Steady-state Plasma Concentrations Research Articles

Quality by design optimization of formulation variables and process parameters for enhanced transdermal delivery of nanosuspension.

This investigation aims to fabricate, characterize, and optimize organogel containing andrographolide nanosuspension to enhance transdermal drug delivery into and across the skinin vitro. We identified the critical material attributes (CMAs) and critical process parameters (CPPs) that impact key characteristics of andrographolide nanosuspension using a systematic quality-by-design approach. We prepared andrographolide nanosuspension using the wet milling technique and evaluated various properties of the formulations. The CMAs were types and concentrations of polymers, types and concentrations of surfactants, drug concentration, and lipid concentration. The CPPs were volume of milling media and milling duration. Mean particle size, polydispersity index, encapsulation efficiency, and drug loading capacity as critical quality attributes were selected in the design for the evaluation and optimization of the formulations. Furthermore, we developed and evaluated organogel formulation to carry andrographolide nanosuspension 0.05% w/w. Drug release and permeation studies were conducted to assess the drug release kinetics and transdermal delivery of andrographolide. We presented the alteration in the average particle size, polydispersity index, encapsulation efficiency, drug-loading capacity, and drug release among various formulations to select the optimal parameters. The permeation study indicated that organogel delivered markedly more drug into the receptor fluid and skin tissue than DMSO gel (n = 3, p < 0.05). This enhancement in transdermal drug delivery was demonstrated by cumulative drug permeation after 24h, steady-state flux, permeability coefficient, and predicted steady-state plasma concentration. Drug quantity in skin layers, total delivery, delivery efficiency, and topical selectivity were also reported. Conclusively, andrographolide nanosuspension-loaded organogel significantly increased transdermal drug delivery in vitro.

Impact of Continuous Infusion Meropenem PK/PD Target Attainment on C-Reactive Protein Dynamics in Critically Ill Patients With Documented Gram-Negative Hospital-Acquired or Ventilator-Associated Pneumonia.

Population pharmacokinetic/pharmacodynamic (PK/PD) modelling of antibiotics including C-reactive protein (C-RP) dynamics could be helpful in predicting the efficacy of antimicrobials. We developed a PK/PD model for assessing the impact of continuous infusion (CI) meropenem PK/PD target attainment on C-RP dynamics in critically ill patients with documented Gram-negative hospital- (HAP) or ventilator-acquired pneumonia (VAP). Patients were grouped according to the type of antibiotic treatment received [meropenem monotherapy; meropenem plus empirical anti-MRSA (methicillin-resistant Staphylococcus aureus) therapy; meropenem in combination with another anti-Gram-negative active agent; meropenem plus a targeted anti-MRSA therapy]. A one-compartment population PK model of CI meropenem was developed by including all patients. A full C-RP production inhibition model was developed for fitting the PD data by including only patients receiving meropenem monotherapy or meropenem plus empirical anti-MRSA therapy. Monte Carlo simulations explored the relationship between the type of PK/PD target attainment of CI meropenem, defined as optimal (steady-state plasma concentration [Css] to minimum inhibitory concentration [MIC] ratio = 4-8), quasi-optimal (Css/MIC = 1-4) and sub-optimal (Css/MIC < 1) and the magnitude of C-RP production inhibition over time. A total of 64 patients providing 211 meropenem concentrations were included in the PK analysis, whereas 47 patients providing 328 C-RP data were included in the PD model. Simulations showed that optimal PK/PD target attainment was associated with the highest and most rapid C-RP production inhibition (44% and 56% at days 2 and 4, respectively). Conversely, sub-optimal PK/PD target attainment was shown to be almost ineffective (< 5% at day 4 and < 10% at day 10). Our PK/PD model predicted that attaining optimal PK/PD target with CI meropenem may grant prompt and intense C-RP decrease among critically ill patients receiving targeted monotherapy for Gram-negative HAP/VAP, thus anticipating efficacy.

Impact of gut permeability on estimation of oral bioavailability for chemicals in commerce and the environment.

Performance of pharmacokinetic models developed using in vitro-to-in vivo extrapolation (IVIVE) methods may be improved by refining assumptions regarding fraction absorbed (Fabs) through the intestine, a component of oral bioavailability (Fbio). Although in vivo measures of Fabs are often unavailable for non-pharmaceuticals, in vitro measures of apparent permeability (Papp) using the Caco-2 cell line have been highly correlated with Fabs. We measured bidirectional Papp for over 400 non-pharmaceutical chemicals using the Caco-2 assay. A random forest quantitative structure-property relationship (QSPR) model was developed using these and peer-reviewed pharmaceutical data. Both Caco-2 data (R²=0.37) and the QSPR model (R²=0.29) were better at predicting human bioavailability compared to in vivo rat data (R²=0.23). After incorporation into a high throughput toxicokinetics (HTTK) framework for IVIVE, the Caco-2 data were used to estimate in vivo administered equivalent dose (AED) for bioactivity assessed in vitro, The HTTK-predicted plasma steady state concentrations (Css) for IVIVE were revised, with modest changes predicted for poorly absorbed chemicals. Experimental data were evaluated for sources of measurement uncertainty, which were then accounted for using the Monte Carlo method. Revised AEDs were subsequently compared with exposure estimates to evaluate effects on bioactivity:exposure ratios, a surrogate for risk. Only minor changes in the margin between chemical exposure and predicted bioactive doses were observed due to the preponderance of highly absorbed chemicals.

A multicentric, randomized, controlled clinical trial to study the impact of bedside model-informed precision dosing of vancomycin in critically ill children—BENEFICIAL trial

BackgroundVancomycin is a commonly prescribed antibiotic to treat serious Gram-positive infections in children. The efficacy of vancomycin is known to be directly related to the pharmacokinetic/pharmacodynamic (PK/PD) index of the area under the concentration–time curve (AUC) divided by the minimal inhibitory concentration (MIC) of the pathogen. In most countries, steady-state plasma concentrations are used as a surrogate parameter for this target AUC/MIC, but this practice has some drawbacks. Hence, AUC-based dosing using model-informed precision dosing (MIPD) tools has been proposed for increasing the target attainment rate and reducing vancomycin-related nephrotoxicity. Solid scientific evidence for these claimed benefits is lacking in children. This randomized controlled trial aims to investigate the large-scale utility of MIPD dosing of vancomycin in critically ill children.MethodsParticipants from 14 neonatal intensive care, pediatric intensive care, and pediatric hemo-oncology ward units from 7 hospitals are randomly allocated to the intervention or standard-of-care comparator group. In the intervention group, a MIPD dosing calculator is used for AUC-based dosing, in combination with extra sampling for therapeutic drug monitoring in the first hours of treatment, as compared to standard-of-care. An AUC24h between 400 and 600 is targeted, assuming an MIC of 1 mg/L. Patients in the comparator group receive standard-of-care dosing and monitoring according to institutional guidelines. The primary endpoint is the proportion of patients reaching the target AUC24h/MIC of 400–600 between 24 and 48 h after the start of vancomycin treatment. Secondary endpoints are the proportion of patients with (worsening) acute kidney injury during vancomycin treatment, the proportion of patients reaching target AUC24h/MIC of 400–600 between 48 and 72 h after the start of vancomycin treatment, time to clinical cure, ward unit length-of-stay, hospital length-of-stay, and 30-day all-cause mortality.DiscussionThis trial will clarify the propagated benefits and provide new insights into how to optimally monitor vancomycin treatment in critically ill children.Trial registrationEudract number: 2019–004538-40. Registered on 2020–09-08ClinicalTrials.gov NCT046666948. Registered on 2020–11-28

A loading dose of clofazimine to rapidly achieve steady-state-like concentrations in patients with nontuberculous mycobacterial disease.

Clofazimine is a promising drug for the treatment of nontuberculous mycobacterial (NTM) diseases. Accumulation of clofazimine to reach steady-state plasma concentrations takes months. A loading dose may reduce the time to steady-state-like concentrations. We evaluated the pharmacokinetics (PK), safety and tolerability of a loading dose regimen in patients with NTM disease. Adult participants received a 4-week loading dose regimen of 300 mg clofazimine once daily, followed by a maintenance dose of 100 mg once daily (combined with other antimycobacterial drugs). Blood samples for PK analysis were collected on three occasions. A population PK model for clofazimine was developed and simulations were performed to assess the time to reach steady-state-like (target) concentrations for different dosing regimens. Twelve participants were included. The geometric mean peak and trough clofazimine concentrations after the 4-week loading phase were 0.87 and 0.50 mg/L, respectively. Adverse events were common, but mostly mild and none led to discontinuation of clofazimine. Our loading dose regimen reduced the predicted median time to target concentrations by 1.5 months compared to no loading dose (3.8 versus 5.3 months). Further time benefit was predicted with a 6-week loading dose regimen (1.4 versus 5.3 months). A 4-week loading dose regimen of 300 mg once daily reduced the time to target clofazimine concentrations and was safe and well-tolerated. Extending the loading phase to 6 weeks could further decrease the time to target concentrations. Using a loading dose of clofazimine is a feasible strategy to optimize treatment of NTM disease. NCT05294146.

Pharmacokinetics, Safety and Tolerability of Single-dose or Multiple-dose Cefiderocol in Hospitalized Pediatric Patients Three Months to Less Than Eighteen Years Old With Infections Treated With Standard-of-care Antibiotics in the PEDI-CEFI Phase 2 Study.

Multidrug-resistant Gram-negative bacterial infections are increasing globally in neonates, infants and children; antibiotic options are limited. This international, multicenter, open-label phase 2 study, investigated the pharmacokinetics, safety and tolerability of single-dose and multiple-dose cefiderocol [as a 3-hour infusion (every 8 hours) dosed at 2000 mg for body weight ≥34 kg and at 60 mg/kg for body weight <34 kg], over a range of renal function, in hospitalized pediatric patients with aerobic Gram-negative bacterial infection; multiple-dose patients required standard-of-care systemic antibiotics for 5-14 days. Four cohorts of pediatric patients were enrolled (cohort 1: 12 to <18 years, cohort 2: 6 to <12 years, cohort 3: 2 to <6 years and cohort 4: 3 months to <2 years). A total of 53 patients (median age: 73.5 months) were enrolled. Plasma concentration profiles were similar with single-dose (n = 24) and multiple-dose (n = 29) cefiderocol, irrespective of age and body weight in those with normal renal function or mild renal impairment. Geometric mean concentrations at the end of infusion ranged between 72.7 and 97.1 μg/mL for single-dose cefiderocol and between 88.8 and 106.0 μg/mL after multiple doses. At 8 hours, corresponding trough concentrations ranged from 7.86 to 10.8 μg/mL with single-dose cefiderocol and from 9.64 to 18.1 μg/mL with multiple doses. There were no deaths, no cefiderocol-related serious adverse events, significant related laboratory abnormalities or discontinuations. Multiple-dose cefiderocol, administered for 5-14 days and according to body weight, achieved steady-state plasma concentrations that remained above the susceptibility breakpoints of Gram-negative bacteria throughout the dosing period. Cefiderocol was well tolerated.

Effect of Genetic Polymorphisms of ABCB1, ABCG2, and SLC22A1 on the Steady-State Plasma Concentrations of Lamotrigine in Treatment-Resistant Depressed Patients Treated With Lamotrigine Augmentation Therapy.

The authors have demonstrated that a plasma lamotrigine concentration of 12.7 μmol/L may be a threshold for a good therapeutic response to lamotrigine augmentation therapy in treatment-resistant depressed patients. Lamotrigine is a substrate of P-glycoprotein, breast cancer resistant protein and organic cation transporter 1, which are encoded by ABCB1 , ABCG2 , and SLC22A1 , respectively. There have been several polymorphisms that affect its function. The present study investigated the relationship between these polymorphisms and the steady-state plasma concentrations (Css) of lamotrigine in treatment-resistant depressed patients receiving lamotrigine as augmentation therapy. One hundred twenty-nine treatment-resistant depressed patients were included in this study. Treatment resistance is defined as lack of therapeutic response to at least 3 psychotropics despite adequate doses and duration. Their diagnoses were as follows: major depressive disorder (n = 58), bipolar II disorder (n = 52), and bipolar I disorder (n = 19). Lamotrigine augmentation therapy for 8 weeks was conducted. The final lamotrigine doses were 75 mg/d for 39 patients with valproate and 100 mg/d for 90 without it. Blood was sampled at 8:00 am after the 8th week of treatment. Plasma lamotrigine levels were quantified by using LC/MS/MS. The polymorphisms of ABCB1 1236C>T, 2677G>T/A, 3435C>T, ABCG2 421C>A, and SLC22A1 1222G>A were detected by polymerase chain reaction analyses. No significant relationships were observed between these polymorphisms and the Css of lamotrigine in the patients with or without valproate. The present study suggests that these genetic polymorphisms do not play a role in controlling the Css of lamotrigine in treatment-resistant depressed patients treated with lamotrigine augmentation therapy.

Guidance on Selecting Optimal Steady-State Tacrolimus Concentrations for Continuous IV Perfusion: Insights from Physiologically Based Pharmacokinetic Modeling.

Introduction: The dose-response relationships of tacrolimus have been primarily assessed through trough concentrations during intermittent administrations. In scenarios where oral administration (PO) is unfeasible, continuous intravenous (IV) administration is advised. Under these circumstances, only steady-state (Css) plasma or blood concentrations are measured, with the absence of distinct trough levels (Cmin). Consequently, the measured concentrations are frequently misinterpreted as trough concentrations, potentially resulting in sub-therapeutic true tacrolimus blood levels. This study employs physiologically based pharmacokinetic modeling (PBPK) to establish the Css/Cmin ratio for tacrolimus across various clinical scenarios. Method: Using a validated PBPK model, the tacrolimus dose (both PO and IV) and the Css/Cmin ratios corresponding to matching area under the blood concentration-time curve during a dosage interval (AUCτ) values were estimated under different conditions, including healthy subjects and individuals exhibiting cytochrome P450 3A (CYP3A) interactions or CYP3A5 polymorphisms, along with a demonstration of a real-life clinical application. Result: In healthy volunteers, the oral/intravenous (PO/IV) dose ratio was found to be 4.25, and the Css/Cmin ratio was 1.40. A specific clinical case substantiated the practical applicability of the Css/Cmin ratio as simulated by PBPK, demonstrating no immediate clinical complications related to the transplant. When considering liver donors versus recipients expressing CYP3A5, the tacrolimus AUCτ was notably affected, yielding a PO/IV dose ratio of 4.00 and a Css/Cmin ratio of 1.75. Furthermore, the concomitant administration of the CYP3A inhibitor itraconazole given PO resulted in a PO/IV ratio of 1.75 with and a Css/Cmin ratio of 1.28. Notably, the inhibitory effect of itraconazole was diminished when administered IV. Conclusions: Through the application of PBPK methodologies, this study estimates the PO/IV dose ratios and Css/Cmin ratios that can enhance dose adjustment and therapeutic drug monitoring during the switch between IV and PO administration of tacrolimus in transplant patients, ultimately guiding clinicians in real-time decision-making. Further validation with in vivo data is recommended to support these findings.

Pharmacokinetics of nirmatrelvir/ritonavir and the drug-drug interaction with calcineurin inhibitor in renal transplant recipients.

To describe the pharmacokinetic (PK) characteristics of nirmatrelvir/ritonavir in renal transplant recipients and explore the potential factors that related to the PK variance of nirmatrelvir/ritonavir and its interaction with calcineurin inhibitor (CNI). Renal transplant recipients treated with CNI and nirmatrelvir/ritonavir were prospectively enrolled. Steady-state plasma concentrations of nirmatrelvir/ritonavir were determined by high-performance liquid chromatography-tandem mass spectrometry, and the PK parameters were calculated using non-compartmental analysis. Spearman correlation analysis was used for exploring influencing factors. A total of eight recipients were enrolled; for nirmatrelvir and ritonavir, AUC/dose was 0.24179 ± 0.14495 and 0.06196 ± 0.03767μg·h·mL-1·mg-1. Red blood cell (RBC), hematocrit (Ht), hemoglobins (Hb), and creatinine clearance (Ccr) were negatively correlated with AUC/dose of nirmatrelvir, while Ccr, CYP3A5 genotype, and CYP3A4 genotype were related to the AUC/dose of ritonavir. Ccr was negatively correlated with the C0/dose of tacrolimus (TAC) after termination of nirmatrelvir/ritonavir (rs = -0.943, p = 0.008). The PK characteristics of nirmatrelvir/ritonavir vary greatly among renal transplant recipients. Factors including Ccr and CYP3A5 genotype were related to the in vivo exposure of nirmatrelvir/ritonavir. During the whole process before and after nirmatrelvir/ritonavir therapy, it is recommended to adjust the CNI basing on renal function to avoid CNI toxicity exposure.

Polymeric Microneedles Enhance Transdermal Delivery of Therapeutics.

This research presents the efficacy of polymeric microneedles in improving the transdermal permeation of methotrexate across human skin. These microneedles were fabricated from PLGA Expansorb® 50-2A and 50-8A and subjected to comprehensive characterization via scanning electron microscopy, Fourier-transform infrared spectroscopy, and mechanical analysis. We developed and assessed a methotrexate hydrogel for physicochemical and rheological properties. Dye binding, histological examinations, and assessments of skin integrity demonstrated the effective microporation of the skin by PLGA microneedles. We measured the dimensions of microchannels in the skin using scanning electron microscopy, pore uniformity analysis, and confocal microscopy. The skin permeation and disposition of methotrexate were researched in vitro. PLGA 50-8A microneedles appeared significantly longer, sharper, and more mechanically uniform than PLGA 50-2A needles. PLGA 50-8A needles generated substantially more microchannels, as well as deeper, larger, and more uniform channels in the skin than PLGA 50-2A needles. Microneedle insertion substantially reduced skin electrical resistance, accompanied by an elevation in transepidermal water loss values. PLGA 50-8A microneedle treatment provided a significantly higher cumulative delivery, flux, diffusion coefficient, permeability coefficient, and predicted steady-state plasma concentration; however, there was a shorter lag time than for PLGA 50-2A needles, base-treated, and untreated groups (p < 0.05). Conclusively, skin microporation using polymeric microneedles significantly improved the transdermal delivery of methotrexate.

EMITT-1: Proof-of-mechanism immunopeptidome (ImPD) effects at target PK exposure, in a phase 1 study of GRWD5769 (a first-in-class inhibitor of Endoplasmic Reticulum Aminopeptidase 1 [ERAP1]) in patients with solid malignancies.

2589 Background: GRWD5769 is a first-in-class, orally bioavailable ERAP1 inhibitor that significantly modulates the peptide repertoire displayed on MHC-1 on tumor cells, driving novel T cell response and causing tumor cell killing in preclinical studies. This unique approach has potential to overcome central mechanisms of immune resistance by driving de-novo recognition of previously hidden tumor neoantigens and addressing T cell exhaustion. Here we report initial safety, pharmacokinetic (PK) and pharmacodynamic (PD) endpoints from Part A (monotherapy dose escalation) in the ongoing multicentre, modular phase I dose escalation study (ACTRN12623000108617). Methods: Patients with advanced refractory solid tumors are enrolled using a BOIN escalation design. GRWD5769 is administered BID on days 1-14 during 21-day cycles. The first cycle is the dose-limiting toxicity (DLT) observation period. The PK / PD relationship of GRWD5769 is being evaluated using mass spectrometry analysis of the ImPD. Tumor responses are evaluated by RECIST v1.1 / iRECIST. Results: As of 03 January 2024, a total of 12 patients had been treated with GRWD5769 in 3 dose cohorts (25 mg, 50 mg, 100 mg BID). On average patients have remained on treatment for 4 cycles (range 1-10) No Serious Adverse Reactions, DLTs, immune related AEs or deaths were reported. Two Gr 3 serious adverse events have occurred in 2 treated subjects (aspiration pneumonia and Urinary Tract Infection, neither attributable to GRWD5769). Gr 1+2 AEs were infrequent and manageable. PK analyses for the first 3 cohorts show dose proportional plasma levels, with Tmax at ~3 h and a ~8 h Thalf. The minimum biologically active dose (MBAD) is defined as an average steady state plasma concentration above the IC50 for ERAP1, which was achieved at the 100 mg BID dose level. PD data shows dose-dependent target engagement, with marked shifts in the ImPD. This is consistent with the expected mechanistic effects of ERAP1 inhibition seen in preclinical models and is the first demonstration that the human ImPD can be manipulated pharmacologically in cancer patients, potentially allowing T cells to recognise new targets on tumors. Dose escalation with GRWD5769 monotherapy continues to determine the recommended phase 2 dose (RP2D). GWRD5769 in combination with Immune Checkpoint Inhibition will be investigated in Part B now that the MBAD has been reached. Conclusions: GRWD5769 has been well tolerated at doses up to 100 mg BID. PK / PD data support dose-dependent target engagement of ERAP1. Proof of mechanism has been achieved for this first-in-class therapy, and this is the first demonstration that the human ImPD can be manipulated pharmacologically in cancer patients. Further PD analyses will explore shifts in the T cell repertoire and modulation of immune cell phenotypes. Clinical trial information: ACTRN12623000108617.

Correlation Between Warfarin Levels in the Blood and the Value of Normal INR in Fibrillation Atrium Inpatients

Background: Warfarin is an anticoagulant inhibitor of vitamin K that is effective in preventing systemic embolization in atrial fibrillation patients. Warfarin has a narrow therapeutic index, so it requires monitoring of rates to prevent the occurrence of toxic effects and to ensure the passage of INR values.Objectives: The study aims to find out the correlation between warfarin levels and normal INR values.Methods: Observational research method with the collection of retrospective data on the medical records of patients treated with atrial fibrillation at Prof. Dr. Margono Soekarjo Hospital, Purwokerto, in January 2019–December 2021. Warfarin levels were calculated pharmacokinetically using the steady-state concentration (Css) and plasma concentration (Cp) formulas. Data analysis is carried out using the Spearman test to determine the correlation between warfarin levels and normal INR values.Results: The number of patients with normal INR values was less than the number of patients with abnormal INR values, namely 21 patients and 48 patients. The Spearman test results show a p-value of 0.31 (p&gt;0.05), showing that the correlation between warfarin levels in the blood and the corresponding INR value is not significant (p&gt; 0.05), and the R value in the Spearman test is 0.122, showing that the direction of the correlation is positive with very weak correlation strength.Conclusion: The correlation between warfarin levels in the blood and the appropriate INR value is not significant (p&gt;0.05), where the R value in the Spearman test shows R=0.122, meaning the direction of the correlation is positive with a very weak correlation strength.

The impact of CYP2C19 genotypes on steady-state plasma concentration of escitalopram in South Indian population with Major Depressive Disorder

Background: Among depressed patients, escitalopram plasma levels differed between those who were considered as extensive metabolizers and poor metabolizers of CYP2C19. However, the majority of research utilized the dose-response relationship. Consequently, we investigated the effect of variations in the CYP2C19 gene on the levels of drug in the bloodstream of individuals suffering from Major Depressive Disorder (MDD) in south India. Methods: A total of 109 individuals with MDD who were prescribed escitalopram at doses of 5, 10, 15, or 20 mg daily participated in this research. We used HPLC with SPD-10AVP UV-Visible detector to measure the escitalopram concentrations in the blood. The polymorphisms of the CYP2C19 were determined by employing the PCR techniques. Results: Our study found that 55% of the subjects were intermediate metabolizers, followed by extensive (19.3%), poor (17.4%), and ultra-rapid (8.3%). The significant correlation is identified between the steady state plasma concentration and Sex with (P - Value &amp;lt; 0.05), insignificant correlation was seen in Age and BMI with (P - Value &amp;gt; 0.05). The majority of gene variants seen in the study population were CYP2C19*1/*2, accounting for 49 individuals (44.9%). Conclusion: These findings showed that sex had a substantial impact on the CYP2C19 genetic variation. Medication administration to individuals with CYP2C19PM requires special caution.

Cannabinoid levels description in a cohort of patients with chronic and neuropathic pain treated with Cannabis decoction: A possible role of TDM

The phytocomplex of Cannabis is made up of approximately 500 substances: terpeno-phenols metabolites, including Δ-9-tetrahydrocannabinol and cannabidiol, exhibit pharmacological activity.Medical Cannabis has several pharmacological potential applications, in particular in the management of chronic and neuropathic pain. In the literature, a few data are available concerning cannabis pharmacokinetics, efficacy and safety.Thus, aim of the present study was the evaluation of cannabinoid pharmacokinetics in a cohort of patients, with chronic and neuropathic pain, treated with inhaled medical cannabis and decoction, as a galenic preparation.In this study, 67 patients were enrolled. Dried flower tops with different THC and CBD concentrations were used: Bedrocan® medical cannabis with THC level standardized at 19% and with a CBD level below 1%, Bediol® medical cannabis with THC and CBD level standardized at similar concentration of 6.5% and 8%, respectively.Cannabis was administered as a decoction in 47 patients and inhaled in 11 patients. The blood withdrawn was obtained before the new dose administration at the steady state and metabolites plasma concentrations were measured with an UHPLC-MS/MS method.Statistically significant differences were found in cannabinoids plasma exposure between inhaled and oral administration of medical cannabis, between male and female and cigarette smokers.For the first time, differences in cannabinoid metabolites exposures between different galenic formulations were suggested in patients. Therapeutic drug monitoring could be useful to allow for dose adjustment, but further studies in larger cohorts of patients are required in order to confirm these data.

Efficacy, Safety, and Long-Term Disease Control of Ruxolitinib Cream Among Adolescents with Atopic Dermatitis: Pooled Results from Two Randomized Phase 3 Studies.

Atopic dermatitis (AD), a highly pruritic, inflammatory skin disease, affects approximately 7% of adolescents globally. A topical formulation of ruxolitinib, a Janus kinase (JAK)1/JAK2 inhibitor, demonstrated safety and efficacy among adolescents/adults in two phase 3 studies (TRuE-AD1/TRuE-AD2). To describe safety and efficacy of 1.5% ruxolitinib cream versus vehicle and long-term disease control of ruxolitinib cream among adolescents aged 12-17 years from pooled phase 3 study data. Patients [≥ 12 years old with AD for ≥ 2 years, Investigator's Global Assessment score (IGA) 2/3, and 3-20% affected body surface area (BSA) at baseline] were randomized 2:2:1 to ruxolitinib cream (0.75%/1.5%) or vehicle for 8 weeks of continuous use followed by a long-term safety (LTS) period up to 52 weeks with as-needed use. Patients originally applying vehicle were rerandomized 1:1 to 0.75%/1.5% ruxolitinib cream. Efficacy measures at week 8 included IGA treatment success (IGA-TS; i.e., score of 0/1 with ≥ 2 grade improvement from baseline), ≥ 75% improvement in Eczema Area and Severity Index (EASI-75), and ≥ 4-point improvement in itch numerical rating scale (NRS4). Measures of disease control during the LTS period included IGA score of 0 (clear) or 1 (almost clear) and percentage affected BSA. Safety was assessed throughout the study. Of 1249 randomized patients, 245 (19.6%) were aged 12-17 years. Of these, 45 patients were randomized to vehicle and 92 patients to 1.5% ruxolitinib cream. A total of 104/137 (75.9%) patients continued on 1.5% ruxolitinib cream in the LTS period [82/92 (89.1%) continued on 1.5% ruxolitinib cream; 22/45 (48.9%) patients on vehicle were reassigned to 1.5% ruxolitinib cream], and 83/104 (79.8%) of these patients completed the LTS period. At week 8, substantially more patients who applied 1.5% ruxolitinib cream versus vehicle achieved IGA-TS (50.6% versus 14.0%), EASI-75 (60.9% versus 34.9%), and NRS4 (52.1% versus 17.4%; P = 0.009). The mean (SD) reduction in itch NRS scores was significantly greater in patients applying 1.5% ruxolitinib cream versus vehicle from day 2 [- 0.9 (1.9) versus -0.2 (1.4); P = 0.03]. During the LTS period, mean (SD) trough steady-state ruxolitinib plasma concentrations at weeks 12/52 were 27.2 (55.7)/15.5 (31.5) nM. The percentage of patients achieving IGA score of 0 or 1 was sustained or further increased with 1.5% ruxolitinib cream; mean affected BSA was generally low (< 3%; i.e., mild disease). Through 52 weeks, application site reactions occurred in 1.8% of adolescent patients applying 1.5% ruxolitinib cream at any time; no patients had serious adverse events. There were no serious infections, malignancies, major adverse cardiovascular events, or thromboembolic events. Meaningful anti-inflammatory and antipruritic effects were demonstrated with 1.5% ruxolitinib cream in the subset of adolescent patients with AD, comparable with those observed in the overall study population; long-term, as-needed usemaintained disease control and was well tolerated. ClinicalTrials.gov identifiers NCT03745638 (registered 19 November 2018) and NCT03745651 (registered 19 November 2018).

Dysregulation of adipogenesis and disrupted lipid metabolism by the antidepressants citalopram and sertraline

Selective Serotonin Reuptake Inhibitors (SSRIs) are widely used medications for the treatment of major depressive disorder. However, long-term SSRI use has been associated with weight gain and altered lipid profiles. These findings suggest that SSRIs may have negative effects on metabolism. Exposure to certain chemicals called ‘obesogens’ is known to promote lipid accumulation and obesity by modulating adipogenesis. Here, we investigated whether citalopram (CIT) and sertraline (SER) interfere with the process of adipogenesis, using human mesenchymal stem cells (MSCs) in a 2D and a 3D model. Assessment of intracellular lipid accumulation by fluorescence staining was used as a measure for enhanced adipogenesis. To explore possible mechanisms behind SSRIs' effects, receptor mediated activity was studied using responsive cell lines for various nuclear receptors. Furthermore, RNA sequencing was performed in the 3D model, followed by differential gene expression and pathway analysis. A dose dependent increase in lipid accumulation was observed in both models with CIT and SER. For the 3D model, the effect was seen in a range close to reported steady-state plasma concentrations (0.065–0.65 μM for SER and 0.12–0.92 μM for CIT). Pathway analysis revealed unexpected results of downregulation in adipogenesis-related pathways and upregulation in phospholipids and lysosomal pathways. This was confirmed by an observed increase in lysosomes in the 2D model. Our findings suggest lysosomal dysfunction and disrupted lipid metabolism in mature adipocytes, leading to excessive phospholipid synthesis. Moreover, important adipogenic processes are inhibited, potentially leading to dysfunctional adipocytes, which might have implications in the maintenance of a healthy metabolic balance.

Retrospective Analysis of Steady-State Sodium Valproate Plasma Concentrations in Chinese Patients With Bipolar Disorder: Impact of Demographic and Clinical Characteristics.

This study comprehensively examined the demographic and clinical characteristics of patients undergoing valproic acid therapy and explored their potential impact on plasma valproic acid concentrations. All enrolled patients were administered the extended-release formulation. An in-depth investigation of factors, including dose, age, sex, body mass index, co-administered medications, and laboratory test findings, was conducted to evaluate their potential influence on study outcomes. In total, 164 patients met the inclusion criteria and were included in the analysis. The patient age ranged from 13 to 60 years, with a median age of 25.71 years. Most patients (89%) received a daily dose of 1 g valproic acid. Co-administered psychiatric medications included aripiprazole, quetiapine, and lorazepam. Laboratory test results, such as hemoglobin and transaminase levels, were also collected as part of the study. The average plasma valproic acid plasma concentration was 79.8 mg/L. The dose significantly affected valproic acid concentrations, as a higher percentage of measurements exceeded the therapeutic range at a daily dose of 1 g. Furthermore, females exhibited significantly higher valproic acid concentrations compared with males at the same dose ( P < 0.05). However, different age groups showed no statistically significant differences in valproic acid concentrations ( P > 0.05). The co-administered antipsychotic and antidepressant medications significantly affected valproate concentrations, as reflected in the multiple regression model ( P < 0.01). This study offers valuable insights into the demographic and clinical characteristics of patients undergoing valproic acid therapy. It highlights the influence of dose, sex, and concomitant medications on plasma valproic acid concentrations. Overall, these findings can help guide dose adjustments and implement personalized treatment strategies in valproic acid therapy.

Pharmacokinetics of a continuous intravenous infusion of hydromorphone in healthy dogs.

Dosing recommendations for hydromorphone intravenous constant rate infusion (IV CRI) are derived from simulations following IV bolus administration. While this extrapolated dose regimen has been described clinically, pharmacokinetics (PK) of hydromorphone infusions in dogs are not yet described. The study objective was to describe the PK of hydromorphone in healthy dogs receiving an IV bolus followed by an IV CRI for 48 h. A prospective, experimental study was performed involving the administration of hydromorphone (0.1 mg/kg IV bolus then IV CRI 0.01 mg/kg/h over a 48 h period) to 6 healthy Beagle dogs. Blood samples were collected at 16 time points between 0 and 58 h relative to the initial bolus. Plasma hydromorphone concentrations were analyzed by high pressure liquid chromatography with tandem mass spectrometry detection. Pharmacokinetic parameter estimates were obtained with compartmental methods using commercially available software. A two-compartment model with first order elimination was used. At the end of the infusion, median (range) plasma hydromorphone concentrations were 6.8 (5.5-19.6) ng/mL. The median total body clearance was 30.4 (19.8-36.7) mL/min/kg; volume of distribution at steady state was 4.5 (3.2-7.8) L/kg; and terminal elimination half-life was 11.2 (7.6-24.3) h. Hydromorphone (0.1 mg/kg IV bolus then IV CRI of 0.01 mg/kg/h) maintained steady-state plasma concentrations above the minimum human analgesic target in healthy Beagle dogs with minimal side effects. Further studies are needed to determine the effective plasma concentrations of hydromorphone in painful dogs.

Impact of Viloxazine Extended-Release Capsules (Qelbree®) on Select Cytochrome P450 Enzyme Activity and Evaluation of CYP2D6 Genetic Polymorphisms on Viloxazine Pharmacokinetics.

Viloxazine extended-release (ER) [Qelbree®] is a nonstimulant attention-deficit/hyperactivity disorder (ADHD) treatment. In vitro studies suggested potential for viloxazine to inhibit cytochrome450 (CYP) enzymes 1A2, 2B6, 2D6 and 3A4. This clinical study therefore evaluated viloxazine ER effects on index substrates for CYP1A2, 2D6, and 3A4, and secondarily evaluated the impact of CYP2D6 polymorphisms on viloxazine pharmacokinetics. Thirty-seven healthy subjects received a modified Cooperstown cocktail (MCC; caffeine 200mg, dextromethorphan 30mg, midazolam 0.025 mg/kg) on Day 1, viloxazine ER 900 mg/day on Days 3-5, and a combination of viloxazine ER 900 mg and MCC on Day 6. Viloxazine ER effects on MCC substrates were evaluated using analysis of variance. The impact of CYP2D6 genetic polymorphisms on steady-state viloxazine plasma concentrations was evaluated using Student's t test assessing pharmacokinetic parameter differences between poor versus extensive metabolizers. The least squares geometric mean ratio [GMR%] (90% CI) of MCC substrate + viloxazine ER/MCC substrate alone for caffeine maximum concentration (Cmax), area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUCt), and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC∞) was 99.11 (95.84-102.49), 436.15 (398.87-476.92), and 583.35 (262.41-1296.80), respectively; 150.76 (126.03-180.35), 185.76 (155.01-222.61), and 189.71 (160.37-224.42) for dextromethorphan Cmax, AUCt, and AUC∞, respectively; and 112.81 (104.71-121.54), 167.56 (153.05-183.45), and 168.91 (154.38-184.80) for midazolam Cmax, AUCt, and AUC∞, respectively. At steady state, viloxazine least squares GMR (90% CI) for poor/extensive CYP2D6 metabolizers were Cmax 120.70 (102.33-142.37) and area under the plasme concentration-time curve from time 0 to 24 hours (AUC0-24 125.66 (105.36-149.87)). Viloxazine ER is a strong CYP1A2 inhibitor and a weak CYP2D6 and CYP3A4 inhibitor. CYP2D6 polymorphisms did not meaningfully alter the viloxazine ER pharmacokinetic profile.

Abstract CT222: Efficacy and safety of ceralasertib in the PLANETTE study in patients (pts) with ATM-altered advanced solid tumors (ASTs) or metastatic castration-resistant prostate cancer (mCRPC)

Abstract Background: Ceralasertib, a potent, selective ATR inhibitor, is synthetically lethal in ATM-deficient preclinical models. This Phase 2a study (NCT04564027) assessed ceralasertib monotherapy in previously treated pts with ATM-altered tumors. Methods: Adult pts had ASTs excluding NSCLC (Cohort [Co] A; data cutoff [DCO] Dec 21 2022) or mCRPC (Co B; DCO Apr 28 2023) and germline/somatic ATM pathogenic/likely pathogenic variants (PVs) by local assessment. ATM alterations were centrally confirmed by FMI F1CDx in tumor and/or FMI F1 liquid CDx in circulating tumor DNA, and/or by ATM protein deficiency by immunohistochemistry (cutoff ≤5%). Primary endpoints were objective response rate (ORR) in Co A and composite response rate (CRR) in Co B. Safety was a secondary endpoint. Results: The initial starting dose of 240 mg BID PO ceralasertib on Days 1-14 of a 28-day cycle was reduced to 160 mg BID due to hematologic toxicity. Results are reported for 30 pts in Co A and 15 pts in Co B with a starting dose of 160 mg BID. In Co A, the 28 pts with centrally confirmed ATM alterations (93.3% [28/30] with ATM PV and 36.7% [11/30] ATM-deficient) had an ORR of 7.1% (80% CI: 1.9, 17.9): 1 complete response in breast cancer (ongoing at 12 mos) and 1 partial response in endometrial cancer (ongoing at 9 mos), both ATM-deficient. In Co B, the 13 pts with centrally confirmed ATM alterations (73.3% [11/15] with ATM PV and 46.7% [7/15] ATM-deficient) had a CRR of 7.7% (80% CI: 0.8, 26.8): 1 pt with conversion of circulating tumor cell count from unfavorable to favorable (ongoing at 3 mos) with unknown ATM expression. The safety profile was manageable (Table). Steady-state ceralasertib plasma concentrations exceeded the IC90 for ~23 hrs/day. Conclusion: Responses to ceralasertib monotherapy were limited in ATM-altered tumors, despite reaching target plasma levels. Alternative pt selection and combination treatment strategies are being explored. TABLE 1: NAND Efficacy, safety of ceralasertib 160 mg BID on D1-14 of D28 cycle in pts with ATM-altered ASTs/mCRPC Cohort A: ASTs Cohort B: mCRPC Efficacy Response rate in pts with centrally confirmed ATM alterations, % (80% CI)* N=28 7.1 (1.9, 17.9)† N=13 7.7 (0.8, 26.8)‡ Response rate in pts with centrally confirmed ATM PVs, % (80% CI) N=28 7.1 (1.9, 17.9) N=11 9.1 (1.0, 31.0) Response rate in pts with centrally confirmed ATM-deficiency, % (80% CI) N=11 18.2 (4.9, 41.5) N=7 0.0 (0.0, 28.0) Safety, n (%) N=30 N=15 TEAEs 30 (100) 15 (100) Grade ≥3 TEAEs 15 (50.0) 8 (53.3) TRAEs 21 (70.0) 13 (86.7) Grade ≥3 TRAEs 6 (20.0) 5 (33.3) Serious TEAEs 4 (13.3) 4 (26.7) Serious TRAEs 2 (6.7) 1 (6.7) TEAEs leading to discontinuation 1 (3.3)§ 0 TEAEs leading to death 0 0 TEAEs (any grade) occurring in ≥20% of pts in either cohort, n (%) N=30 N=15 Nausea 13 (43.3) 8 (53.3) Abdominal pain 9 (30.0) 1 (6.7) Anemia 8 (26.7) 7 (46.7) Fatigue 8 (26.7) 5 (33.3) Asthenia 8 (26.7) 2 (13.3) Decreased appetite 7 (23.3) 3 (20.0) *Centrally confirmed ATM-altered patients were patients with either ATM PV confirmed by FMI F1CDx in tumor and/or by FMI F1 liquid CDx in circulating tumor DNA and/or ATM protein-deficient by immunohistochemistry assay at Ventana with cut-off ≤5%. Thus, ATM PV patients could also have ATM protein-deficiency. †Objective response by RECIST v1.1, in centrally confirmed ATM-altered patients. ‡Composite response: by RECIST v1.1 for soft tissue and visceral lesions and PCWG3 criteria for bone lesions; confirmed conversion of circulating tumor cell count from ≥5/7.5 mL blood to &amp;lt;5/7.5 mL; or confirmed prostate-specific antigen decline of &amp;gt;50%, in centrally confirmed ATM-altered patients. §Discontinuation due to decreased appetite classified as a serious adverse event. ASTs, advanced solid tumors; CI, confidence interval; mCRPC, metastatic castration-resistant prostate cancer; PV, pathogenic variant; pts, patients; TEAE, treatment-emergent adverse event; TRAE, treatment-related adverse event Citation Format: Rahul Aggarwal, Antoine Italiano, Susan Domchek, Oscar Goodman, Sophie Postel-Vinay, Jesus Garcia-Donas, Tanya Dorff, Zachery Reichert, Philippe Cassier, Neal Shore, Catherine Marshall, Graeme Parr, Itziar Irurzun-Arana, Neel Shah, Natalia Lukashchuk, Olga Murina, Daniel Slade, Bienvenu Loembé, Emma Dean, Elhan Sanai, Wassim Abida. Efficacy and safety of ceralasertib in the PLANETTE study in patients (pts) with ATM-altered advanced solid tumors (ASTs) or metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT222.