to identify an optimal limited sampling strategy using Bayesian forecasting to rapidly achieve the target AUC. Two validated population pharmacokinetic models generated a virtual population of 1000 individuals (models 1 and 2 represent diverse patients and kidney transplant recipients, respectively). The AUC for each blood sample was assessed using the probability of achieving the estimated/reference AUC ratio on the second day (AUC24-48) and at the steady state (AUCss). In Model 1, Bayesian posterior probabilities for AUC24-48 increased from 50.7% (a priori) to 59.4% and for AUCss from 48.9% (a priori) to 61.9%, with one-point Ctrough sampling at 24 h. With two-point sampling at 7 and 24 h, the probabilities increased to 73.8% for AUC24-48 and 69.7% for AUCss. In Model 2, the probabilities for both AUC24-48 and AUCss with one-point Ctrough or two-point sampling incorporating Ctrough sampling increased compared to a priori probabilities. These results suggest that two-point sampling incorporating Ctrough during initial dosing enhanced achieving the target AUC24-48 and AUCss rapidly.

Evaluation of pharmacokinetics and relative bioavailability of pentoxifylline and its metabolite in beagle dogs following different formulations.

A single-oral-dose, two-period cross-over study with a 5-day washout period under fed condition was conducted in six beagle dogs to explore the pharmacokinetic characteristics and relative bioavailability between sustained-release (SR) tablets and enteric-coated (EC) tablets of pentoxifylline (PTX) and its metabolite. The results showed that M5 exhibited the highest exposure level, while M1 demonstrated the lowest in both the SR and EC tablet groups. For PTX and M1, T1/2 were 0.42 and 0.55h, with tmax of 1.83 and 1.83h, respectively, in the SR tablet group; in the EC tablet group, T1/2 were 0.38 and 0.47h, respectively. However, a significantly prolonged absorption process was noted, with tmax values of 5.06 and 5.78h. In contrast, M5 exhibited distinct pharmacokinetic differences compared to PTX and M1. For the SR tablet group, T1/2 and tmax were recorded at 2.03 and 3.08h, respectively. In the EC tablet group, T1/2 and tmax were 1.67 and 5.78h, respectively. With regard to the geometric least squares mean (LSM) of AUC and Cmax for SR tablets and EC tablets, the ratios of SR/EC of PTX, M1 and M5 were 67.62% (90% CI, 50.49%-90.55%), 78.18% (90% CI, 54.15%-112.88%), and 119.11% (90% CI, 99.62%-142.41%), respectively, for AUC(0-t). The ratios were 67.62% (90% CI, 50.50%-90.55%), 78.36% (90% CI, 54.48%-112.72%), and 119.39% (90% CI, 100.03%-142.50%) for AUC(0-∞) and 54.36% (90% CI, 36.63%-80.67%), 58.80% (90% CI, 40.84%-84.66%), and 100.51% (90% CI, 89.50%-112.88%) for Cmax, respectively. The AUC ratio predictions of bioconversion results indicated that there was no significant difference in the bioconversion of M1 between the SR tablets and EC tablets, with conversion rates of 0.37 and 0.36, respectively. In contrast, the conversion rate of M5 demonstrated a significant difference (p < 0.05) between the SR tablets and EC tablets, with the ratio of 3.09 and 1.91, respectively. Furthermore, the EC tablet group demonstrated notable inter-individual differences and irregular drug absorption, following meals. Consequently, the SR tablets appeared to provide a more stable and controllable therapeutic effect in beagle dogs.

DDEL-15. PHARMACOKINETIC ANALYSIS OF CARBOPLATIN AND FLUORESCEIN BRAIN PENETRATION AND PERMANENCE FOLLOWING ULTRASOUND-BASED BLOOD-BRAIN BARRIER OPENING ON GLIOBLASTOMA CLINICAL TRIAL

Abstract The blood-brain barrier (BBB) impedes the passage of most circulating drugs into the brain. Low-intensity pulsed ultrasound with microbubbles (LIPU/MB) transiently opens the BBB, improving drug delivery to the brain. The implication of this transient BBB opening on parenchymal drug permanence is unknown. We compared the parenchymal levels and permanence/retention of temozolomide, carboplatin, and fluorescein, and investigated in a clinical trial (NCT04528680) the effect of LIPU/MB on the permanence of carboplatin and fluorescein in the human brain. Four patients underwent intraoperative LIPU/MB (SonoCloud-9, Carthera) with intravenous carboplatin and fluorescein infusion. Microdialysis catheters were implanted into sonicated and non-sonicated brain for continuous drug measurement over 24 hours. Published data from a microdialysis study of temozolomide were used for comparison. Temozolomide and carboplatin exhibited similar brain-to-plasma AUC ratios (17.8 ± 13.3%; 16.3 ± 8.2%, respectively) which were higher than that of fluorescein (10.4 ± 6.9%). Parenchymal half-life was the longest for fluorescein (13.6 ± 11.0 hours), followed by carboplatin (5.1 ± 1.9 hours) and temozolomide (2.9 ± 1.6 hours). LIPU/MB led to sustained elevated parenchymal drug concentrations, achieving a 3.1-fold increase in AUC for both carboplatin (P = 0.02), and fluorescein (P = 0.04), and higher parenchymal than systemic drug levels starting at 21 hours and 7 hours for these drugs respectively (P &amp;lt; 0.05), timepoints where these drugs had mostly cleared from the plasma. Fluorescein exhibits prolonged permanence in the brain parenchyma and may be “trapped” by the BBB. In the context of transient BBB opening by LIPU/MB, parenchymal carboplatin and fluorescein concentrations remain elevated over time, supporting the notion that the BBB exhibits a bi-directional restriction of drug passage. Future studies are warranted to explore the efficacy of drug trapping to achieve prolonged/sustained exposure of cytotoxic drugs for brain tumor therapy.

Effects of GLPG3970 on Sulfasalazine and Methotrexate Pharmacokinetics in Healthy Adults: Two Open-Label, Phase I, Drug-Drug Interaction Studies.

GLPG3970 is a selective salt-inducible kinase 2/3 inhibitor intended for the treatment of inflammatory diseases. In vitro studies suggest GLPG3970 strongly inhibits breast cancer resistance protein (BCRP), indicating a possible interaction with BCRP substrates such as sulfasalazine (SSZ; a probe substrate for intestinal BCRP inhibition) and methotrexate (MTX), both inflammatory disease medications. Two open-label, nonrandomized, phase I, drug-drug interaction (DDI) studies assessed the pharmacokinetics of SSZ 1,000 mg (NCT04720183) and MTX 7.5 mg (EudraCT: 2020-000391-37) with and without GLPG3970 350 mg. Healthy participants aged 18-55 years with wild-type homozygous BCRP genotype (c421C/C) received: SSZ on day (D)1, GLPG3970 + SSZ on D5, and GLPG3970 2 hours after SSZ on D9 (N = 8; SSZ/GLPG3970 DDI study); MTX on D1, GLPG3970 + MTX on D5, and GLPG3970 on D6-8 (N = 15; MTX/GLPG3970 DDI study). Primary end points were AUC and Cmax ("exposure") of SSZ and its metabolite (sulfapyridine [SPD]), SPD:SSZ AUC ratio (SSZ/GLPG3970 study), and AUC and Cmax ("exposure") of MTX (MTX/GLPG3970 study). DDIs were evaluated using the geometric mean ratio of each end point; a > 2-fold increase in SSZ or MTX exposure was deemed clinically relevant. GLPG3970 demonstrated mild inhibition of intestinal BCRP in vivo: GLPG3970 + SSZ increased SSZ exposure ~1.7-1.8-fold and decreased SPD:SSZ ratio ~ 2-fold vs. SSZ alone. GLPG3970 administered 2 hours after SSZ did not change the magnitude of the interaction. GLPG3970 + MTX had no relevant effect on MTX pharmacokinetics vs. MTX alone. Therefore, the strong in vitro BCRP inhibition was not confirmed in vivo. No safety concerns were observed when GLPG3970 was coadministered with SSZ or MTX.

Pharmacokinetic profile of novel multi-layer stable effervescent tablet: a cross-over study with an established European brand in healthy young male adults.

Effervescent formulation helps in faster and better absorption of drugs, especially those that are rapidly soluble in water. However, these tablets require special packaging in order to prevent them from absorbing moisture, hence increasing cost. We compared an effervescent tablet prepared using an in-house developed method (multi-layer tablet with acid and base part separated by an inert layer) to a European effervescent tablet (Efferalgan®) in a single-center, randomized cross-over study among twelve healthy volunteers. Blood samples were collected for 8h and analyzed for paracetamol concentration using HPLC. Our results showed that both the products have similar pharmacokinetic profiles with no significant difference observed for Clast, Thalf, Kelim, and MRT (p-value > 0.05). Moreover, to assess bioequivalence we did not find any significant difference (p-value > 0.05) in AUC (27.12 ± 6.02 vs. 27.29 ± 2.64µg.h/ml), Cmax (7.42 ± 1.06 vs. 7.83 ± 1.19µg/ml) and tmax (0.85 ± 0.22 vs. 0.83 ± 0.25h). The TR ratios for AUC, Cmax, and tmax were 0.99, 0.95, and 1.02 respectively, and were all within the specified FDA limits i.e., 0.8-1.25. We found our test tablet to be bioequivalent to that of Efferalgan®.

Long-term time-to-ventricular arrhythmic event prediction using a deep learning based model on the electrocardiogram signal

Abstract Background Ventricular arrhythmias (VA) risk stratification tools in individuals without known cardiovascular disease are still insufficient. Previous studies have used convolutional neural networks (CNN) to classify VA by the end of an established follow-up period using the electrocardiogram (ECG), showing a moderate performance (area under the curve [AUC] of 0.610). We hypothesised that the appearance of the VA substrate on the ECG signal depends on the proximity of the ECG acquisition to the VA event. Thus, the performance could improve if the CNN was trained to predict time-to-VA event instead, and if the presence of censored data was considered. Purpose We developed and tested a CNN to predict time-to-VA event in middle-aged individuals without known cardiovascular disease, and we compared its performance with that from ECG indices, such as QRS duration, QT interval and T-wave morphology variations (TMV), as well as sex and age. Methods A total of 69,283 individuals without known cardiovascular disease from the UK Biobank were used as the training set. We applied 10-fold cross validation to train a CNN, where the input was a 15-second ECG at rest (lead I), and the output was ‘occurrence of VA’, ‘censored’, or ‘survival’, up to 1, 2, 3, 4, 6, 8, 10 and 12 years after the ECG acquisition. We used 15-second ECG (lead I) from an independent cohort of 17,320 individuals without cardiovascular disease also from UK Biobank as a test set, where we set a follow-up of 10 years. The above ECG indices were derived from the median heartbeat from the ECG using in-house algorithms. We derived optimal cut-off thresholds from the training test, and we evaluated the AUC, sensitivity, specificity and Cox regression hazard ratios (HR) in the test set. Results In the test set, 9,206 individuals (53%) reached the 10-year follow-up, during which 60 (0.7%) had a VA event. The AUC, sensitivity and specificity values of the CNN were 0.715, 0.881 and 0.400, respectively. These values were 0.592, 0.686 and 0.383 for the QRS duration, 0.569, 0.156 and 0.717 for the QT interval and 0.552, 0.712 and 0.350 for TMV. The combination of sex and age alone showed performance values of 0.760, 0.694 and 0.683, respectively. Survival analyses showed a HR of 3.883 (P = 3.0 x 10-7) for individuals with a CNN prediction greater than the threshold derived in the training set after adjusting for age and gender. Conclusions A CNN that is trained to predict time-to-VA event and accounts for censored data outperforms previous classification proposed models and the predictive value of individual ECG indices of risk. Although the predictive value of the CNN does not show a better long-term VA predictive value than sex and age alone, it provides a significant contribution independently from these two risk factors. Our findings support the use of the ECG to improve long-term VA risk stratification, which might be particularly useful in age- and sex-stratified analyses.

Pharmacokinetics and bioequivalence of two formulations of mifepristone tablets in healthy Chinese subjects under fasting conditions: a single-center, open, randomized, single-dose, double-period, two-sequence, crossover trial.

A bioequivalence (BE) study was performed to evaluate the pharmacokinetics, safety, and bioequivalence of two formulations of mifepristone tablets in healthy Chinese volunteers under fasting conditions. A single-center, open, randomized, single-dose, double-period, two-sequence, crossover study in healthy subjects under fasting conditions was performed. The subjects received a single fasting dose of mifepristone (10mg/tablet) during the first and second periods, followed by a 14-day washout period, during which frequent pharmacokinetic (PK) sampling occurred up to 120h. The pharmacokinetic parameters of mifepristone were calculated based on the plasma drug concentration-time profile. Primary endpoints were the BE of major pharmacokinetic parameters (AUC0-t and AUC0-∞) and the maximum observed serum concentration (Cmax). Secondary endpoints were safety parameters. Forty subjects (34 male and 6 female subjects) were randomly assigned to treatment, with 39 completing the two-period study. After the single administration of mifepristone tablets (test preparation vs. reference preparation) under fasting conditions, the geometric mean ratios (GMRs) of Cmax, AUC0-t, and AUC0-∞ were 98.76%, 104.28%, and 104.83%, respectively. The primary metabolites of mifepristone (RU42633 and RU42698),the GMRs of Cmax, AUC0-t, AUC0-∞ were 102.33% and 100.97%, 103.17% and 103.71%, 104.02% and 103.84%, respectively. Similarly, for another metabolite of mifepristone (RU42698), the GMRs of Cmax, AUC0-t, and AUC0-∞ were 100.97%, 103.71%, and 103.84%, respectively. All 90% confidence intervals (CIs) for the test/reference AUC ratio and Cmax ratio were within the acceptable range (80%-125%) for BE, which met the requirements of bioequivalence. No serious adverse events (AEs) occurred, and all AEs were classified as level 1 or 2. The PK parameters of mifepristone and its metabolites (RU42633 and RU42698) were measured using the (GMRs) of AUC0-t, AUC0-∞, and Cmax and were similar between the test and reference drug. The two formulations of mifepristone showed good tolerability and a similar safety profile. chinadrugtrials.org.cn, identifier CTR20182413.

Pharmacovigilance of drug-drug interactions: A pharmacokinetic study on the combined oral administration of lurasidone and clozapine in rats by using LC-MS/MS

In recent years, the expanding array of psychotropic medications has led to an increase in drug-drug interactions, particularly with combinations of different antipsychotics or psychotropic medications in clinical practice. However, the potential pharmacokinetic interactions between Lurasidone and Clozapine have not been extensively studied. Thus, this study aims to investigate these potential interactions by analyzing their pharmacokinetics in rat plasma after single oral administrations using developed LC-MS/MS methods. The study revealed notable changes in Lurasidone's pharmacokinetic parameters between single and combination administrations. Specifically, there were significant reductions in t1/2 and Vd by 3.3 and 1.5-fold (p < 0.05) respectively, while Cmax and AUC0-t proved a significant increase by 1.8 and 1.6-fold (p < 0.05) respectively following the combination administration. Furthermore, separate co-administration markedly decreased Clozapine's Cmax and AUC 0-t by 1.6 and 1.3-fold (p < 0.05) respectively, after the combination administration. Moreover, the AUC ratio for Lurasidone was 0.2, indicating a diminished therapeutic effect, whereas the AUC ratio for Clozapine suggested an elevated risk of adverse effects. These findings confirm the presence of drug-drug interactions between Lurasidone and Clozapine, suggesting potential implications for treatment efficacy. Recommendations for future clinical research include conducting pharmacodynamic studies to evaluate the impact of Lurasidone and Clozapine combination therapy. This underscores the importance of thoroughly assessing these interactions for clinical relevance and provides a scientific foundation for future evaluations of this drug combination.

Comparison of CA-125 and HE4 in ovarian cancer recurrence detection

Purpose: This study aims to comprehensively evaluate CA-125 and HE4 as predictors of ovarian cancer (OC) recurrence in the same patient population. Methods: We systematically searched the WOS, PubMed, and Scopus databases on May 8, 2024, for studies investigating both tumor markers CA-125 and HE4 in the same patient population of ovarian cancer recurrence. We calculated pooled values of AUC, sensitivity, specificity, and univariate or multivariate hazard ratios (HR) for both tumor markers in serum using a random effects model and StataMP 17.0 software. Results: Thirteen articles comprising 1026 patients satisfied the inclusion criteria. Liquid-biopsy-based HE4 and CA-125 measurements were both proven to have high predictive value for detecting OC recurrence with comparable AUC values (AUCHE4:0.78, 95% CI=0.73-0.83; AUCCA125:0.80, 95% CI=0.73-0.88). While sensitivity of HE4 tests was higher than their specificity (SensitivityHE4=80.7%; 95% CI=73-88.4; I²=77.05%; p

Drug-drug interactions of icenticaftor (QBW251) with a 5-probe cytochrome P450 cocktail and oral contraceptives.

A drug-drug interaction (DDI) study was conducted to evaluate the effect of icenticaftor (QBW251) on the pharmacokinetics (PK) of a 5-probe cytochrome P450 (CYP) substrate cocktail, guided by invitro studies in human hepatocytes and liver microsomes. Another DDI study investigated the effect of icenticaftor on the PK and pharmacodynamics (PD) of a monophasic oral contraceptive (OC) containing ethinyl estradiol (EE) and levonorgestrel (LVG) in premenopausal healthy female subjects. The static-mechanistic DDI assessment indicated that icenticaftor may moderately induce the metabolic clearance of co-medications metabolized by CYP3A4 (area under the concentration-time curve [AUC] ratio: 0.47) and potentially CYP2C; icenticaftor may also weakly inhibit the metabolic clearance of co-medications metabolized by CYP1A2 and CYP3A4 (AUC ratio: 1.35 and 1.86, respectively) and moderately inhibit CYP2B6 (AUC ratio: 2.11). In the CYP substrate cocktail DDI study, icenticaftor 300 mg twice daily (b.i.d.) moderately inhibited CYP1A2 (AUC ratio: 3.35) and CYP2C19 (AUC ratio: 2.70). As expected from the results of the invitro studies, weak induction was observed for CYP3A4 (AUC ratio: 0.51) and CYP2C8 (AUC ratio: 0.66). In the OC DDI study, co-administration of icenticaftor 450 mg b.i.d. with monophasic OC containing 30-μg EE and 150-μg LVG once daily reduced the plasma exposure of both components by approximately 50% and led to increased levels of follicle-stimulating hormone and luteinizing hormone. These results provide valuable guidance for the use of icenticaftor in patients taking concomitant medications that are substrates of CYP enzymes or patients using OCs.

Food and bile micelle binding of zwitterionic antihistamine drugs.

The food effects on oral drug absorption are challenging to predict from in vitro data. Food intake has been reported to reduce the oral absorption of several zwitterionic antihistamine drugs. However, the mechanism for this negative food effect has not been clear. The purpose of the present study was to evaluate the bile micelle and food binding of zwitterionic antihistamine drugs as a possible mechanism for the negative food effects on their oral drug absorption. Bilastine (BIL), cetirizine (CET), fexofenadine (FEX), and olopatadine (OLO) were employed as model drugs. The fed/fasted AUC ratios of BIL, CET, FEX, and OLO after oral administration are reported to be 0.60 to 0.7, 0.92, 0.76 to 0.85, and 0.84, respectively. The unbound fraction (f u) of these drugs in the fasted and fed state simulated intestinal fluids (FaSSIF and FeSSIF, containing 3 and 15 mM taurocholic acid, respectively) with or without FDA breakfast homogenate (BFH) was measured by dynamic dialysis. The FeSSIF/ FaSSIF fu ratios were 0.90 (BIL), 0.46 (CET), 0.76 (FEX), and 0.78 (OLO). In the presence of BFH, the fu ratios were reduced to 0.52 (BIL), 0.22 (CET), 0.39 (FEX), and 0.44 (OLO). Despite being zwitterion at pH 6.5, the antihistamine drugs were bound to bile micelles. Bile micelle and food binding were suggested to cause a negative food effect on the oral absorption of these drugs. However, the AUC ratio was not quantitatively predicted by using FeSSIF + BFH.

Momelotinib: Mechanism of action, clinical, and translational science.

Myelofibrosis is a chronic myeloproliferative disorder characterized by bone marrow fibrosis, splenomegaly, anemia, and constitutional symptoms, with a median survival of ≈6 years from diagnosis. While currently approved Janus kinase (JAK) inhibitors (ruxolitinib, fedratinib) improve splenomegaly and symptoms, most can exacerbate myelofibrosis-related anemia, a negative prognostic factor for survival. Momelotinib is a novel JAK1/JAK2/activin A receptor type 1 (ACVR1) inhibitor approved in the US, European Union, and the UK and is the first JAK inhibitor indicated specifically for patients with myelofibrosis with anemia. Momelotinib not only addresses the splenomegaly and symptoms associated with myelofibrosis by suppressing the hyperactive JAK-STAT (signal transducer and activator of transcription) pathway but also improves anemia and reduces transfusion dependency through ACVR1 inhibition. The recommended dose of momelotinib is 200 mg orally once daily, which was established after review of safety, efficacy, pharmacokinetic, and pharmacodynamic data. Momelotinib is metabolized primarily by CYP3A4 and excreted as metabolites in feces and urine. Steady-state maximum concentration is 479 ng/mL (CV%, 61%), with a mean AUCtau of 3288 ng.h/mL (CV%, 60%); its major metabolite, M21, is active (≈40% of pharmacological activity of parent), with a metabolite-to-parent AUC ratio of 1.4-2.1. This review describes momelotinib's mechanism of action, detailing how the JAK-STAT pathway is involved in myelofibrosis pathogenesis and ACVR1 inhibition decreases hepcidin, leading to improved erythropoiesis. Additionally, it summarizes the pivotal studies and data that informed the recommended dosage and risk/benefit assessment.