AUC Ratio Research Articles

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 < 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.

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.

Busulfan Exposure Target Attainment in Adults Undergoing Allogeneic Hematopoietic Cell Transplantation: A Single Day Versus a Multiple Day Therapeutic Drug Monitoring Regimen

Busulfan exposure has previously been linked to clinical outcomes, hence the need for therapeutic drug monitoring (TDM). Study objective was to evaluate the effect of day 1 TDM-guided dosing (regimen d1) versus days 1 + 2 TDM-guided dosing (regimen d1 + 2) on attaining adequate busulfan exposure. In this observational study, we included all adults who received an allogeneic HCT with intravenous once daily busulfan over 4 days as part of the conditioning regimen at the University Medical Centre Utrecht or between July 31, 2014 and November 12, 2021. The primary outcome was attainment of the therapeutic busulfan target (cumulative area under the curve [AUCcum] 80-100 mg*h/L). Dose adjustment was based on the estimated AUC of the preceding dosing day(s). Additional TDM was performed in the event of large dose adjustments (≥25%). The choice of TDM regimen was solely based on the first day the busulfan dose was administered (regimen d1 + 2 occurred when conditioning started on a Saturday). In all patients, blood sampling was performed on day 4 for evaluation. The AUCcum was estimated using a validated population pharmacokinetic model. Busulfan target exposure was compared between both TDM regimen groups using a propensity score adjusted logistic regression model. The variance in the AUCcum between the TDM regimens was compared using the F-test. Patients were stratified for age (categorical). In regimen d1, 87.6% (n = 113/129) attained a therapeutic busulfan exposure, while in regimen d1 + 2 a proportion of 97.4% was found (n = 74/76, adjusted odds ratio for non-therapeutic AUC = 0.19, 95% confidence interval [95% CI]: 0.04-0.89). Variance of busulfan exposure in the regimen d1 group (SD = 6.8 mg*h/L) differed significantly from the variance in the regimen d1 + 2 group (SD = 3.6 mg*h/L, F-test, P < .001). Performing busulfan TDM on both day 1 and day 2, rather than only on day 1, improves busulfan target exposure attainment in adults undergoing HCT, provided that subsequent TDM is carried out if required.

Impact of advanced age on the gastric emptying of water under fasted and fed state conditions

Although older people are the main users of oral medications, few studies are reported on the influence of advanced age on gastric emptying rate of non-caloric liquids. This study aimed at evaluating the gastric emptying of 240 ml water in healthy older and young adults in fasted and fed state conditions using the established method of salivary caffeine kinetics. The gastric emptying of water was evaluated in 12 healthy older volunteers (mean age: 73 ± 6 years) and 12 healthy younger volunteers (mean age: 25 ± 2 years) with the ingestion of a rapid disintegrating tablet containing 20 mg of 13C3-caffeine. The gastric emptying of water was assessed indirectly by calculating the AUC ratios of salivary caffeine concentrations in specific time segments. Comparison of the AUC ratios showed no statistically significant difference between young and older volunteers in both fasted and fed state conditions (p > 0.05). Advanced age itself seems to have no relevant effect on gastric emptying of water in either fasted or fed state conditions and the phenomenon of Magenstrasse appears to follow a similar pattern in healthy older adults as in healthy younger adults.

Effect of a High-Fat Meal on the Pharmacokinetics of an Immediate Release Atogepant Tablet.

Atogepant, an oral calcitonin gene-related peptide receptor antagonist, is approved for the preventive treatment of migraine. A phase 1, open-label, single-dose, 2-period crossover study evaluated the effect of a high-fat meal on the pharmacokinetics and safety of atogepant in 20 healthy adults. Administration of atogepant 60mg immediate-release (IR) tablets under fed conditions reduced the area under the plasma concentration-time curve (AUC) from 0 to time t and from 0 to time infinity by approximately 18% and reduced the maximum plasma concentration (Cmax) by 22%. The 90% confidence intervals for the geometric mean ratios of Cmax and AUC were not contained within the bioequivalence limits of 80%-125%. There was no change in the median time to maximum plasma concentration in the fed versus fasted state. The incidence of treatment-emergent adverse events (TEAEs) was similar between fed and fasted conditions. Four TEAEs were considered related to study intervention and were reported after participants received atogepant under fasted conditions (3 participants). A single-dose atogepant 60mg IR tablet was safe and tolerated under both fed and fasted states. Due to the wide effective dose range of 10-60mg/day for atogepant for the preventive treatment of migraine, the food effect on its pharmacokinetics is not considered clinically relevant.

Study on pharmacokinetics and tissue distribution of deoxypodophyllotoxin and its metabolites in tumour-bearing mice

To study the pharmacokinetics of deoxypodophyllotoxin and its metabolites in non-small cell lung cancer (NSCLC) bearing mice. Using the established LC-MS/MS method for simultaneous determination of deoxypodophyllotoxin and its three main metabolites (M1, M2 and M7) in biological samples, the concentrations of deoxypodophyllotoxin and its metabolites in plasma, tumour and major tissues of tumour-bearing mice were investigated after 6.25 and 25 mg/kg intravenous administration of deoxypodophyllotoxin. The exposure results of drug concentration showed that after intravenous injection of 6.25 and 25 mg/kg of DPT into tumour-bearing mice, the AUC ratio of DPT in tumour tissue to DPT in plasma was 4.23 and 3.80, respectively. While, the AUC ratio of metabolite M2 in tumour tissue to M2 in plasma was 0.82 and 0.76, respectively. Deoxypodophyllotoxin had higher affinity with tumour tissues than plasma, while its metabolite M2 had less affinity with tumour tissues than deoxypodophyllotoxin, but the exposure level of M2 in plasma was higher than that of deoxypodophyllotoxin. Deoxypodophyllotoxin was widely distributed in tumour-bearing mice. After intravenous injection of 25 mg/kg deoxypodophyllotoxin, the concentration of deoxypodophyllotoxin in other tissues except liver and muscle was relatively high, especially in lung, fat and reproductive organs.

Pregnane X receptor activation induces liver enlargement and regeneration and simultaneously promotes the metabolic activity of CYP3A1/2 and CYP2C6/11 in rats.

Human pregnane X receptor (PXR) is critical for regulating the expression of key drug-metabolizing enzymes such as CYP3A and CYP2C. Our recent study revealed that treatment with rodent-specific PXR agonist pregnenolone-16α-carbonitrile (PCN) significantly induced hepatomegaly and promoted liver regeneration after two-thirds partial hepatectomy (PHx) in mice. However, it remains unclear whether PXR activation induces hepatomegaly and liver regeneration and simultaneously promotes metabolic function of the liver. Here, we investigated the metabolism activity of CYP1A2, CYP3A1/2 and CYP2C6/11 during PXR activation-induced liver enlargement and regeneration in rats after cocktail dosing of CYP probe drugs. For PCN-induced hepatomegaly, a notable increase in the metabolic activity of CYP3A1/2 and CYP2C6/11, as evidenced by the plasma exposure of probe substrates and the AUC ratios of the characteristic metabolites to its corresponding probe substrates. The metabolic activity of CYP1A2, CYP3A1/2 and CYP2C6/11 decreased significantly after PHx. However, PCN treatment obviously enhanced the metabolic activity of CYP2C6/11 and CYP3A1/2 in PHx rats. Furthermore, the protein expression levels of CYP3A1/2 and CYP2C6/11 in liver were up-regulated. Taken together, this study demonstrates that PXR activation not only induces hepatomegaly and liver regeneration in rats, but also promotes the protein expression and metabolic activity of the PXR downstream metabolizing enzymes such as CYP3A1/2 and CYP2C6/11 in the body.

Minimal Involvement of P-gp and BCRP in Oral Absorption of Ensitrelvir, An Oral SARS-CoV-2 3C-like Protease Inhibitor, in a Non-Clinical Investigation

P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are important transporters causing drug-drug interaction (DDI). Here, we investigated the involvement of P-gp and BCRP in the oral absorption of ensitrelvir in non-clinical studies and estimated the DDI risk mediated by P-gp and BCRP inhibition in humans. Although ensitrelvir is an in vitro P-gp and BCRP substrate, it demonstrated high bioavailability in rats and monkeys after oral administration. Plasma exposures of ensitrelvir following oral administration were comparable in wild type (WT) and Bcrp (-/-) mice. On the other hand, the area under the plasma concentration-time curve (AUC) ratio of ensitrelvir in the Mdr1a/1b (-/-) mice to the WT mice was 1.92, indicating that P-gp, but not BCRP, was involved in the oral absorption of ensitrelvir. Based on our previous retrospective analyses, such a low AUC ratio (<3) in the Mdr1a/1b (-/-) mice indicates a minimal impact of P-gp on the oral absorption in humans. In conclusion, our studies demonstrate that the involvement of both P-gp and BCRP in the oral absorption of ensitrelvir is minimal, and suggest that ensitrelvir has a low risk for DDIs mediated by P-gp and BCRP inhibition in humans.

Pharmacokinetic profile and incurred sample stability of hydroxychloroquine in Volumetric Absorptive Microsampling (VAMS) using high-performance liquid chromatography-photodiode array

Background: Hydroxychloroquine (HCQ) is a quinoline compound derived from chloroquine used to treat SLE. An in vitro stability evaluation was conducted to develop and validate the hydroxychloroquine analysis method. However, an assessment of the incurred sample stability is needed to ensure drug effectiveness, as in vitro evaluation doesn't reflect drug metabolism processes in the body. Objective: This research aims to obtain a pharmacokinetic profile of hydroxychloroquine using Volumetric Absorptive Microsampling (VAMS) as a safe sampling technique to use during the COVID-19 pandemic and evaluate the incurred sample stability of hydroxychloroquine samples. Methods: The chromatographic conditions used were column C18 (Waters, XBridge; 250 × 4.6 mm; 5μm); mobile phase acetonitrile-1% diethylamine (65:35); flow rate of 0.8 mL/min; column temperature 45°C; PDA detector analysis wavelength of 332 nm; and chloroquine as internal standard. Results: The pharmacokinetic profile of hydroxychloroquine in VAMS samples gave results that the Cmax ranged from 322.61-505.32 ng/mL with an average of 425.33 ± 65.90 ng/mL; tmax was 4 hours; mean t1/2 was 23.32 ± 9.65 hours; mean AUC0-72 was 5103.63 ± 1419.66 ng.h/mL; mean AUC0-∞ was 5763.97 ± 2155.26 ng.h/mL, and the AUC ratio was above 80%. Conclusion: The incurred sample stability of hydroxychloroquine in VAMS met the 2011 EMEA Bioanalytical Guideline requirements up to day 30.

Development of a deep learning model for predicting recurrence of hepatocellular carcinoma after liver transplantation.

Liver transplantation (LT) is one of the main curative treatments for hepatocellular carcinoma (HCC). Milan criteria has long been applied to candidate LT patients with HCC. However, the application of Milan criteria failed to precisely predict patients at risk of recurrence. As a result, we aimed to establish and validate a deep learning model comparing with Milan criteria and better guide post-LT treatment. A total of 356 HCC patients who received LT with complete follow-up data were evaluated. The entire cohort was randomly divided into training set (n = 286) and validation set (n = 70). Multi-layer-perceptron model provided by pycox library was first used to construct the recurrence prediction model. Then tabular neural network (TabNet) that combines elements of deep learning and tabular data processing techniques was utilized to compare with Milan criteria and verify the performance of the model we proposed. Patients with larger tumor size over 7 cm, poorer differentiation of tumor grade and multiple tumor numbers were first classified as high risk of recurrence. We trained a classification model with TabNet and our proposed model performed better than the Milan criteria in terms of accuracy (0.95 vs. 0.86, p < 0.05). In addition, our model showed better performance results with improved AUC, NRI and hazard ratio, proving the robustness of the model. A prognostic model had been proposed based on the use of TabNet on various parameters from HCC patients. The model performed well in post-LT recurrence prediction and the identification of high-risk subgroups.

Pharmacogenetics of Efavirenz Exposure in Cervicovaginal Fluid during Pregnancy and Postpartum.

In this study, we investigated the combined influence of pregnancy and genetic polymorphisms on efavirenz pharmacokinetics in cervicovaginal fluid (CVF) of women receiving antiretroviral therapy. Women receiving efavirenz-containing antiretroviral therapy were recruited from two hospitals in Nigeria during 2017-2020. Sparse CVF and plasma samples were obtained during pregnancy to assess the possible association between drug concentration and CYP2B6 polymorphisms (stage I). Participants were stratified into three CYP2B6 516G>T (rs3745274) genotype groups and re-enrolled for intensive pharmacokinetic sampling (stage II). Overall, 159 women (142 pregnant and 12 postpartum) contributed samples in stage I (88 CVF, 81 plasma and 73 paired). CYP2B6 516G>T (rs3745274) remained independently associated with log10 efavirenz CVF concentration during pregnancy after adjusting for plasma concentration, with β (Log10 efavirenz concentration, 95%CI) of 0.204 (0.027, 0.382), P = 0.025). Median (IQR) efavirenz C min in CVF during pregnancy (n = 12) vs. postpartum (n = 12) was 243 ng/mL (168-402) vs. 447 ng/mL (159-974), C max was 1,031 ng/mL (595-1,771) vs. 1,618 ng/mL (675-2,695), and AUC0-24h was 16,465 ng.h/mL (9,356-30,417) vs. 30,715 ng.h/mL (10,980-43,714). CVF-to-plasma AUC ratio was 0.36 during pregnancy and 0.46 postpartum. Upon stratification, efavirenz clearance during pregnancy was 57.9% higher than postpartum in patients with the CYP2B6 516GT genotype; the AUC0-24h and C max were 33.8% and 8.6% lower, respectively. Efavirenz C min in CVF exceeded the protein binding-adjusted IC90 (PBIC90) of 126 ng/mL during pregnancy and postpartum. Efavirenz is well distributed into the CVF; both pregnancy and CYP2B6 polymorphisms affect the extent of exposure.

Evaluating drug interaction potential from cytokine release syndrome using a physiologically based pharmacokinetic model: A case study of teclistamab.

Cytokine release syndrome (CRS) was associated with teclistamab treatment in the phase I/II MajesTEC-1 study. Cytokines, especially interleukin (IL)-6, are known suppressors of cytochrome P450 (CYP) enzymes' activity. A physiologically based pharmacokinetic model evaluated the impact of IL-6 serum levels on exposure of substrates of various CYP enzymes (1A2, 2C9, 2C19, 3A4, 3A5). Two IL-6 kinetics profiles were assessed, the mean IL-6 profile with a maximum concentration (Cmax) of IL-6 (21 pg/mL) and the IL-6 profile of the patient presenting the highest IL-6 Cmax (288 pg/mL) among patients receiving the recommended phase II dose of teclistamab in MajesTEC-1. For the mean IL-6 kinetics profile, teclistamab was predicted to result in a limited change in exposure of CYP substrates (area under the curve [AUC] mean ratio 0.87-1.20). For the maximum IL-6 kinetics profile, the impact on omeprazole, simvastatin, midazolam, and cyclosporine exposure was weak to moderate (mean AUC ratios 1.90-2.23), and minimal for caffeine and s-warfarin (mean AUC ratios 0.82-1.25). Maximum change in exposure for these substrates occurred 3-4 days after step-up dosing in cycle 1. These results suggest that after cycle 1, drug interaction from IL-6 effect has no meaningful impact on CYP activities, with minimal or moderate impact on CYP substrates. The highest risk of drug interaction is expected to occur during step-up dosing up to 7 days after the first treatment dose (1.5 mg/kg subcutaneously) and during and after CRS.

Population pharmacokinetics of trastuzumab deruxtecan (T-DXd) in subjects with HER2-mutant and HER2-overexpressing non-small cell lung cancer (NSCLC).

e20537 Background: T-DXd is a novel human epidermal growth factor receptor 2 (HER2) targeting antibody drug conjugate, approved globally at the dose of 5.4 mg/kg in HER2-positive or HER2-low breast cancer (BC) and HER2-mutant (HER2m) NSCLC1,2. The aim of the analysis was to characterize the populaton pharmacokinetics (PopPK) of T-DXd and its released payload, deruxtecan (DXd), in HER2m or HER2-overexpressing (HER2-OE) NSCLC subjects using data across tumor types (BC, NSCLC and others) from 12 Phase 1 to 3 studies with T-DXd doses ranging from 0.8-8.0 mg/kg. Methods: Analysis wasperformed using nonlinear mixed-effects modeling methods in NONMEM (version 7.4.3), similar to the previous analysis in HER2-positive BC1. Covariate effects were explored on the PK parameters of T-DXd and DXd. Results: Analysis included data across 1822 subjects, including 346, 1128, and 348 subjects with NSCLC, BC, and other cancers, respectively. The PK of T-DXd and DXd were adequately described by a PopPK model, judging by standard model diagnostics3. Covariate effects on T-DXd and DXd steady-state area under the concentration-time curve (AUC) were not clinically meaningful (within 0.8 to 1.25 AUC ratio interval for tested covariate level versus reference), except for subjects with high body weight (e.g., 90 kg; 95th percentile) showing a 31% and 37% higher T-DXd and DXd AUC, respectively, relative to typical subject with 58 kg body weight (median).The T-DXd and DXd AUC were also similar across subjects with BC, HER2m or HER2-OE NSCLC, with the same T-DXd dose. T-DXd and DXd AUC in NSCLC subjects were similar across subjects with mild hepatic or mild or moderate renal impairment (vs. normal counterparts), region (Asia, North America, Europe, and rest of the world), and race-country (Asian-Japan, Asian-Non-Japan, and Non-Asian) groups. Conclusions: T-DXd and DXd exposures were similar across subjects with BC and HER2m or HER2-OE NSCLC, as well as across hepatic function, renal function, region, and race-country groups within NSCLC supporting the use of 5.4 mg/kg dose (approved dose in BC) in HER2m or HER2-OE NSCLC from PK perspective. Reference: Enhertu [package insert]. Basking Ridge, NJ: Daiichi Sankyo, Inc.; 2022. Enhertu [summary of product characteristics]. Daiichi Sankyo Europe GmbH, Munich; 2022 Yin O et al. Clin Pharmacol Ther. 2021;109(5):1314-1325. Clinical trial information: NCT04644237 , NCT03505710 .