Plasma Concentrations Research Articles

Evaluating the Real-World Pharmacokinetics of Risperidone ISM® in Routine Clinical Practice

Background/Objectives: Risperidone ISM® is a long-acting injectable (LAI) formulation approved for monthly administration in schizophrenia treatment. It employs innovative in situ microimplant technology for biphasic drug release, achieving immediate and sustained therapeutic plasma concentrations without the need for oral supplementation or loading doses. This study evaluates the pharmacokinetic profile of Risperidone ISM® in a real-world clinical setting, focusing on plasma concentrations of the active moiety (Risperidone + 9-OH-Risperidone). Methods: An observational study was conducted to measure plasma concentrations of patients receiving Risperidone ISM® (75 mg or 100 mg). Samples were collected at pre-dose, 2 h, 24 h, 14 days, 21 days, and 25 days post-injection. Pharmacokinetic parameters, including Cmax, Cmin, Tmax, and AUC, were calculated and stratified by dose (75 mg and 100 mg) and injection site (gluteal vs. deltoid). Results: A total of 44 patients were included. Therapeutic plasma levels were reached within hours post-injection and sustained throughout the 28-day interval. Cmin values averaged 34.4 ng/mL and 36.1 ng/mL for the 75 mg and 100 mg doses, respectively. The median Tmax occurred at 24 h with a mean Cmax of 55.7 ng/mL and 59 ng/mL for 75 mg and 100 mg, respectively. Higher systemic exposure was observed for deltoid administration. Significant interindividual variability was noted, with 45.4% of patients exhibiting trough levels outside the therapeutic range. Conclusions: Risperidone ISM® achieves rapid and sustained therapeutic plasma levels, offering significant benefits in schizophrenia treatment. However, the high interindividual variability observed must be thoroughly studied, and the contributing factors identified to ensure the therapy is as effective and safe as possible.

Size distribution of extracellular vesicles in pretreatment ascites and plasma is correlated with primary treatment outcome in advanced high-grade serous carcinoma

Abstract To improve the treatment outcome and survival of patients with advanced high-grade serous carcinoma (HGSC), prognostic biomarkers for assessing the feasibility of complete (R0) or optimal (R1) primary cytoreductive surgery are needed. Additionally, biomarkers for predicting the response to neoadjuvant chemotherapy (NACT) in patients with primary inoperable disease could help stratify patients for tailored therapy and improve personalised approach. Such promising biomarkers are extracellular vesicles (EVs), which are present in ascites and plasma and are available for minimally invasive liquid biopsy. EV concentration and EV molecular profile have been at the forefront of research in the field of biomarkers for many years now, but recent studies have highlighted the importance of EV size distribution. Our study aimed to evaluate the potential of the EV concentration and size distribution in pretreatment ascites and plasma samples from patients with advanced HGSC as prognostic biomarkers. In our prospective cohort study, nanoparticle tracking analysis (NTA) was used to determine EV characteristics in paired pretreatment ascites and plasma samples from 37 patients with advanced HGSC. Patients were treated with primary cytoreductive surgery followed by adjuvant chemotherapy (ACT) (N = 15) or NACT followed by interval debulking surgery (IDS) when optimal cytoreduction was not feasible (N = 22). The correlations of the EV concentration and size distribution in ascites and plasma with treatment outcome, progression-free survival (PFS) and overall survival (OS) were analysed. We found a significant correlation between the EV size distribution in ascites and residual disease after primary cytoreductive surgery. Larger EVs in ascites correlated with worse resection success after primary cytoreductive surgery. A significant correlation between the D10 value of EVs in plasma and the chemotherapy response score (CRS) after NACT was observed. A smaller D10 value of plasma EVs was correlated with a better chemotherapy response. Receiver operating characteristic (ROC) curve analysis revealed excellent performance for D10 value in ascites for the prediction of suboptimal (R2) resection at primary debulking surgery and excellent performance for D10 value in plasma for the prediction of complete or near-complete chemotherapy response score (CRS 3) at interval debulking surgery. There was a significant correlation between the mean diameter, D90 value and proportion of medium/large (> 200 nm) EVs in ascites and those in plasma. On the other hand, there was no correlation of the EV concentration or D10 and D50 values between the ascites fluid and plasma samples. Our results indicate that the EV size distribution in ascites has the potential to predict resection success after primary cytoreductive surgery and that the EV size distribution of the smallest EVs in plasma might help predict the chemotherapy response of patients treated with NACT. In the future, molecular analyses of size-dependent EV cargo could provide more insight into their biological functions and potential as predictive biomarkers.

Model-informed dose optimization for prophylactic piperacillin-tazobactam in perioperative pediatric critically ill patients.

Piperacillin/tazobactam (PTZ) is frequently prescribed during the perioperative period as prophylaxis in critically ill patients. Current international guidelines recommend that the pediatric intraoperative dosing regimen for PTZ be 90-112.5 mg/kg (80-100 mg/kg as piperacillin [PIP]) administered every 2 hours (Q2H). Concerns have been raised not only about the risk of nephrotoxicity due to elevated PIP exposure but also regarding the practicality of adhering to a 2-h dosing interval in clinical settings. To address these concerns, we employed population pharmacokinetic (PK) modeling and simulation approaches to optimize PTZ dosing regimens in pediatric intraoperative patients. PIP plasma concentration data were obtained from 34 patients using an opportunistic sampling strategy. A two-compartment model was found to adequately describe the PK data. Creatinine clearance was identified as a significant covariate on clearance. The inclusion of inter-occasion variability significantly improved model fit. Simulations across body weights of 10-70 kg and creatinine clearance of 20-130 mL/min/1.73 m2 demonstrated that 6-15 mg/kg Q2H, or a 10 mg/kg loading dose followed by 1.0-2.75 mg/kg/h continuous infusion would achieve free PIP concentrations being above the minimum inhibitory concentration (MIC) for 100% of the dosing interval (100% fT >1× MIC). For achieving 100% fT >4× MIC, 25-55 mg/kg Q2H or a 20 mg/kg loading dose followed by 3.25-9.25 mg/kg/h continuous infusion was derived. The model-informed simulations indicated that both lower Q2H doses and continuous infusion methods are clinically viable options and potentially resolve current clinical challenges during intraoperative dosing.

Pharmacokinetics and bioequivalence of a molnupiravir tablet formulation compared with the molnupiravir capsule formulation in healthy adult participants-a randomized, open-label, three-period, crossover study.

Molnupiravir, a prodrug of β-D-N4-hydroxycytidine (NHC), is administered orally as four 200 mg capsules twice daily for 5 days to treat COVID-19. This randomized, open-label, four-treatment sequence, three-period crossover study (NCT06615869) evaluated the bioequivalence of a new single 400 mg oral dose of the molnupiravir tablet Formulation 1 (F1) to a 400 mg oral dose of the currently authorized molnupiravir capsule formulation (administered as two 200 mg capsules) by comparing the plasma pharmacokinetics of NHC following administration to healthy participants. The effect of food on the plasma NHC pharmacokinetics following the administration of the molnupiravir F1 tablet, safety and tolerability of a single oral 400 mg dose of molnupiravir, and pharmacokinetics of a separate molnupiravir tablet Formulation 2 (F2) with a slower in vitro dissolution rate were also evaluated. The geometric mean ratio and 90% confidence intervals ([1 × 400-mg F1 tablet]/[2 × 200 mg reference capsules]) for plasma NHC area under the concentration-time curve (AUC) from time 0-infinity, AUC from time 0-last measurable time point, and maximum plasma concentration were 1.00 (0.97, 1.03), 1.00 (0.97, 1.03), and 0.98 (0.93, 1.03), respectively. All estimates were within prespecified limits (0.80, 1.25), demonstrating bioequivalence of the molnupiravir F1 tablet and reference capsules. Administration of the F1 tablet with a high-fat meal did not meaningfully impact the rate or extent of absorption. The pharmacokinetics of the F2 tablet were similar to the reference capsules. Administered in either formulation, molnupiravir was generally safe and well tolerated. In conclusion, a single 400 mg tablet of molnupiravir is bioequivalent to the reference capsule formulation in healthy adults.CLINICAL TRIALSThis study was registered at ClinicalTrials.gov as NCT06615869.

A Novel LC-MS/MS Method for the Measurement of Elexacaftor, Tezacaftor and Ivacaftor in Plasma, Dried Plasma Spot (DPS) and Whole Blood in Volumetric Absorptive Microsampling (VAMS) Devices

Background: The combination of ivacaftor, tezacaftor and elexacaftor (ETI) is approved for patients with cystic fibrosis (CF) aged two years and older and at least one F508del mutation in the CFTR gene. Variability in ETI treatment response has been repeatedly reported, and its reasons are unclear and understudied. Objectives: We present a novel liquid chromatography–tandem mass spectrometry (LC–MS/MS) method for the rapid and simultaneous quantification of ETI in plasma, dried plasma spots (DPS), and whole blood volumetric absorptive microsampling (VAMS). Methods: The method utilizes a rapid extraction protocol with 200 μL methanol after the addition of deuterated internal standards. Chromatographic separation was achieved using a reversed-phase Hypersil Gold aQ column (Thermo Fisher Scientific). The method was validated according to ICH (International Council on Harmonisation) guidelines M10 for bioanalytical method validation, demonstrating linearity in the concentration range 0.020–12.000 µg/mL. It was also proved accurate and reproducible with no matrix effect. This method was applied to anonymized samples from patients undergoing ETI treatment: eight plasma and DPS and five VAMS samples were analyzed. Results: ETI concentrations measured in plasma and DPS were interchangeable, whereas ETI concentrations in VAMS were lower than in plasma, as expected for molecules with high plasma protein binding (99%). A correction factor based on the hematocrit value was used to calculate the equivalent plasma concentration from VAMS concentrations. Conclusions: This method is suitable for pharmacokinetic (PK) studies and could facilitate the centralization of samples to specialized laboratories, supporting multicenter studies.

Effect of Riociguat on Adenine-Induced Chronic Kidney Disease in Rats

Riociguat is a soluble guanylate cyclase (sGC) activator that increases the levels of cyclic guanosine monophosphate (cGMP). cGMP is known to play a key role in regulating kidney function. This research sought to investigate the possible protective effects of riociguat on the kidneys in the context of chronic kidney disease (CKD). CKD was induced in male Wistar rats through adenine administration. A total of 24 rats were allocated into four groups and administered treatments over a period of 35 days. Group 1 received a normal diet and a vehicle (carboxymethylcellulose (0.5%)), serving as the control. Group 2 received adenine (0.25% w/w) in the feed and a vehicle. Groups 3 and 4 received adenine in the feed (0.25% w/w) plus riociguat (3 mg/kg/day) and riociguat (10 mg/kg/day), respectively. Adenine administration significantly elevated systolic blood pressure, plasma creatinine, urea, and neutrophil gelatinase-associated lipocalin (NGAL). Furthermore, adenine reduced creatinine clearance and increased the urinary albumin-to-creatinine ratio and urinary N-Acetyl-β-D-Glucosaminidase (NAG). Histopathologically, adenine caused renal tubular necrosis and fibrosis. Furthermore, adenine elevated the plasma concentration of interleukins (IL-1β and IL-6) and tumor necrosis factor-alpha (TNF-α). Adenine significantly increased renal malondialdehyde (MDA) and reduced glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT), and total antioxidant capacity (TAC). Treatment with riociguat attenuated adenine-induced hypertension, improved kidney function, and ameliorated histopathological changes. Riociguat also reduced kidney injury markers, inflammation, and renal oxidative stress. The renoprotective effect of riociguat is probably due to anti-inflammatory and antioxidant actions. This indicates that riociguat may have the potential to slow the progression of kidney damage in chronic kidney disease (CKD).

Bioanalytical method development, in-vivo pharmacokinetic evaluation, ex-vivo platelet aggregation inhibition activity of a novel solid dispersion formulation of ticagrelor

BackgroundTicagrelor, a potential antithrombotic drug indicated for cardiovascular events with acute coronary syndrome, has been restricted from its oral use due to poor aqueous solubility. The present investigation aimed to develop validated bioanalytical method for the analysis of plasma samples for improving the oral bioavailability of Ticagrelor. Additionally, evaluation of the improved antiplatelet activity of the Ticagrelor formulation compared to the marketed formulation.MethodsA bioanalytical method was developed in rat plasma samples using the isocratic separation mode. Plasma samples were processed by liquid-liquid extraction and analyzed by using reverse phase HPLC. A validated method was used for evaluating the pharmacokinetic profile of the developed formulation and marketed formulation in Sprague Dawley rats. Additionally, the ex-vivo antiplatelet aggregation activity was evaluated.ResultsThe developed method was accurate and linear (100 ng−800 ng) to quantify the drug in plasma. An in-vivo pharmacokinetic study was conducted for formulation at 10 mg/kg and different pharmacokinetic parameters were evaluated. From the results, we observed∼64% enhancements in the oral bioavailability of the Ticagrelor relative to the marketed formulation. The developed formulation (SD1) showed more significant inhibition of ADP-induced platelet aggregation compared to the marketed ticagrelor (RLD) formulation.ConclusionIn conclusion, we have successfully developed a validated analytical method for estimating Ticagrelor plasma concentration. Additionally, our study successfully enhanced Ticagrelor's oral bioavailability, and the developed formulation has more significant inhibition of ADP-induced platelet aggregation relative to the marketed formulation, indicating its substantial therapeutic potential.

A randomised controlled trial to evaluate the use of genotyping and therapeutic drug monitoring versus only therapeutic drug monitoring as a strategy for risk minimisation in patients of epilepsy on phenytoin therapy

Objectives: Phenytoin has a unique feature of accumulating in the body due to its non-linear elimination kinetics. Being a drug with a narrow therapeutic index, phenytoin needs routine therapeutic drug monitoring (TDM) to adjust the dose. Polymorphisms in cytochrome P450 (CYP [2C9 and C19]) genes reduce drug metabolism, increase drug concentrations and thus produce adverse drug reactions (ADRs). Detection of polymorphisms helps to predict the susceptibility to toxicity. Hence, this study was designed to compare the addition of genotyping to TDM of phenytoin as an investigational tool for assessing plasma levels and occurrence of ADRs in epileptic patients on phenytoin therapy as a part of risk minimisation. Materials and Methods: This randomised controlled trial was prospective and double-blind. Epileptic patients were randomised into two groups. One group received therapeutic doses of phenytoin based on their CYP2C9 and CYP2C19 genotyping, followed by monitoring drug levels by TDM. The other group was treated with phenytoin based on the clinician’s judgement. Monitoring of blood levels was done by TDM. Chi-squared test was used to analyse the difference in the occurrence of ADRs between the two groups. Results: In each group, Group A (genotyping and TDM) and Group B (TDM alone), 30 patients were enrolled, totalling 60 patients. Baseline characteristics of participants with or without CYP2C9 and CYP2C19 expression were statistically not significant. At the 6-month follow-up visit, in both CYP2C9 and CYP2C19 groups, the plasma concentration of phenytoin was statistically significant. We found 10 ADRs, and between the two groups, the difference in the occurrence of ADRs was non-significant. Conclusion: We found no significant utility of the addition of the genotyping in risk minimisation of phenytoin when used with TDM. Genotyping can be considered at the time of initiation of phenytoin therapy in epileptic patients.

Specific airway resistance according to early maternal vitamin D status during pregnancy in children aged 5 to 6 years old from the FEPED cohort (RESPIFEPED)

There are conflicting results on the association between maternal vitamin D concentrations during pregnancy and respiratory outcomes for their offspring. However, published studies have mainly focused on the second and third trimesters of pregnancy or on high-risk population. The main objective of this study was to evaluate the association between vitamin D plasma concentrations in the first trimester (T1) of pregnancy and effective specific airway resistance (sReff) for children aged 5 to 6. Secondary objectives were to evaluate this association in the third trimester (T3) and in cord blood as well as the association between vitamin D plasma concentration and interrupter resistance (Rint), bronchiolitis, asthma, and allergen sensitization at the same time points. This multicenter study included 140 children born from women enrolled in the FEPED cohort. Associations between sReff and maternal vitamin D plasma concentration at T1, T3 of pregnancy, and in cord blood were assessed. sReff was analyzed according to in-utero and postnatal exposure to tobacco smoke and the occurrence of an episode of bronchiolitis before 6 months of age. The impact of maternal vitamin D status on the secondary outcomes was similarly assessed. sReff values were not associated with the maternal vitamin D status at T1 and T3, nor asthma status or allergen sensitization.Conclusion: In a cohort of young children, airway resistance and asthma were not associated with early vitamin D deficiency during pregnancy.Trial registration: This study is registered with the ClinicalTrials.gov identifier NCT03229317.What is Known:• There are conflicting results on the association between maternal vitamin D concentrations during pregnancy and respiratory outcomes for their offspring. However, published studies have mainly focused on the second and third trimesters of pregnancy or on high-risk population.What is New:• In a cohort of 5- to 6-year-old children assessed prospectively, there was no significant difference in sReff or any other lung function measurements depending on maternal vitamin D status during the first trimester of pregnancy.

Efficacy, safety, and pharmacokinetics of lenacapavir oral bridging when subcutaneous lenacapavir cannot be administered.

To assess efficacy, safety and pharmacokinetics (PK) of oral lenacapavir (LEN) when used as oral bridging (OB) between delayed subcutaneous (SC) LEN injections. Posthoc analysis of participants in two clinical trials of SC LEN for HIV-1 treatment who required OB when LEN SC dosing was interrupted. Oral LEN [300 mg once weekly (QW)] was initiated within 2 weeks of the next scheduled injection (dosing interval: 26 weeks). Efficacy, safety, and PK were assessed every 10-12 weeks. Overall, 139 participants received ≥1 dose of oral 300 mg QW LEN plus other antiretrovirals. Median duration of OB was 19 weeks in both clinical trials. By missing = excluded analysis, over 95% of participants maintained virologic suppression (HIV-1 RNA <50 copies/ml) at Weeks 10, 20, and 30. Treatment-emergent AEs (TEAEs) were similar to those with SC LEN (excluding injection site reactions). No Grade ≥3 or serious TEAEs were considered related to oral LEN. Throughout OB, mean LEN plasma concentrations and lower bound 90% confidence intervals (CIs) were consistently above inhibitory quotient 4 (4-fold in-vitro protein binding-adjusted 95% effective concentration). OB adherence (by pill count) was ≥95% in the majority of participants in both clinical trials. High rates of virological suppression were maintained during OB. Oral 300 mg QW LEN was well tolerated and provided adequate plasma concentrations to bridge SC LEN dosing. This analysis supports using 300 mg QW LEN for OB when SC LEN treatment is interrupted.

Voriconazole Steady-State Trough Concentrations and Clinical Outcomes in Patients with Talaromycosis.

Voriconazole (VRC) has been used as an alternative treatment for talaromycosis. However, there are few studies reporting the VRC plasma concentration in patients with talaromycosis. The purpose of this study was to analyze the correlations between VRC initial steady-state trough concentration and clinical outcomes. We prospectively enrolled patients who were diagnosed with talaromycosis and received VRC as initial antifungal treatment regime. Medical information, VRC initial steady-state trough concentration, clinical outcomes and adverse events (AEs) were recorded for analysis. This study included 69 patients with talaromycosis receiving VRC treatment, including 38 HIV-positive patients and 31 HIV-negative patients. The average age of the HIV-positive patients was 42years, and that of the HIV-negative patients was 51years. After 12 weeks of antifungal treatment, 55 patients achieved clinical remission, 3 patients were transferred to amphotericin B treatment because of persistent clinical symptoms, and 5 patients died, 2 patients discontinued VRC treatment due to AEs. Follow up to6 months,a total of 14 AEs were observed in 12 patients, and 3 patients discontinued VRC treatment due to AEs. The average VRC initial steady-state trough concentration was 5.26mg/L, with a range of 0.23-16.95mg/L, indicating high variability. No correlation was found between the VRC initial steady-state trough concentration and treatment failure (P = 0.079). A significant correlation between AEs and the VRC initial steady-state trough concentration was found (P = 0.048). The VRC initial steady-state trough concentration threshold for AEs was 5.88mg/L according to the ROC curve analysis. In addition, there was a significant correlation between mortality and the APACHE II score (P = 0.029). The risk of death significantly increased when the APACHE II score was > 10. Voriconazole is an effective antifungal drug for talaromycosis in patients with APACHE II scores < 10. VRC steady-state trough concentration may not be significantly correlated with poor prognosis. A high VRC trough concentration was significantly correlated with AEs, and it may promote the management of AEs.

Pharmacokinetic comparison of a fixed-dose combination of telmisartan/rosuvastatin/ezetimibe/amlodipine 80/20/10/5 mg and a loose-dose combination of ezetimibe/rosuvastatin 10/20 mg and telmisartan/amlodipine 80/5 mg in healthy male subjects.

This study aimed to compare the pharmacokinetic (PK) profiles of a fixed-dose combination (FDC) tablet of telmisartan/rosuvastatin/ezetimibe/amlodipine 80/20/10/5 mg and a loose-dose combination (LDC) of two FDC tablets, ezetimibe/rosuvastatin 10/20 mg and telmisartan/amlodipine 80/5 mg, in healthy Korean male subjects. This study was conducted as a randomized, open-label, two-sequence, four-period crossover study. The subjects received the FDC or the LDC of telmisartan, rosuvastatin, ezetimibe, and amlodipine twice, with a 21-day washout in each period. Each sequence was composed of either FDC/LDC/FDC/LDC or LDC/FDC/LDC/FDC in that order. Serial blood samples for PK analysis were collected up to 48 h after rosuvastatin dosing and 72 h after telmisartan, ezetimibe, and amlodipine dosing. The PK parameters were calculated by a noncompartmental method, and safety profiles were evaluated throughout the study. Fifty-four healthy Korean male subjects were enrolled, and 42 subjects completed the study. The concentration‒time profiles of telmisartan, rosuvastatin, ezetimibe, and amlodipine were similar between the FDC and LDC groups. For each compound, the geometric mean ratios (90% confidence intervals) of the peak concentration and area under the plasma concentration‒time curve of FDC to LDC were within the conventional bioequivalence criteria of 0.8-1.25. Both the FDC and LDC treatments were well tolerated and determined to be safe. The FDC and LDC treatments with telmisartan, rosuvastatin, ezetimibe, and amlodipine showed pharmacokinetic bioequivalence, indicating that the FDC of telmisartan/rosuvastatin/ezetimibe/amlodipine 80/20/10/5 mg can be used as an alternative to the LDC treatment.

Population Pharmacokinetics of Cobicistat and its Effect on the Pharmacokinetics of the Anticancer Drug Olaparib.

Pharmacokinetic (PK) boosting is the intentional use of strong inhibitors of metabolic enzymes or transporters to boost the systemic exposure of a therapeutic drug. PK boosting is expanding to therapeutic areas outside human immunodeficiency virus (HIV) therapy. Data on the PK of the booster cobicistat and its effect on CYP3A-substrates outside of HIV therapy are lacking. This study aimed to describe the PK of once- and twice-daily cobicistat regimens in healthy volunteers and patients with rheumatoid arthritis, cancer, or HIV infection and to investigate the interplay between cobicistat and the anticancer drug olaparib. Cobicistat levels from 683 samples from 66 subjects in four clinical trials were included in the analysis. For olaparib, 261 samples from 12 subjects from one trial were included. Population PK analysis was performed by nonlinear mixed-effects modelling. Both cobicistat and olaparib PK were adequately described by a well-stirred liver model with one central compartment and Erlang type absorption. Cobicistat PK was similar across patient populations and dosing regimens. Cobicistat increased olaparib prehepatic bioavailability 1.65-fold (RSE 6%) and decreased intrinsic clearance 0.34-fold (RSE 6.5%). A correlation between olaparib PK and cobicistat exposure could not be identified. The interindividual variability in olaparib clearance was lower with cobicistat than without cobicistat. The developed pharmacokinetic models adequately described cobicistat and olaparib plasma concentrations. PK boosting with cobicistat at 150 mg twice daily led to an increase in olaparib bioavailability and decrease in clearance. This effect was not correlated with cobicistat exposure, which may reflect saturation of the boosting effect of cobicistat at this dose. NCT02565888 (30-09-2015), NCT00825929 (19-01-2009), Netherlands Trial Register NL7766 (18-12-2018), NCT05078671 (22-09-2021).

Drug Loss at Arterial Bends Can Dominate Off-Target Drug Delivery by Paclitaxel-Coated Balloons

Background/Objective: Paclitaxel-coated balloons (PCBs) can deliver efficacious drug concentrations to treated arterial segments but are known to exhibit high tracking losses. We aimed to define the governing factors impacting tracking loss and to contrast its drug distribution consequences with those of PCB inflation at the treatment site. Methods: Four naïve and four in-stent restenosis (ISR) porcine superficial femoral arteries (SFA) were treated with PCBs, and plasma samples were collected post-tracking and post-inflation. Animals were sacrificed &lt;1 h post-intervention, and local, upstream, and downstream tissues were collected for paclitaxel quantification. Computationally driven quantitative benchtop-tracking and frictional PCB-sliding experiments modeled paclitaxel loss and delivery to upstream tissue. Results: Paclitaxel concentrations in plasma peaked pre-inflation and declined 30-fold immediately post-inflation. Correspondingly, losses of 30% and 1% of nominal PCB load were measured in vitro during, respectively, tracking over single bend and during device insertion. Mean paclitaxel concentrations were equally high at ISR and naïve SFA treatment sites (56,984 vs. 79,837 ng/g, p &gt; 0.99) and ranged from 9 to 89 ng/g in tissues downstream of these treatment sites. Sampling of non-target upstream iliac artery tissues revealed paclitaxel concentration of 4351 ± 4084 ng/g. Benchtop sliding of PCB samples onto ex vivo porcine artery samples exhibited efficient, pressure independent frictional paclitaxel transfer (124 µg at 0.05 atm vs. 126 µg at 0.1 atm, p &gt; 0.99). Conclusions: PCB interactions at porcine vessel bends led to premature tracking loss, resulting in peak plasma concentrations exceeding post-inflation concentrations, and delivery to upstream tissue that is plausibly explained as arising from efficient friction-mediated coating transfer.

Development of a PBPK Model for Lamotrigine which Incorporates Metabolism by UGT2B10: Impact of UGT2B10 Poor Metabolizer Phenotype and Pregnancy.

An updated physiologically based pharmacokinetic (PBPK) model was developed for lamotrigine by incorporating a component of metabolism due to a UDP-glucuronyltransferase (UGT) 2B isozyme. This was assigned to UGT2B10 based on recent in vitro data in our laboratory demonstrating metabolism of lamotrigine by this isozyme (Tang et al. AAPS J 26:107, 2024). The PBPK model developed in this work was able to reasonably recapitulate the exposure of lamotrigine after single (IV and Oral) and multiple (Oral) doses. The predicted/observed maximal plasma concentration (Cmax) ratio ranged from 0.8 to 1.4 across all simulated studies and for 16 out of 18 simulated studies was between 0.8 and 1.25. Similarly, the predicted/observed area under the curve (AUC) ratio ranged from 0.6 to 1.44 across all simulated studies and for 18 out of 26 of the simulated studies the ratio was between 0.8 and 1.25. There was a slight tendency to overpredict the lamotrigine AUC on multiple dosing. The median predicted fraction metabolised (fm) by UGT2B10 in the model was 60%. With this fm value, the in vivo clinical DDI between lamotrigine and valproate was reasonably recapitulated considering only UGT2B10 inhibition (Predicted/Observed AUC ratios ranged from 0.65 - 1.2). Information on the prevalence of UGT2B10 poor metabolizer phenotypes and longitudinal changes in UGT1A4 and UGT2B10 expression during pregnancy were incorporated into the PBPK model and the plasma concentrations in subjects with different UGT2B10 phenotypes and in different trimesters of pregnancy were simulated. The simulated concentrations in pregnant subjects were in line with those reported during pregnancy.

Population Pharmacokinetics of Perampanel in Chinese Pediatric and Adult Patients With Epilepsy.

Perampanel is a promising epilepsy treatment with an innovative mechanism of action. This study was performed to investigate the factors affecting perampanel clearance in a population pharmacokinetic (PPK) model of Chinese pediatric and adult patients with epilepsy. A total of 135 perampanel plasma concentrations from 125 patients with epilepsy were analyzed using the PPK model with nonlinear mixed-effects modeling. One-compartment and proportional residual models best described the pharmacokinetics of perampanel. Covariate effects on the model parameters were assessed using forward and backward elimination. Goodness-of-fit, bootstrapping, visual predictive checks, and normalized prediction distribution errors were used to evaluate the model. Monte Carlo simulations were conducted to assess the impact of covariate combinations on perampanel plasma concentrations at different dosages. In the final PPK model, body weight (BW), concomitant carbamazepine (CBZ), oxcarbazepine (OXC), and C-reactive protein (CRP) levels significantly influenced perampanel clearance. The interindividual clearance was calculated as follows: 0.84 × (BW/70)0.53 × eCBZ × eOXC × eCRP (CBZ = 0.98, when comedicated with carbamazepine; OXC = 0.43, when comedicated with oxcarbazepine; CRP = -0.69, when CRP >15 mg/L, otherwise = 0). The estimates (relative standard error) for clearance and apparent volume of distribution of the final model were 0.84 L/h (8.75%) and 64.35 L (19.78%), respectively. The model maintained its stability and effectiveness with moderate predictability. BW and CBZ, OXC, and CRP levels may influence perampanel clearance in both pediatric and adult patients with epilepsy according to a population pharmacokinetic model that included real-world data.

Adhered macrophages as an additional marker of cardiomyocyte injury in biopsies of patients with dilated cardiomyopathy

Abstract Background Macrophage accumulation found in biopsy specimens of patients with dilated cardiomyopathy (DCM) has been thought to reflect chronic myocarditis. However, it is unsettled whether they are responsible for the active or persistent phase of the disease. Objective The aim of this study was to count the number of macrophages in relation to plasma concentrations of cardiac troponin T (cTnT). Methods We studied the biopsies of 181 patients with DCM by immunohistochemistry using anti-CD68(+) antibodies. The total number of CD68(+) and the number of CD68(+) cells attached to injured cardiomyocytes were counted and presented as the number of cells/mm2. Results Two expression patterns of CD68(+) macrophages were observed: those localized freely in the interstitial space only, and the cells attached to injured cardiomyocytes. As regards macrophages adhered to injured cardiomyocytes, 72 out of 181 (39.8%) patients presented these cells in the biopsy sections. Both the total number of CD68(+) macrophages and the number of CD68(+) cells directly adhered correlated negatively with cTnT in the serum of DCM patients (Spearman’s rho, r = −0.45, P &lt; 0.001 and r = −0.31, P = 0.009, respectively). Conclusion Macrophages attached to injured cardiomyocytes may reflect chronic (ongoing) inflammation in the myocardium.

The Proteome Content of Blood Clots Observed Under Different Conditions: Successful Role in Predicting Clot Amyloid(ogenicity)

A recent analysis compared the proteome of (i) blood clots seen in two diseases—sepsis and long COVID—when blood was known to have clotted into an amyloid microclot form (as judged by staining with the fluorogenic amyloid stain thioflavin T) with (ii) that of those non-amyloid clots considered to have formed normally. Such fibrinaloid microclots are also relatively resistant to fibrinolysis. The proteins that the amyloid microclots contained differed markedly both from the soluble proteome of typical plasma and that of normal clots, and also between the diseases studied (an acute syndrome in the form of sepsis in an ITU and a chronic disease represented by Long COVID). Many proteins in the amyloid microclots were low in concentration in plasma and were effectively accumulated into the fibres, whereas many other abundant plasma proteins were excluded. The proteins found in the microclots associated with the diseases also tended to be themselves amyloidogenic. We here ask effectively the inverse question. This is: can the clot proteome tell us whether the clots associated with a particular disease contained proteins that are observed uniquely (or are highly over-represented) in known amyloid clots relative to normal clots, and thus were in fact amyloid in nature? The answer is in the affirmative in a variety of major coagulopathies, viz., venous thromboembolism, pulmonary embolism, deep vein thrombosis, various cardiac issues, and ischaemic stroke. Galectin-3-binding protein and thrombospondin-1 seem to be especially widely associated with amyloid-type clots, and the latter has indeed been shown to be incorporated into growing fibrin fibres. These may consequently provide useful biomarkers with a mechanistic basis.

Pharmacokinetics and Chicken Meat Residue of Tilmicosin after Administration Through Drinking Water in Broiler Chicken

Background: Tilmicosin is an antimycoplasmic drug of great utility in controlling mycoplasmosis in chicken. The drug despite its efficacy, has a high residue impact leading to a long withdrawal period. In this study, an attempt has been made to rationalize the dosage to reduce the residue burden by adopting a lower dose. Methods: The dose of tilmicosin was arrived at based on a pilot study wherein different doses were administered, and the levels were checked in plasma and meat. In the main study, tilmicosin was administered to broiler chicken as a bolus oral dose or “in drinking water” at the dose rate of 25 mg. kg-1 body weight. Blood was collected at different time points for the study. A trial to assay drug residues in tissues was also carried out. The assay of tilmicosin in chicken plasma/tissues was done using a sensitive HPLC assay. Result: In both pharmacokinetics study groups, tilmicosin concentrations could be reasonably detected only in 4 of the eight birds tested. In the birds that responded, the mean plasma concentrations remained above the MIC values of 0.05 µg.ml-1. The residue level in the lung and muscle could be detected up to day 14, and no residue from 18th day, after administration of tilmicosin through drinking water. The lung, the organ of mycoplasma infection revealed high concentrations of tilmicosin up to 14 days after the last dose. The results show that the Tilmicosin administered at a reduced rate of 25 mg.Kg-1 can be useful therapeutically, with a reduced residue burden in broiler chicken.

Patients with chronic heart failure and predominant left atrial versus left ventricular myopathy

BackgroundLeft atrial (LA) and ventricular (LV) functional impairment often co-exist in patients with heart failure (HF). However, some patients with HF have a disproportionate LA or LV dysfunction. We aimed to characterize patients with predominant LA and LV myopathy in a cohort of patients with chronic HF across the spectrum of LV ejection fraction (LVEF).MethodsFrom a nationwide, prospective, multi-center, observational HF cohort, transthoracic echocardiographic examination was performed on each patient. LA reservoir strain and LV global longitudinal strain (LVGLS) were measured using dedicated software of the two-dimensional speckle tracking analysis to evaluate LA and LV function and to define the myopathy.ResultsA total of 374 patients with chronic HF (mean age 58.9±11.5 years, 20% female, mean LVEF 39±17%) were included. By calculating the residuals from the linear regression between LA reservoir and LVGLS, we identified 47 patients with predominant LA myopathy, 271 patients with balanced LA/LV and 56 patients with predominant LV myopathy. Patients with predominant LA myopathy were older, had a higher prevalence of atrial fibrillation (AF), diabetes, higher plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP), Growth differential factor 15(GDF15), high sensitivity Troponin T (hs-TNT) as well as more dilated left and right atria, and worse right atrial function compared to other groups (all p-values < 0.05). Using multivariable logistic regression adjusted for LVEF and LA size, independent predictors of predominant LA myopathy were the presence of AF, diabetes, and higher GDF15, whereas absence of diabetes independently predicted predominant LV myopathy. Patients with predominant LA myopathy group had a lower probability of survival than the other groups (Log rank p-value = 0.01).ConclusionWhile most patients with HF have balanced LA/LV myopathy, those with predominant LA myopathy are characterized by older age, more AF, more diabetes, higher circulating biomarkers of cardiac stress and injury, and worse outcomes.