AUC Ratio Research Articles

A phase I study to evaluate the safety, tolerability, and pharmacokinetics of a novel, potent GABA analog HSK16149 in healthy Chinese subjects.

Purpose: HSK16149 is a novel, potent gamma-aminobutyric acid (GABA) analog for the treatment of neuropathic pain. This study aimed to evaluate the safety, tolerability, and pharmacokinetics of HSK16149 after single and multiple doses in healthy Chinese subjects. Methods: The randomized, double-blind, placebo-controlled study comprised two parts: SAD (single ascending-dose study) and MAD (multiple ascending-dose study). A total of 122 healthy subjects were enrolled in this study. HSK16149 capsule or placebo was administered as the protocol required. The safety of the drug was evaluated through clinical examinations and adverse events. Blood and urine samples were collected at the designated time intervals for pharmacokinetic analysis. Results: Subjects were generally well tolerated after HSK16149 administration and the most common treatment-emergent adverse event (TEAEs) was dizziness, which was expected based on the mechanism of action of HSK16149. In SAD, AUC and Cmax were shown to have a dose-proportional relationship in the dose range of 5-120mg. The t1/2 of HSK16149 is 3.7-6.4h. In MAD, after a single and multiple administration of 15-80mg, AUC and Cmax are proportional to the increased dose of HSK16149, and the accumulative ratios of AUC and Cmax at steady-state were 1.05-1.44 and 1.07-1.36, respectively, indicating that HSK16149 only accumulated slightly after repeated administration. Conclusion: HSK16149 was well tolerated in healthy Chinese subjects. Based on the safety and pharmacokinetic data, 80mg twice daily (BID) was suggested as the highest target dose for further clinical development. Clinical Trial Registration: http://www.chinadrugtrials.org.cn, identifier CTR20182535 and CTR20191317.

Oral Decitabine/Cedazuridine Vs Intravenous Decitabine for Acute Myeloid Leukemia: Final Results of a Randomized, Crossover, Registration-Enabling, Pharmacokinetics Study

Background: Parenterally administered hypomethylating agents (HMAs), decitabine (DEC) and azacitidine (AZA), are approved in Europe for adult patients with acute myeloid leukemia (AML) who are not candidates for standard induction chemotherapy as single agent or in combination with venetoclax. Cedazuridine(C) is a novel, potent, and safe inhibitor of cytidine deaminase (CDA) and when given in combination with decitabine, cedazuridine enables efficient oral availability of decitabine.ASTX727 (DEC-C) is a fixed-dose combination (FDC) tablet of 35 mg DEC and 100 mg cedazuridine, DEC-C has been approved for MDS in the US, Canada, and Australia. Here we present final results using DEC-C in an AML population appropriate for single-agent decitabine treatment. Aims: Describe the final clinical outcomes of patients with AML with additional analysis of genetic profiles. Methods: The ASCERTAIN study used a randomized two-period, two-sequence, two-treatment, crossover study design. Patients were randomized 1:1 to either Sequence A: DEC-C (35 mg DEC/100 mg cedazuridine) in Cycle 1 followed by IV-DEC at 20 mg/m 2 in Cycle 2, or Sequence B: receiving IV-DEC in Cycle 1 followed by DEC-C on Cycle 2 to compare pharmacokinetics (PK) [primary endpoint Area Under the Curve (AUC) equivalence over 5 days of dosing]. All patients received DEC-C from Cycle 3 until treatment discontinuation to assess safety and clinical efficacy. Patients were eligible as per the EMA-approved decitabine label (newly diagnosed AML who are not candidates for standard induction chemotherapy). Clinical responses were assessed according to modified International Working Group (IWG) 2003 response criteria. Pre-treatment peripheral blood was used for DNA isolation from leukocytes, and molecular abnormalities identified using a NGS hematologic malignancy panel. Cox-regression analysis on the various factors (eg binary mutational status, CR, etc.) was used for analyses of risk-factors for overall survival (OS). Results: 89 patients were randomized, of whom 87 were treated. The median age of patients was 78.0 years (range, 61 to 92) with 31 (35.6%) males and 56 (64.4%) females. Cytogenetic risk classification was poor-risk in 33 (37.9%), intermediate-risk in 45 (51.7%), and 9 (10.4%) not evaluated patients. For the primary endpoint, preliminary PK data was available from 69 patients who successfully completed PK assessments for both IV-DEC and DEC-C cycles, and the DEC AUC 0-24 (h*ng/mL) 5-Day geometric mean estimate was 904 for DEC-C and 907 for IV-DEC resulting in an oral/IV geometric LSM AUC ratio of 99.64% (90% CI of 91.23-108.8%). Safety findings were consistent with those anticipated for IV-DEC (related Grade ≥ 3 AEs in more than 10% were thrombocytopenia, neutropenia, anaemia, and febrile neutropenia). As of the database lock (25May2023), median follow up was 24.5 (20.2, 25.0) months (25% of 19.7 and 75% of 25.2 months). The best response was complete response (CR) in 19/87 (21.8%, 95% CI: 13.7, 32.0%); CR with incomplete blood cell count recovery (CRi) in 5 patients (5.7%); and CR with incomplete platelet recovery (CRp) in 2 (2.3%); resulting in composite response rate [CR + CRi] of 27.6%. The median overall survival was approximately 8.9 months (95% CI: 6.0, 13.1).These results obtained with DEC-C are consistent with those observed for IV-DEC. Multiple genes, including ASXL1, TP53, RUNX1, and SRSF2 genes were present in more than 20% of the AML patients. TP53 mutation was associated with worse survival. Summary/Conclusion: This randomized phase 3 study in AML patients not candidates for standard induction chemotherapy demonstrates that Daily X 5 dosing of the oral FDC of DEC-C resulted in an equivalent DEC AUC exposure to IV-DEC at 20 mg/m 2 over 5 days. Pharmacodynamic data showed similar demethylation rates (≤1.1% difference). In addition, safety findings and observed clinical activity (response rates and OS) are consistent with published data from IV-DEC, suggesting that DEC-C has the potential to be an oral alternative to the standard IV-DEC Daily×5 regimen. These findings support the use of DEC-C in patients with AML who are not candidates for standard induction chemotherapy.

Unveiling the Influence of a High-Fat Meal on the Pharmacokinetics of Oral Globalagliatin, A Glucokinase Activator, in Healthy Chinese Volunteers.

Glucokinase (GK) plays a pivotal role in maintaining glucose homeostasis; globalagliatin, a newly developed drug, is a GK activator (GKA). This study constitutes a randomized, open-label, two-cycle, two-crossover, single-dose, phase I clinical trial conducted at a single center with healthy Chinese volunteers, aiming to examine the influence of a high-fat meal on the pharmacokinetics (PK) of orally administered globalagliatin. Twenty-four healthy volunteers were randomly divided into two groups, with a washout period of 16 days between the two cycles. The first cycle involved Group 1 volunteers who were orally administered globalagliatin 80 mg with 240 mL of water while fasting on Day 1. In contrast, Group 2 volunteers began oral administration of globalagliatin 80 mg with 240 mL of water, 30 min after consuming a high-fat meal (where high-fat content contributed to 54% of the total calories; the high-calorie meal amounted to 988.4 kcal). After the washout period, both groups of volunteers entered the second cycle of drug administration, with meals and medication being swapped on Day 17. Each volunteer collected blood samples at the following time points: 0h (within 1h before administration), and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, and 168h after administration on both trial Day 1 and Day 17. The primary and secondary PK parameters were collected. The validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was used to determine the concentration of globalagliatin in collected plasma samples, and the results were analyzed using Phoenix WinNonlin software. Safety evaluation was conducted by detecting or observing various adverse events (AEs) and serious AEs (SAEs). All 24 healthy Chinese volunteers enrolled completed the study and underwent PK analysis. The maximum concentration (Cmax; ng/mL), area under the plasma concentration-time curve (AUC) from time zero to time of the last quantifiable concentration (AUCt; h·ng/mL), and AUC from time zero extrapolated to infinity (AUC∞; h·ng/mL) of fasting administration were 22.35±7.02, 725.74±303.04, and 774.07±343.89, respectively, while the Cmax, AUCt, and AUC∞ administered after a high-fat meal were 28.95±12.60, 964.84±333.99, and 1031.28±392.80, respectively. The geometric mean ratios of Cmax, AUCt, and AUC∞ for high-fat meal/fasting administration of globalagliatin were 124.81%, 135.24%, and 135.42%, respectively, with 90% confidence intervals of 109.97-141.65, 124.24-147.20, and 124.42-147.39, respectively. Compared with the fasting state, healthy volunteers who consumed a high-fat meal showed a 24.8% increase in Cmax, a 35.2% increase in AUCt, and a 35.4% increase in AUC∞. The geometric mean of Tmax was 4.69h under fasting conditions and 5.93h in a high-fat state, with a median of 4.98h. Among the 24 enrolled volunteers, 9 cases (37.5%) had 11 AEs, and 6 cases (25.0%) had 7 adverse drug reactions (ADRs) after medication, all of which were cured or improved without taking any treatment measures. There were no SAEs in this study, no volunteers withdrew from the study due to AEs or ADRs, and no hypoglycemic events occurred during the trial. A high-fat meal increased the Cmax, AUCt, and AUC∞ of globalagliatin compared with fasting conditions in healthy Chinese adult volunteers. Meanwhile, globalagliatin showed favorable safety and tolerability under fasting or high-fat meal conditions.

Pharmacokinetics and Safety of the Tyrosine Kinase2 Inhibitor Deucravacitinib in Healthy Chinese Subjects.

Deucravacitinib, an oral, selective, allosteric tyrosine kinase2 inhibitor, blocks cytokine signaling involved in psoriasis pathogenesis. This ethnic-bridging study evaluated deucravacitinib pharmacokinetics, tolerability, and safety in healthy Chinese subjects. This phaseI, double-blind, single-/multiple-dose study randomized healthy Chinese subjects 4:1 to a single dose of deucravacitinib 6mg or placebo (group1) or deucravacitinib 12mg or placebo (group2) on day1; groups1 and 2 received deucravacitinib 6mg and 12mg once daily, respectively, or placebo on days5-19. Blood samples were collected on days1-5 (0 predose-96h postdose), day5 (0-24h postdose), days9 and 12 (0h), and day19 (0-24h postdose). Deucravacitinib and metabolite (BMT-153261, BMT-158170) concentrations were determined using liquid chromatography/mass spectrometry; pharmacokinetic parameters were calculated using noncompartmental analysis. Urine was collected on days1-4 (4h predose-96h postdose). Safety was monitored throughout. Forty healthy Chinese subjects (groups1 and 2: deucravacitinib, n = 32; placebo, n = 8) were enrolled. Deucravacitinib was rapidly absorbed after single-/multiple-dose administration, with median time to maximal plasma concentration of 1.5-2.3 h. Systemic exposure after single or multiple doses increased approximately twofold with twofold dose increase. Modest deucravacitinib accumulation was observed after multiple-dose administration (1.3- to 1.4-fold increase in area under the curve [AUC] under one dosing interval). Metabolite-to-parent ratios for maximal plasma concentration and AUC remained consistent in each dose group. Mean urinary percent recovery and renal clearance were similar between dose groups. Most adverse events (AEs) were mild/moderate, with no serious treatment-related AEs, deaths, or discontinuations due to AEs. Deucravacitinib was safe and well tolerated in healthy Chinese subjects. Deucravacitinib exhibited rapid absorption, dose-related increases in exposure, comparable half-life, and no evidence of time-dependent pharmacokinetics, suggesting minimal effect of Chinese ethnicity on deucravacitinib pharmacokinetics. NCT03956953.

Ecological niche modelling in identifying habitats for effective species conservation: A study on Endemic aquatic plant Crinum malabaricum

Ecological niche modelling (ENM) aids in identifying new species populations and suitable habitats for species translocation, addressing the conservation challenge of endemic species with limited distribution. The current study aims to develop a habitat suitability map of Crinum malabaricum Lekhak & S. R. Yadav, an endemic species with a very limited geographical range, using Maxent-based ecological niche modelling to identify suitable receptor sites for conservation translocation. Out of 23 species occurrence records, 11 were used for this study. Seven predictive variables are selected based on Pearson’s correlation coefficient (r = ±0.8) and permutation importance (>3%) from a group of nineteen bioclimatic and two topographic variables. The study area encompasses the Malabar Plains of the Western Ghats. The accuracy of the model was assessed using the ROC curve method, and the contribution of variables was estimated using a Jackknife analysis. The results show that precipitation of the driest quarter and mean temperature of the driest quarter were the leading predictors of habitat suitability. The model shows high accuracy with a value of 1.6 for AUC ratios and values > 8 for AUC, partial AUC, Kappa, and TSS metrics. The model predicted a fundamental niche for this species with 2393 KM2 (3.6% of the study area) as a highly suitable area for C. malabaricum (where habitat suitability index ≥ 0.85), which is much higher than the calculated extend of occurrence (EOO = 283 KM2) of this species. The realized niche of this species was identified using field explorations, and ten suitable areas were selected for species translocation. These selected habitats are distributed across various regions of the southern Western Ghats. As a species with limited distribution and a lack of proper dispersal mechanisms, a successful species translocation to these sites will overcome the endemism in this species. For selecting appropriate sites for conservation translocations, this methodology will be reliable and effective, and it could be useful for other endemic species.

Toward improved predictions of pharmacokinetics oftransported drugs in hepatic impairment: Insights fromthe extended clearance model.

Hepatic impairment (HI) moderately (<5-fold) affects the systemic exposure (i.e., area under the plasma concentration-time curve [AUC]) of drugs that are substrates of the hepatic sinusoidal organic anion transporting polypeptide (OATP) transporters and are excreted unchanged in the bile and/or urine. However, the effect of HI on their AUC is much greater (>10-fold) for drugs that are also substrates of cytochrome P450 (CYP) 3A enzymes. Using the extended clearance model, through simulations, we identified the ratio of sinusoidal efflux clearance (CL) over the sum of metabolic and biliary CLs as important in predicting the impact of HI on the AUC of dual OATP/CYP3A substrates. Because HI may reduce hepatic CYP3A-mediated CL to a greater extent than biliary efflux CL, the greater the contribution of the former versus the latter, the greater the impact of HI on drug AUC ratio (AUCRHI ). Using physiologically-based pharmacokinetic modeling and simulation, we predicted relatively well the AUCRHI of OATP substrates that are not significantly metabolized (pitavastatin, rosuvastatin, valsartan, and gadoxetic acid). However, there was a trend toward underprediction of the AUCRHI of the dual OATP/CYP3A4 substrates fimasartan and atorvastatin. These predictions improved when the sinusoidal efflux CL of these two drugs was increased in healthy volunteers (i.e., before incorporating the effect of HI), and by modifying the directionality of its modulation by HI (i.e., increase or decrease). To accurately predict the effect of HI on AUC of hepatobiliary cleared drugs it is important to accurately predict all hepatobiliary pathways, including sinusoidal efflux CL.

Comprehensive Physiologically Based Pharmacokinetic Model to Assess Drug-Drug Interactions of Phenytoin.

Regulatory agencies worldwide expect that clinical pharmacokinetic drug-drug interactions (DDIs) between an investigational new drug and other drugs should be conducted during drug development as part of an adequate assessment of the drug's safety and efficacy. However, it is neither time nor cost efficient to test all possible DDI scenarios clinically. Phenytoin is classified by the Food and Drug Administration as a strong clinical index inducer of CYP3A4, and a moderate sensitive substrate of CYP2C9. A physiologically based pharmacokinetic (PBPK) platform model was developed using GastroPlus® to assess DDIs with phenytoin acting as the victim (CYP2C9, CYP2C19) or perpetrator (CYP3A4). Pharmacokinetic data were obtained from 15 different studies in healthy subjects. The PBPK model of phenytoin explains the contribution of CYP2C9 and CYP2C19 to the formation of 5-(4'-hydroxyphenyl)-5-phenylhydantoin. Furthermore, it accurately recapitulated phenytoin exposure after single and multiple intravenous and oral doses/formulations ranging from 248 to 900 mg, the dose-dependent nonlinearity and the magnitude of the effect of food on phenytoin pharmacokinetics. Once developed and verified, the model was used to characterize and predict phenytoin DDIs with fluconazole, omeprazole and itraconazole, i.e., simulated/observed DDI AUC ratio ranging from 0.89 to 1.25. This study supports the utility of the PBPK approach in informing drug development.

Prediction of ROS1 and TRKA/B/C occupancy in plasma and cerebrospinal fluid for entrectinib alone and in DDIs using physiologically based pharmacokinetic (PBPK) modeling approach.

Entrectinib (ENT) is a potent c-ros oncogene 1(ROS1) and neurotrophic tyrosine receptor kinase (NTRKA/B/C) inhibitor. To determine the optimum dosage of ENT using ROS1 and NTRKA/B/C occupancy in plasma and cerebrospinal fluid (CSF) in drug-drug interactions (DDIs), physiologically-based pharmacokinetic (PBPK) models for healthy subjects and cancer population were developed for ENT and M5 (active metabolite). The PBPK models were built using the modeling parameters of ENT and M5 that were mainly derived from the published paper on the ENT PBPK model, and then validated by the observed pharmacokinetics (PK) in plasma and CSF from healthy subjects and patients. The PBPK model showed that AUC, Cmax, and Ctrough ratios between predictions and observations are within the range of 0.5-2.0, except that the M5 AUC ratio is slightly above 2.0 (2.34). Based on the efficacy (> 75% occupancy for ROS1 and NTRKA/B/C) and safety (AUC < 160μM·h and Cmax < 8.9μM), the appropriate dosing regimens were identified. The appropriate dosage is 600mg once daily (OD) when administered alone, reduced to 200mg and 400mg OD with itraconazole and fluconazole, respectively. ENT is not recommended for co-administration with rifampicin or efavirenz, but is permitted with fluvoxamine or dexamethasone. The PBPK models can serve as a powerful approach to predict ENT concentration as well as ROS1 and NTRKA/B/C occupancy in plasma and CSF.

Predicting Maternal and Infant Tetrahydrocannabinol Exposure in Lactating Cannabis Users: A Physiologically Based Pharmacokinetic Modeling Approach.

A knowledge gap exists in infant tetrahydrocannabinol (THC) data to guide breastfeeding recommendations for mothers who use cannabis. In the present study, a paired lactation and infant physiologically based pharmacokinetic (PBPK) model was developed and verified. The verified model was used to simulate one hundred virtual lactating mothers (mean age: 28 years, body weight: 78 kg) who smoked 0.32 g of cannabis containing 14.14% THC, either once or multiple times. The simulated breastfeeding conditions included one-hour post smoking and subsequently every three hours. The mean peak concentration (Cmax) and area under the concentration-time curve (AUC(0-24 h)) for breastmilk were higher than in plasma (Cmax: 155 vs. 69.9 ng/mL; AUC(0-24 h): 924.9 vs. 273.4 ng·hr/mL) with a milk-to-plasma AUC ratio of 3.3. The predicted relative infant dose ranged from 0.34% to 0.88% for infants consuming THC-containing breastmilk between birth and 12 months. However, the mother-to-infant plasma AUC(0-24 h) ratio increased up to three-fold (3.4-3.6) with increased maternal cannabis smoking up to six times. Our study demonstrated the successful development and application of a lactation and infant PBPK model for exploring THC exposure in infants, and the results can potentially inform breastfeeding recommendations.

Polycaprolactone microparticles for the subcutaneous administration of cannabidiol: in vitro and in vivo release.

Cannabidiol (CBD) has become a highly attractive entity in therapeutics. However, its low aqueous solubility, instability and handling problems limit the development of effective CBD formulations. Subcutaneously administered CBD-loaded polycaprolactone microparticles (MP) represent an interesting strategy to overcome these challenges. This work focuses on evaluating the pharmacokinetics of CBD formulated in polymer microparticles for subcutaneous administration and characterising its release. The mean release time (MRLT) parameter is used to compare the release of CBD from two microparticle formulations in vitro and in a mouse model. After the administration of CBD in solution, a bicompartmental distribution is observed due to the extensive diffusion to the brain, being the brain/blood AUC ratio 1.29. The blood and brain mean residence time (MRT) are 0.507 ± 0.04 and 0.257 ± 0.0004days, respectively. MP prepared with two drug/polymer ratios (15/150-MP and 30/150-MP) are designed, showing similar in vitro dissolution profiles (similarity factor (f2) is 63.21), without statistically significant differences between MRLTin vitro values (4.68 ± 0.63 and 4.32 ± 0.05days). However, considerable differences in blood and brain profiles between both formulations are detected. The blood and brain MRT values of 15/150-MP are 6.44 ± 0.3days and 6.15 ± 0.25days, respectively, whereas significantly lower values 3.91 ± 0.29days and 2.24 ± 0.64days are obtained with 30/150-MP. The extended release of CBD during 10days after a single subcutaneous administration is achieved.

Utilization of OATP1B Biomarker Coproporphyrin-I to Guide Drug-Drug Interaction Risk Assessment: Evaluation by the Pharmaceutical Industry.

Drug-drug interactions (DDIs) involving hepatic organic anion transporting polypeptides 1B1/1B3 (OATP1B) can be substantial, however, challenges remain for predicting interaction risk. Emerging evidence suggests that endogenous biomarkers, particularly coproporphyrin-I (CP-I), can be used to assess in vivo OATP1B activity. The present work under the International Consortium for Innovation and Quality in Pharmaceutical Development was aimed primarily at assessing CP-I as a biomarker for informing OATP1B DDI risk. Literature and unpublished CP-I data along with pertinent in vitro and clinical DDI information were collected to identify DDIs primarily involving OATP1B inhibition and assess the relationship between OATP1B substrate drug and CP-I exposure changes. Static models to predict changes in exposure of CP-I, as a selective OATP1B substrate, were also evaluated. Significant correlations were observed between CP-I area under the curve ratio (AUCR) or maximum concentration ratio (Cmax R) and AUCR of substrate drugs. In general, the CP-I Cmax R was equal to or greater than the CP-I AUCR. CP-I Cmax R < 1.25 was associated with absence of OATP1B-mediated DDIs (AUCR < 1.25) with no false negative predictions. CP-I Cmax R < 2 was associated with weak OATP1B-mediated DDIs (AUCR < 2). A correlation was identified between CP-I exposure changes and OATP1B1 static DDI predictions. Recommendations for collecting and interpreting CP-I data are discussed, including a decision tree for guiding DDI risk assessment. In conclusion, measurement of CP-I is recommended to inform OATP1B inhibition potential. The current analysis identified changes in CP-I exposure that may be used to prioritize, delay, or replace clinical DDI studies.

Quantitative prediction of transporter-mediated drug-drug interactions using the mechanistic static pharmacokinetic (MSPK) model

Guidance/guidelines on drug-drug interactions (DDIs) have been issued in Japan, the United States, and Europe. These guidance/guidelines provide decision trees for conducting metabolizing enzyme-mediated clinical DDI studies; however, the decision trees for transporter-mediated DDIs lack quantitative prediction methods. In this study, the accuracy of a net-effect mechanistic static pharmacokinetics (MSPK) model containing the fraction transported (ft) of transporters was examined to predict transporter-mediated DDIs. This study collected information on 25 oral drugs with new active reagents that were used in clinical DDI studies as perpetrators (42 cases) from drugs approved in Japan between April 2016 and June 2020. The AUCRs (AUC ratios with and without perpetrators) of victim drugs were predicted using the net-effect MSPK model. As a result, 83 and 95% of the predicted AUCRs were within 1.5- and 2-fold error in the observed AUCRs, respectively. In cases where the victims were statins in which pharmacokinetics several transporters are involved, 70 and 91% of the predicted AUCRs were within 1.5- and 2-fold errors, respectively. Therefore, the net-effect MSPK model was applicable for predicting the AUCRs of victims, which are substrates for multiple transporters.

The Excretion of Cisplatin after Hyperthermic Intrathoracic Chemotherapy.

Hyperthermic intrathoracic chemotherapy (HITOC) is an additional intraoperative treatment option within the multimodality therapy of pleural malignancies. A chemotherapy perfusion with high-dose cisplatin is performed over a period of 60 min after surgical cytoreduction to improve local tumour control through the eradication of residual tumour cells. Although HITOC is increasingly used, there is only little scientific evidence about the necessary safety measures after HITOC. Therefore, the objective of this study was an analysis of cisplatin excretion via various body fluids after HITOC, with the aim of providing recommendations on occupational health and safety. Five patients undergoing HITOC were included. Before and after the HITOC, as well as during the following days, serum, urine, and bronchial secretion, as well as pleural effusion, were sampled. The platinum levels in the samples were measured using ICP-MS (inductively coupled plasma-mass spectrometry). Immediately after the HITOC, the mean levels of cisplatin increased dramatically in the serum (from 0.79 to 1349 µg/L), urine (from 3.48 to 10,528 µg/g creatinine), and bronchial secretion (from 0.11 to 156 µg/L). Thereafter, the cisplatin levels dropped to 133 µg/L in the serum and 994 µg/g creatinine in the urine within nine days after the HITOC. The AUC ratio shows 59% of the cisplatin being excreted via the urine after 48 h. The sampling of pleural effusion started 24 h after the HITOC, and the cisplatin levels decreased from 618 to 93 µg/L within nine days. Although the cisplatin levels in the body fluids of HITOC patients are much lower compared to patients receiving intravenous chemotherapy, a significant amount of cisplatin is excreted via these body fluids. Consequently, safety precautions must be implemented in the post-HITOC care of patients to avoid occupational exposure to cisplatin.

Effect of nivasorexant (ACT-539313), a selective orexin-1-receptor antagonist, on multiple cytochrome P450probe substrates in vitro and in vivo using a cocktail approach in healthy subjects.

Nivasorexant, a selective orexin-1-receptor antagonist, has recently been assessed in the treatment of humans with binge-eating disorder. Herein, the inhibitory potential of nivasorexant on cytochromes P450 (CYPs) 2C9, 2C19, and 3A4 was evaluated. Human liver microsomes/recombinant CYP enzymes were evaluated in vitro. In vivo, a single-center, open-label, fixed-sequence study was performed in healthy adults to explore the effect of 100 mg nivasorexant administered twice daily (b.i.d.) on the pharmacokinetics (PK) of flurbiprofen (50 mg, CYP2C9), omeprazole (20 mg, CYP2C19), midazolam (2 mg, CYP3A4) making use of a cocktail approach. Plasma PK sampling was performed over 24 h on Day 1 (Cocktail alone), 8 (Cocktail + nivasorexant), and 15 (Cocktail + nivasorexant at steady state). Genotyping of subjects' CYPs was performed while safety and tolerability were also assessed. In vitro, nivasorexant inhibited CYP2C9, 2C19, and 3A4 in competitive inhibition assays with IC50 values of 8.6, 1.6, and 19-44 μM, respectively, while showing a significant time-dependent CYP2C19 inhibition. In 22 subjects, exposure to flurbiprofen, omeprazole, and midazolam was generally higher during concomitant single- (i.e., area under the plasma concentration-time curve [AUC] ratio increased by 1.04-, 2.05-, and 1.56-fold, respectively) and repeated-dose (i.e., AUC ratio increased by 1.47-, 6.84-, and 3.71-fold, respectively) nivasorexant administration compared with the cocktail substrates administered alone. The most frequently reported adverse event was somnolence. According to regulatory guidance, nivasorexant is classified as a moderate CYP2C19 and weak CYP3A4 inhibitor after 1 day and as a weak CYP2C9, strong CYP2C19, and moderate CYP3A4 inhibitor after 8 days of 100 mg b.i.d. administration. Clinicaltrials.gov ID: NCT05254548.

Toxicokinetics and tissue distribution of phalloidin in mice.

Phalloidin, a bicyclic heptapeptide found in Amanita mushroom, specifically binds to F-actin in the liver causing cholestatic hepatotoxicity. However, the toxicokinetics and tissue distribution properties of phalloidin as well as their underlying mechanisms have to be studied further. The area under the plasma concentration curve (AUC) of phalloidin increased in proportion to the doses (0.2, 0.4, and 0.8mg/kg for intravenous injection and 2, 5, and 10mg/kg for oral administration). Phalloidin exhibited dose-independent low volume of distribution (395.6-456.9mL/kg) and clearance (21.4-25.5mL/min/kg) and low oral bioavailability (2.4%-3.3%). This could be supported with its low absorptive permeability (0.23±0.05×10-6cm/s) in Caco-2cells. The tissue-to-plasma AUC ratios of intravenously injected and orally administered phalloidin were the highest in the liver and intestines, respectively, and also high in the kidneys, suggesting that the liver, kidneys, and intestines could be susceptible to phalloidin exposure and that active transport via the hepatic and renal organic anion transporters (OATP1B1, OATP1B3, and OAT3) may contribute to the higher distribution of phalloidin in the liver and kidneys.

Preclinical Evaluation of a New Series of Albumin-Binding 177Lu-Labeled PSMA-Based Low-Molecular-Weight Radiotherapeutics.

Prostate-specific membrane antigen (PSMA)-based low-molecular-weight agents using beta(β)-particle-emitting radiopharmaceuticals is a new treatment paradigm for patients with metastatic castration-resistant prostate cancer. Although results have been encouraging, there is a need to improve the tumor residence time of current PSMA-based radiotherapeutics. Albumin-binding moieties have been used strategically to enhance the tumor uptake and retention of existing PSMA-based investigational agents. Previously, we developed a series of PSMA-based, β-particle-emitting, low-molecular-weight compounds. From this series, 177Lu-L1 was selected as the lead agent because of its reduced off-target radiotoxicity in preclinical studies. The ligand L1 contains a PSMA-targeting Lys-Glu urea moiety with an N-bromobenzyl substituent in the ε-amino group of Lys. Here, we structurally modified 177Lu-L1 to improve tumor targeting using two known albumin-binding moieties, 4-(p-iodophenyl) butyric acid moiety (IPBA) and ibuprofen (IBU), and evaluated the effects of linker length and composition. Six structurally related PSMA-targeting ligands (Alb-L1-Alb-L6) were synthesized based on the structure of 177Lu-L1. The ligands were assessed for in vitro binding affinity and were radiolabeled with 177Lu following standard protocols. All 177Lu-labeled analogs were studied in cell uptake and selected cell efficacy studies. In vivo pharmacokinetics were investigated by conducting tissue biodistribution studies for 177Lu-Alb-L2-177Lu-Alb-L6 (2 h, 24 h, 72 h, and 192 h) in male NSG mice bearing human PSMA+ PC3 PIP and PSMA- PC3 flu xenografts. Preliminary therapeutic ratios of the agents were estimated from the area under the curve (AUC0-192h) of the tumors, blood, and kidney uptake values. Compounds were obtained in >98% radiochemical yields and >99% purity. PSMA inhibition constants (Kis) of the ligands were in the ≤10 nM range. The long-linker-based agents, 177Lu-Alb-L4 and 177Lu-Alb-L5, displayed significantly higher tumor uptake and retention (p < 0.001) than the short-linker-bearing 177Lu-Alb-L2 and 177Lu-Alb-L3 and a long polyethylene glycol (PEG) linker-bearing agent, 177Lu-Alb-L6. The area under the curve (AUC0-192h) of the PSMA+ PC3 PIP tumor uptake of 177Lu-Alb-L4 and 177Lu-Alb-L5 were >4-fold higher than 177Lu-Alb-L2, 177Lu-Alb-L3, and 177Lu-Alb-L6, respectively. Also, the PSMA+ PIP tumor uptake (AUC0-192h) of 177Lu-Alb-L2 and 177Lu-Alb-L3 was ~1.5-fold higher than 177Lu-Alb-L6. However, the lowest blood AUC0-192h and kidney AUC0-192h were associated with 177Lu-Alb-L6 from the series. Consequently, 177Lu-Alb-L6 displayed the highest ratios of AUC(tumor)-to-AUC(blood) and AUC(tumor)-to-AUC(kidney) values from the series. Among the other agents, 177Lu-Alb-L4 demonstrated a nearly similar ratio of AUC(tumor)-to-AUC(blood) as 177Lu-Alb-L6. The tumor-to-blood ratio was the dose-limiting therapeutic ratio for all of the compounds. Conclusions: 177Lu-Alb-L4 and 177Lu-Alb-L6 showed high tumor uptake in PSMA+ tumors and tumor-to-blood ratios. The data suggest that linker length and composition can be modulated to generate an optimized therapeutic agent.

A Comparative Pharmacokinetic Study of Fexuprazan 10 mg: Demonstrating Bioequivalence with the Reference Formulation and Evaluating Steady State.

Fexuprazan is a potassium-competitive acid blocker approved for treating gastric-acid-related diseases. Although the effectiveness of the recent formulation fexuprazan 10 mg has been demonstrated in Phase 3 clinical trials, data on the pharmacokinetics (PKs) of administering fexuprazan 10 mg twice daily at a 12 h interval are lacking. Moreover, it is imperative to ensure the bioequivalence of the new formulation with the previously approved 40 mg formulation. This study evaluated the pharmacokinetics (PKs) of the single- and multiple-dose oral administration of fexuprazan 10 mg tablets in healthy participants (Part 1) and investigated their bioequivalence with 40 mg tablets (Part 2). Part 1 comprised a single- and multiple-dose, one-sequence, two-period design and eight participants, while Part 2 comprised a single-dose, 2 × 2 crossover design and 24 participants. In Part 1, in Periods 1 and 2, participants received single and multiple doses (twice daily) of fexuprazan 10 mg, respectively. The maximum plasma concentration (Cmax) area under the concentration-time curve from 0 to 12 h (AUC0-12h) of the multiple-dose participants was approximately double that of the single-dose participants. In Part 2, the geometric mean ratios (90% confidence intervals) for Cmax and AUC from zero to the time of the last quantifiable concentration (AUClast) of the use of four fexuprazan 10 mg tablets to those of one fexuprazan 40 mg tablet were 1.0290 (0.9352-1.1321) and 1.0290 (0.9476-1.1174), respectively, meeting the bioequivalence criteria. Favorable PKs were observed after single and multiple administrations of one fexuprazan 10 mg tablet, and four fexuprazan 10 mg tablets were pharmacokinetically equivalent to one fexuprazan 40 mg tablet.

The relation of right ventricular outflow tract measurements with in-hospital clinical outcomes after tricuspid valve surgery.

Right ventricular (RV) function is a determining factor for clinical outcomes in patients undergoing tricuspid valve surgery (TVS). Our aim was to investigate the importance of the function of the right ventricular outflow tract (RVOT), which is an important anatomical region of the RV, in patients underwent TVS. 104 patients who underwent TVS were analyzed retrospectively. Patients with previous cardiac surgery, congenital heart disease, or heart failure were excluded. The parasternal short-axis view at the level of the aortic root was used to measure RVOT dimensions and RVOT fractional shortening (RVOT-FS). The effect of RVOT diameter and function on major adverse cardiac events (MACE) after TVS was investigated. In our study, MACE, consisting of pacemaker implantation, acute kidney injury, postoperative atrial fibrillation and mortality, was developed at 44 (42.3%) patients.We compared the predictive performances of RVOT end-systolic (RVOTs) diameter, RVOT end-diastolic (RVOTd) diameter, RVOT-FS and RV diameters in prediction of MACE. The model including the RVOTs had higher AUC, R2 and likelihood ratio X2 values (0.775, 0.287 and 25.0, respectively) than RVOTd (0.770, 0.279 and 24.2, respectively) and RVOT-FS (0.750, 0.215 and 18.1, respectively). RVOT diameters showed better performance in predicting MACE than RV diameters. Moreover, there was statistically significant association between RVOTs, RVOTd and MACE (p value were 0.014 and 0.027, respectively), while no association between RVOT-FS and MACE (p value was 0.177). In summary, we determined that the RVOT diameters are important predictors for the in-hospital clinical outcomes of patients who underwent TVS.

Exact solutions for area-based delay discounting analyses.

Novel methods are provided for calculating a model-based area under curve (MB-AUC) using exact solution. These model-specific calculations produce an AUC ratio that does not need numerical approximation nor access to the source discounting data to perform. This approach supports a calculation of MB-AUC that is useful in summarizing current and retrospective discounting analyses using fitted models (e.g., k and s) and corresponding study parameters (i.e., range of delays). Solutions were compared against numerical methods for various discounting models and results indicated that each approach provided identical results. This newer, simpler, and more efficient method is reviewed and demonstrated to show how comparisons can be drawn between the fitted discounting models and empirical methods, such as the empirical point-based area under curve. Reanalyses of published findings revealed that reconstituting published findings using a common scale (i.e., area) yielded similar AUC ratios, despite varying approaches, suggesting new avenues for research synthesis (e.g., reducing sources of measurement error). The MB-AUC measure is discussed as one means of addressing the challenges encountered when research synthesis includes metrics on varying scales and differing domains. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

PRELIMINARY SAFETY, EFFICACY AND PHARMACOKINETICS (PK) RESULTS OF KN026 (A HER2 BISPECIFIC ANTIBODY) MONOTHERAPY IN ADVANCED SOLID TUMOR PATIENTS WITH HER2 EXPRESSION

Abstract Background KN026 is a novel bispecific antibody and simultaneously binds to two distinct HER2 epitopes which are the same domains as trastuzumab (ECD4) and pertuzumab (ECD2). It showed higher maximal binding than monospecific HER2 antibodies and favors that crosslinking of HER2 receptors could enhance the receptors internalization in preclinical studies. KN026 significantly inhibited the growth of human cancer cell lines and demonstrated obviously antitumor activity against different xenografts models. The encouraging efficacy and manageable safety of KN026 were reported in Chinese cancer patients (pts) with HER2 expression and ph3 study is ongoing in gastric cancer (NCT05427383). Methods The late line solid tumor pts with HER2 expression who were refractory to or ineligible for standard therapy were recruited in this phase I dose-escalation study in US (NCT03847168). All pts intravenously received KN026 monotherapy at ascending dose of 10 mg/kg (QW), 20 mg/kg (Q2W) or 30 mg/kg (Q3W). Dose escalation followed standard “3 + 3” design. Expansion was determined by Safety Monitoring Committee (SMC). The primary objectives were to evaluate safety and tolerability of KN026 and determine the MTD and/or RP2D. Safety was evaluated according to CTCAE v 5.0, and efficacy was assessed by RECIST 1.1. Results A total of 22 pts with median 4 lines prior treatment were enrolled, including 5 breast cancer pts, 3 gastric or gastroesophageal junction cancer pts and 14 other solid tumor pts. 21 pts were included in the efficacy analysis. The median age was 57.0 (47-79), with 8 males and 14 females and most of pts were Caucasian (72.7%). 3, 10 (7 at expansion phase), and 9 (6 at expansion phase) pts were treated at 10mg/kg, 20mg/kg, 30mg/kg, respectively. No dose-limiting toxicities (DLTs) were observed and MTD wasn’t reached. 20 pts (90.9%) occurred TRAEs and the common (≥20%) TRAEs were diarrhea (45.5%), fatigue (40.9%), chills (36.4%) and nausea (27.3%). Most of TRAE were Gr 1-2, and only 3 pts (13.6%) experienced ≥ Gr3 TRAE (anemia, fatigue and pneumonitis) without treatment discontinuation and death caused by KN026. 4 of 21 pts (1 at 10mg/kg, 2 at 20 mg/kg, 1 at 30mg/kg) achieved objective response (ORR 19.0%, 95% CI: 5.5, 41.9), and DCR was 61.9% (95% CI: 38.4, 81.9). The exposure of KN026 and T1/2 increased with dose escalation. Accumulation ratio of Cmax and AUC was 1.18-1.42 and 1.14-1.71. The concentration of Ctrough was over 20μM at all dose levels. There was only one positive ADA sample in 20 mg/kg group in C1D1. And the RP2D was 20mg/kg Q2W or 30mg/kg Q3W. Conclusion KN026 was well tolerated and showed the promising anti-tumor activity in US pts with HER2 expression. Besides, KN026 has well pharmacokinetic profile and favorable immunogenicity.