Blood Levels Of Drug Research Articles

MR study on white matter injury in patients with acute diquat poisoning

To explore the microstructural damage of white matter in acute diquat (DQ) poisoning patients using diffusion kurtosis imaging (DKI) and Tract-based Spatial Statistics (TBSS). This study included 19 DQ poisoning patients and 19 age-matched controls. MRI was performed using a 3.0T Philips Achieva scanner with sequences including 3D T1WI, T2WI, DWI, 3D T2WI-FLAIR, and DKI (3 b-values, 15 directions). DICOM to NIFTI image form conversion was done using MRIcron's Dcm2niigui, followed by motion and eddy current correction with FSL to create a brain mask. Scalar indicators (MK, AK, RK, FAK) were calculated with DKE software. TBSS was used for spatial normalization, skeletonization, and projection of DKI indices for group analysis with TFCE for multiple comparison correction (P<0.025). After the screening and enrollment process, 19 DQ-poisoned patients and 19 healthy volunteers were analyzed. No significant age or sex differences were found between groups. For Mean Kurtosis (MK), the right corticospinal tract showed a significant difference with a mean difference of 0.21 (95% CI: 0.15 to 0.27) and P=0.000503. Axial Kurtosis (AK) in the left superior longitudinal fasciculus had a mean difference of 0.18 (95% CI: 0.12 to 0.24) and P=0.0024. Fractional Anisotropy of Kurtosis (FAK) in the right corticospinal tract showed a mean difference of 0.19 (95% CI: 0.13 to 0.25) and P=0.0000318. Axial Kurtosis (AK) positively correlated with blood drug levels (r=0.52, P<0.05). Seven patients developed subcortical leukodystrophy, mainly in the frontal parietal lobe, with possible insular lobe involvement. DQ poisoning primarily damages the right corticospinal tract, right cingulate gyrus, and left superior longitudinal fasciculus, potentially causing movement and visual impairments. The injury involves demyelination and axonal degeneration, with asymmetrical damage between hemispheres. The left superior longitudinal fasciculus injury is dose-dependent, and unlike prior studies, dopaminergic nuclei were unaffected. The frontal parietal lobe is predominantly affected, with some insular lobe involvement in DQ poisoning patients.

High-performance liquid chromatography-tandem mass spectrometry was used to measure 20 antidepressants in human serum.

Aim: This study used high performance liquid chromatography-tandem mass spectrometry to quantify the blood concentrations of 20 antidepressants, such as bupropion and fluoxetine, in human serum samples.Methods: After direct precipitation with a 1:9 protein precipitant of methanol and acetonitrile, serum samples were examined using high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS). The material was separated using a Poroshell 120 EC-C18 column (3.0mm×50mm, 2.7μm) and gradient elution. The mobile phases were phase A 0.01% formic acid aqueous solution (containing 2mmol/ml ammonium acetate) and phase B methanol solution. A 0.45ml/min flow rate was used to divide the sample and inject 5μl. Electrospray ionization source positive ion mode and multiple reaction monitoring modes were used for analysis. Measurement was quantified using an internal standard technique.Results: Accuracy ranged from 90.3 to 114.3%, intra-day precision from 100.1 to 112.3%, inter-day precision from 100.4 to 112.6%, extraction recoveries from 85.5 to 114.5% and matrix effect from 85.6 to 98.7%.Conclusion: This approach is fast, accurate, sensitive and repeatable. It can identify 20 antidepressants in blood simultaneously. This can be used to monitor blood drug levels and medication metabolism.

The Relationship Between Weight Indices and Blood Levels of Immunosuppressive Drugs in Renal Transplant Recipients

Background: Calcineurin inhibitors and mammalian target of rapamycin (mTOR) inhibitors are essential for maintaining transplanted organs. However, determining the appropriate dosage and predicting blood concentrations of these drugs based solely on net body weight may be inadequate. Previous studies have presented contradictory results regarding the impact of obesity on drug concentrations and transplant success. Objectives: This study aims to evaluate various weight indices to identify the most reliable indicator of weight that correlates with the blood levels of drugs used in organ transplantation. Methods: This retrospective descriptive study included patients from nephrology clinics affiliated with Isfahan University of Medical Sciences who were taking calcineurin and/or mTOR inhibitor drugs. Data extracted from medical records included demographic and clinical information, such as height, weight, and various weight indices (total/ideal/adjusted body weight, lean body mass (LBM), Body Mass Index, and predicted normal weight), as well as blood levels of immunosuppressive drugs at each patient's visit. The dosages of each drug (mg/kg) were analyzed to determine which weight indices best correlated with the obtained blood concentrations, using the Generalized Estimating Equation (GEE) model with logistic regression, an independent correlation matrix, and a binary distribution for data analysis. Results: The study analyzed the medical records of 71 patients. Trough (C0) concentrations of drugs were evaluated in relation to each weight index, and odds ratios (OR) were calculated for statistical comparison. All weight indices increased the likelihood of achieving appropriate concentrations for cyclosporine, tacrolimus, and sirolimus. Drug dosing based on LBM (OR: 1.028), ideal body weight (OR: 1.075), and total body weight (OR: 1.041) showed the strongest correlations with achieving proper blood levels for cyclosporine, tacrolimus, and sirolimus, respectively. Conclusions: Integrating various weight indices for calculating individualized doses (mg/kg) of each immunosuppressive drug increases the likelihood of achieving appropriate blood concentrations. However, the optimal weight index varies for each drug. Further studies, particularly those incorporating therapeutic drug monitoring (TDM) plans in transplant centers, are warranted to validate and generalize these findings, providing a potential avenue for improving immunosuppressive therapy and enhancing transplant outcomes.

Nano Encapsulation of An Essential Oil Transpire the Therapeutic Approach.

Essential oils are natural compounds extracted from plants that are volatile and sensitive to heat. Due to their therapeutic value, essential oils are now used in many industries, including the sanitary, cosmetic, agricultural, food, and pharmaceutical industries. These are complex mixtures of a wide range of volatile molecules, including phenol-derived aliphatic and aromatic compounds and terpenoids. Essential oils have been used medicinally since ancient times for their antibacterial, antifungal, antiviral, antiparasitic, insecticidal, sedative, antiinflammatory, and anaesthetic properties. However, essential oils come with inherent limitations; thus, nanoencapsulation is advocated as a remedy as it has the potential to enhance the stability, solubility, and effectiveness of formulations based on essential oils, all while preserving the therapeutic drug blood levels. It is not always viable to use essential oils independently in treatment due to several restrictions; however, nanodelivery technologies appear capable of overcoming these challenges. The therapeutic efficacy that is achieved can be affected by several factors, including the selection of the essential oil as well as the system of nanodelivery. Today, nanoencapsulation is capable of enabling the simultaneous delivery of multiple oils, providing synergistic effects, and facilitating the development of combinational therapies. Additionally, they may have potential applications in preserving food to prolong the shelf life of quickspoiling items and their fragrances. While there is already much research on the characterisation of EOs, this review evaluates the features of the nanoparticles employed for the delivery of essential oils and their impact on the functionality of nano-delivered essential oils and their beneficial uses.

Ceftazidime/avibactam serum concentration in patients on ECMO.

The use of extracorporeal membrane oxygenation (ECMO) may alter blood levels of several drugs, including antibiotics, leading to under dosing of these drugs and thus to potential treatment failure. No data exist on pharmacokinetics of new antimicrobial, in particular ceftazidime/avibactam. We therefore perform this study to evaluate ceftazidime/avibactam blood levels in ECMO patients and find factors associated with underdosing. Retrospective observational study of patients on ECMO having received ceftazidime/avibactam and in whom trough blood levels of ceftazidime and avibactam were available. Main outcome measurement was the number of patients with ceftazidime and avibactam blood levels above predefined cut-off values, derived from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints for Enterobacteriaceae and Pseudomonas aeruginosa, namely 8 mg/L for ceftazidime and 4 mg/L for avibactam, and explored factors associated with underdosing. Twenty-three ceftazidime/avibactam trough levels were available in 14 ECMO patients, all of them having received veno-venous ECMO for SARS-CoV-2-associated pneumonia. Although ceftazidime levels were above 8 mg/L in all except one patient, nine (39%) of the avibactam dosages were below 4 mg/L. Increased renal clearance (creatinine clearance > 130 mL/min) was the main factor associated with under dosing, since 7 out of the 10 dosages below the predefined cut-offs were measured in patients with this condition. In ECMO patients receiving ceftazidime/avibactam, ceftazidime and avibactam serum levels are above EUCAST breakpoints in most cases, justifying the use of normal dosing in ECMO patients. Increased renal clearance may lead to ceftazidime and avibactam under dosing.

Abstract 6486: Correlation of nab-sirolimus tumor drug levels and improved tumor suppression in KRAS G12C non-small cell lung cancer xenografts treated with nab-sirolimus in combination with KRAS inhibitors

Abstract Background: KRAS mutations are found in a variety of tumor types, including non-small cell lung cancer (NSCLC), where KRAS G12C mutation is present in ~12% of NSCLC patients. KRAS G12C inhibitors (KRAS G12Cis), sotorasib and adagrasib, are approved for the treatment of KRAS G12C-mutated, locally advanced or metastatic NSCLC. The mTOR pathway is often activated in patients with KRAS mutations and may contribute to resistance to KRAS G12Cis. nab-Sirolimus is a nanoparticle albumin-bound intravenously (IV) administered form of the mTOR inhibitor (mTORi) sirolimus and is approved for the treatment of patients with advanced malignant perivascular epithelioid cell tumors. This study assessed tumor and blood drug level correlation with antitumor activity of nab-sirolimus or everolimus alone or in combination with KRAS G12Cis. Methods: Athymic mice bearing subcutaneous KRAS G12C- and STK11-mutated NSCLC xenografts (NCI-H2122) were treated with saline, mTORis nab-sirolimus (IV) or everolimus (oral) at clinically relevant and equal weekly dose of 15 mg/kg/wk, or KRAS G12Cis sotorasib (oral) or adagrasib (oral) at 30 mg/kg/day alone or in combination. Tumor volume changes from baseline were assessed; tumor and blood samples were harvested at the end of study (6 wks) for analysis of trough drug levels by LC-MS/MS, and tumor lysates were analyzed for downstream markers for mTOR inhibition by Western blot. Results: In nab-sirolimus plus KRAS G12Ci treated groups, significantly slower tumor growth was observed compared with single agent treated groups and everolimus plus KRAS G12Ci treated groups. Compared with single-agent nab-sirolimus (170.1 ng/g), treatment with nab-sirolimus plus sotorasib resulted in reduced tumor nab-sirolimus drug levels (73.6 ng/g, P=0.0040); while similar tumor nab-sirolimus drug levels were observed for nab-sirolimus plus adagrasib (121.6 ng/g, P=ns). Corresponding to greater antitumor activity, significantly greater tumor trough mTORi drug levels were observed in nab-sirolimus plus either sotorasib or adagrasib treated groups compared with similar everolimus combinations (85-fold, P&amp;lt;0.0001; and 91-fold, P=0.0050, respectively). Correspondingly, stronger mTOR downstream target inhibition of pS6 were observed for nab-sirolimus plus KRAS G12Ci treated groups compared with everolimus plus KRAS G12Ci treated groups. Conclusions: The addition of a KRAS G12Ci to nab-sirolimus significantly reduced tumor volume and increased tumor drug levels, suggesting enhanced tumor targeting compared with everolimus plus KRAS G12Cis and correlating to improved antitumor activity and mTOR target suppression. Clinical dose-finding studies are needed to determine potential drug-drug interactions between nab-sirolimus and KRASis. Citation Format: Shihe Hou, Jorge Nieva, Maria Zalath, Neil Desai. Correlation of nab-sirolimus tumor drug levels and improved tumor suppression in KRAS G12C non-small cell lung cancer xenografts treated with nab-sirolimus in combination with KRAS inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6486.

A Phase IIa Multicenter, Randomized, Vehicle-Controlled, Dose Escalating Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of CBT-001 Ophthalmic Solution in Patients With Primary or Recurrent Pterygium

PurposeTo evaluate the safety and efficacy of CBT-001, a multi-target tyrosine kinase inhibitor (MKI) eyedrop, for pterygia. DesignPhase 2 clinical trial. Stage 1 was a single center, open-labeled, vehicle-controlled study. Stage 2 was a multicenter, randomized, double-masked, vehicle-controlled trial. ParticipantsPatients with primary or recurrent pterygia. Main Outcome MeasuresThe primary efficacy endpoint was lesion vascularity based on masked grading of photographs by an independent reading center. Other endpoints included dimensions of pterygia and safety. MethodsIn Stage 1, 24 eyes of 24 patients received one drop of CBT-001 in a dose escalation fashion (0.02%, 0.05%, and 0.2%) to determine the maximally tolerated dose based on adverse events and blood drug levels. In Stage 2, subjects were randomly assigned to receive the maximally tolerated dose of CBT-001 or vehicle dosed three times a day (TID) for 4 weeks with a 20-week follow up. ResultsIn Stage 1, the plasma maximum concentration (Cmax) values for all doses of CBT-001 were at or below the limit of detection (0.01 ng/mL). The most commonly reported adverse events were mild foreign body sensation and irritation. CBT-001 0.2% was evaluated in Stage 2. Baseline demographic characteristics were similar between patients receiving CBT-001 (n = 25) and vehicle (n = 23). After 4 weeks of dosing, mean change from baseline in pterygium vascularity scores was –0.8 ± 0.7 (mean ± standard deviation) in subjects receiving CBT-001 0.2% and 0.0 ± 0.5 in subjects receiving vehicle (P < 0.001; 95% confidence interval [CI]: -1.12, -0.40). Pterygium vascularity scores remained significantly decreased, after the 4-week dosing period, at weeks 8 and 16, but not at week 24. Mean changes from baseline in the length of the pterygia were also significantly lower in subjects receiving CBT-001 compared to vehicle at weeks 2, 4, and 8 (P≤0.014). The most commonly reported adverse events were ocular, mild in severity, resolved after therapy, and did not result in discontinuation. ConclusionsCBT-001 0.2% decreased pterygia vascularity and lesion length after 4 weeks of dosing with a prolonged effect after dosing. The drug was well tolerated with minimal detected systemic drug levels.

Vedolizumab and Ustekinumab Levels in Pregnant Women With Inflammatory Bowel Disease and Infants Exposed In Utero

Vedolizumab and ustekinumab pharmacokinetics in pregnancy and the infant after in utero exposure remain incompletely defined. We aim to define the antenatal stability of ustekinumab and vedolizumab levels and the time at which infant drug levels become undetectable. This multicenter prospective observational cohort study recruited pregnant or preconception women with inflammatory bowel disease receiving vedolizumab or ustekinumab. Trough drug levels, clinical data, and biochemical data were documented preconception, during each trimester of pregnancy, and postpartum. Maternal and cord blood drug levels were measured at delivery and in infants until undetectable. Infant outcomes were assessed until 2 years of age. A total of 102 participants (vedolizumab, n= 58) were included. The majority of mothers were, and remained, in clinical and biochemical remission. Maternal vedolizumab levels decreased over the course of pregnancy in association with increasing weight, rather than increasing gestation. Maternal ustekinumab levels remained stable. The median time to drug becoming undetectable in the infant was shorter for vedolizumab (11 wk; range, 5-19 wk; n= 32) than ustekinumab (14 wk; range, 9-36 wk; n= 17) and correlated positively with infant delivery level. Thirty-two of 41 (88%) and 17 of 30 (67%) vedolizumab- and ustekinumab-exposed infants had undetectable drug levels by 15 weeks of age, respectively. Pregnancy and infant outcomes were favorable. Twenty infants with undetectable drug levels received the rotavirus vaccine, with no adverse reactions reported. Maternal vedolizumab levels decreased, whereas ustekinumab levels remained stable over the course of pregnancy. Most vedolizumab- and approximately half of ustekinumab-exposed infants had undetectable drug levels by 15 weeks of age. No concerning maternal or infant safety signals were identified.

Nose to brain delivery of mirtazapine via lipid nanocapsules: Preparation, statistical optimization, radiolabeling, in vivo biodistribution and pharmacokinetic study

Mirtazapine (MZPc) is an antidepressant drug which is approved by the FDA. It has low bioavailability, which is only 50%, in spite of its rapid absorption when orally administered owing to high first-pass metabolism. This study was oriented towards delivering intranasal (IN) mirtazapine by a direct route to the brain by means of preparing lipid nanocapsules (LNCs) as a targeted drug delivery system. MZP-LNCs were constructed by solvent-free phase inversion temperature technique applying D-Optimal mixture design to study the impact of 3 formulation variables on the characterization of the formulated nanocapsules. Independent variables were percentage of Labrafac oil, percentage of Solutol and percentage of water. Dependent variables were particle size, polydispersity index (PDI), Zeta potential and solubilization capacity. Nanocapsules of the optimized formula loaded with MZP were of spherical shape as confirmed by transmission electron microscopy with particle diameter of 20.59 nm, zeta potential of − 5.71, PDI of 0.223 and solubilization capacity of 7.21 mg/g. The in vivo pharmacokinetic behavior of intranasal MZP-LNCs in brain and blood was correlated to MZP solution after intravenous (IV) and intranasal administration in mice. In vivo biodistribution of the drug in mice was assessed by a radiolabeling technique using radioiodinated mirtazapine (131I-MZP). Results showed that intranasal MZP-LNCs were able to deliver higher amount of MZP to the brain with less drug levels in blood when compared to the MZP solution after IV and IN administration. Moreover, the percentage of drug targeting efficiency (%DTE) of the optimized MZP-LNCs was 332.2 which indicated more effective brain targeting by the intranasal route. It also had a direct transport percentage (%DTP) of 90.68 that revealed a paramount contribution of the nose to brain pathway in the drug delivery to the brain.Graphical

The prevalence of off-label use and supratherapeutic blood levels of outpatient psychotropic medication in suicidal adolescents.

Adolescents with mental disorders show an increased risk of suicidal phenomena. Vice versa, suicidality is a serious adverse event of psychotropic drug therapy in adolescents. There are only a few new psychotropic agents approved for this young age group. We evaluated the (pre-pandemic) prevalence of off-label use as well as detailed blood concentrations of outpatient psychotropic medication and sex differences in a clinical population of suicidal adolescents. The urine presence and serum levels of psychotropic substances of adolescents hospitalized due to their acute suicidality but without a known actual suicide attempt (i.e., no acute intoxication or serious self-injuries) were investigated routinely between 01.03.2017 and 31.01.2018. Urine (N = 205) and blood samples (N = 193) were taken at the beginning of closed inpatient admission, i.e., the results of the laboratory analysis reflect outpatient drug intake. The serum levels of psychopharmacological medication and OTC medication were measured. Our sample consists of 231 cases (boys: N = 54; girls: N = 177, ratio: 1:3.3), aged 12-17 years (average age: 15,4 years). The most prevalent psychiatric diagnoses were depressive episodes (54%) and adjustment disorders (25%), and girls were more often diagnosed with depressive disorders than boys (boy/girl ratio: 1:9.5, p < 0.0001). More than half of adolescents (56%) used at least one prescribed psychotropic drug at admission (24.8% ≥ two psychotropic drugs). Off-label use of second-generation antipsychotics was significantly more frequent than off-label use of antidepressants (85% vs. 31%, p < 0.01). Adolescents suffering from depressive disorders were significantly more often on-label treated than adolescents with neurotic or stress-related disorders (56% vs. 10%). Female cases with prescribed psychotropic drug use showed significantly more frequent supratherapeutic drug levels than male cases (5% vs. 27%, p < 0.05). Female adolescents may have an increased risk of supratherapeutic blood levels, especially when outpatient prescribed psychotropic drugs are off-label used. Measurement of blood levels of outpatient-prescribed psychotropic drugs could be used to enhance the safety and efficacy of the individual psychopharmacological treatment of adolescent suicidal patients. There is an urgent need for more real-world evidence on the effective treatment of adolescents with psychotropic drugs.

Fabrication Technology of Self-Dissolving Sodium Hyaluronate Gels Ultrafine Microneedles for Medical Applications with UV-Curing Gas-Permeable Mold.

Microneedles are of great interest in diverse fields, including cosmetics, drug delivery systems, chromatography, and biological sensing for disease diagnosis. Self-dissolving ultrafine microneedles of pure sodium hyaluronate hydrogels were fabricated using a UV-curing TiO2-SiO2 gas-permeable mold polymerized by sol-gel hydrolysis reactions in nanoimprint lithography processes under refrigeration at 5 °C, where thermal decomposition of microneedle components can be avoided. The moldability, strength, and dissolution behavior of sodium hyaluronate hydrogels with different molecular weights were compared to evaluate the suitability of ultrafine microneedles with a bottom diameter of 40 μm and a height of 80 μm. The appropriate molecular weight range and formulation of pure sodium hyaluronate hydrogels were found to control the dissolution behavior of self-dissolving ultrafine microneedles while maintaining the moldability and strength of the microneedles. This fabrication technology of ultrafine microneedles expands their possibilities as a next-generation technique for bioactive gels for controlling the blood levels of drugs and avoiding pain during administration.

3D Printing of Dietary Products for the Management of Inborn Errors of Intermediary Metabolism in Pediatric Populations.

The incidence of Inborn Error of Intermediary Metabolism (IEiM) diseases may be low, yet collectively, they impact approximately 6-10% of the global population, primarily affecting children. Precise treatment doses and strict adherence to prescribed diet and pharmacological treatment regimens are imperative to avert metabolic disturbances in patients. However, the existing dietary and pharmacological products suffer from poor palatability, posing challenges to patient adherence. Furthermore, frequent dose adjustments contingent on age and drug blood levels further complicate treatment. Semi-solid extrusion (SSE) 3D printing technology is currently under assessment as a pioneering method for crafting customized chewable dosage forms, surmounting the primary limitations prevalent in present therapies. This method offers a spectrum of advantages, including the flexibility to tailor patient-specific doses, excipients, and organoleptic properties. These elements are pivotal in ensuring the treatment's efficacy, safety, and adherence. This comprehensive review presents the current landscape of available dietary products, diagnostic methods, therapeutic monitoring, and the latest advancements in SSE technology. It highlights the rationale underpinning their adoption while addressing regulatory aspects imperative for their seamless integration into clinical practice.

Colorado drugged driving prevalence and impaired driving conviction rates: Effects of impaired driving definitions and a 5-nanogram limit for delta-9 tetrahydrocannabinol

Objectives: How prevalent is drugged driving among Colorado drivers convicted of Driving Under the Influence (DUI)? What are the conviction rates of Colorado drivers charged with DUI, including impairment by marijuana’s delta-9 tetrahydrocannabinol (THC)? Is Colorado’s THC permissible inference law effective? To answer these questions, this report analyzes data published primarily in appendices of Colorado drugged driving reports. Methods: In 2017 Colorado began requiring annual analyses of Driving Under the Influence (DUI) offenses, including causes and judicial consequences of DUI offenses. These analyses are performed by the Division of Criminal Justice’s Office of Research and Statistics (ORS) within the Department of Public Safety. Each analysis requires ORS to link toxicology and court data bases. Data linking enables reporting of charges and convictions by categories including alcohol only, THC only, and polydrug use (two or more drugs simultaneously). Reports have been published annually for 5 years, the latest published in 2023 which covers case filings for 2020. Results: A rough estimate of one-half of the state’s DUI filings were attributed to drug use and half were attributed to alcohol only. The largest component of drugged driving was polydrug impairment, rather than impairment by a single drug like THC. Conviction rates in 2020 were 91% for alcohol only, 90% for polydrug cases, and 72% for THC only. Blood drug levels and law structure (per se, permissible inference, DUI definition) affected conviction rates significantly by defendant subsets. THC conviction rates in 2020 ranged from 11% to 100%, depending on blood drug levels and the legal charges. Conclusions: Efforts to educate the public about the dangers of drugged driving should emphasize polydrug impairment, not simply THC impairment. States should analyze data on causes and consequences of DUI arrests to understand what their drugged driving problems are and what they are not. Non-zero drug per se levels and defining DUI as “incapable of safe driving” can severely reduce the effectiveness of DUI laws.

What Should We Know about Drug Levels and Therapeutic Drug Monitoring during Pregnancy and Breastfeeding in Inflammatory Bowel Disease under Biologic Therapy?

Data on the real long-term influences of in utero drug exposure in pregnant women on childhood development are scarce and remain not well determined and depend on the duration of in utero drug exposure and maternal drug levels. Therapeutic drug monitoring (TDM) during pregnancy may help limit fetal drug exposure while maintaining an effective dose for the treatment of the underlying inflammatory bowel disease (IBD) in women. Most antibody therapies used in patients with IBD are IgG molecules which are actively transported across the placenta, especially during the third trimester of the pregnancy. Here, we propose an up-to-date clinical review to summarize the available findings of serum drug levels in maternal blood during pregnancy, in the cord blood, infants at delivery and in breast milk of patients with IBD treated with biologics. Conversely, in comparison to adalimumab (ADA) levels, which are relatively stable during pregnancy, infliximab (IFX) drug clearance decreased significantly during the last two trimesters of the pregnancy, leading to increasing drug concentrations in the blood of the pregnant women. As most guidelines recommend using live vaccines in infants at the age of one or earlier in case of negative serum drug levels in newborns, statistical models could help clinicians in making a decision to adjust the last dose of the biologic during pregnancy and to determine the optimal date to vaccinate. Altogether, data from the literature offers strong reassurance in terms of safety for anti-TNFα therapies during pregnancy not only for IBD patients who intend to conceive, but also for pregnant women and for the physicians taking care of these patients. ADA and IFX levels in breast milk are detectable, but at very low levels, and therefore, it is recommended to pursue breast feeding under anti-TNFα therapy. Our knowledge on ustekinumab or vedolizumab levels in pregnant women remains unclear and scarce. These drugs are currently not recommended for patients with IBD in clinical practice. Therefore, TDM and proactive dose adjustment are not necessary during pregnancy since its impact on making a clinical decision have not yet been clearly demonstrated in routine practice. Overall, drug concentrations in the cord blood, an infant at birth and postpartum serum concentrations in infants, due to active placental drug transfer, may have a greater impact than the limited drug transfer in breast milk during lactation on the risk of infection and developmental outcomes. Ustekinumab and vedolizumab exposure during pregnancy and lactation are both considered low risk by the recent ECCO guidelines despite the limited data that are currently available.

Multiplex Immunosuppressant (ISD) Method for the Measurement of Cyclosporine A, Tacrolimus, Sirolimus/Rapamycin, and Everolimus in Whole Blood Using MassTrak™ Kit.

Cyclosporine A, everolimus, sirolimus, and tacrolimus are the most commonly used immunosuppressant drugs in organ transplant and auto-immune patients. The narrow therapeutic window of these immunosuppressant drugs requires close monitoring of drug blood levels to ensure proper therapeutic response. A quick, robust high-throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was introduced for monitoring whole blood levels of these immunosuppressant drugs with the use of the MassTrak™ Immunosuppressant kit. The assay was carried out in 96-well plate format and requires a simple precipitation step; after which, the supernatant is subjected to liquid chromatography separation (2min total run time) using a C18 Cartridge column. Identification and quantitation of cyclosporine A, everolimus, sirolimus, and tacrolimus was achieved by employing multiple reaction monitoring (MRM) in positive mode electrospray ionization (ESI). The method exhibits a linear measuring range from 10 to 1500ng/mL (Cyclosporine A), 1.0-30.0ng/mL (Everolimus), 1.0-26.0ng/mL (Sirolimus), and 1.0-30.0ng/mL (Tacrolimus) and has a within-run and between-run imprecision of <10%.

1897. Therapeutic Drug Monitoring in CSF and Plasma in Tuberculous Meningitis:Correlation with Disease Outcome

Abstract Background Tuberculous meningitis (TBM) is a serious form of extra-pulmonary tuberculosis with significant morbidity and mortality. TBM patients are treated with pulmonary tuberculosis regimen, often requiring extension for 1 year or longer. Current study was designed to find any association of CSF and blood levels of anti-tubercular drugs with treatment response in patients with tuberculous meningitis using therapeutic drug monitoring. Pharmacokinetic Parameters of Rifampicin and Isoniazid in CSF and Plasma Methods A prospective observational study was conducted in a tertiary care institute in North India among clinic-radiologically and/or microbiologically diagnosed TBM patients. Plasma and CSF levels of anti TB drugs (rifampicin, isoniazid, pyrazinamide and ethambutol) were determined using Liquid Chromatography Mass Spectrometry technology at 1 week and 1 month (follow up) after initiating treatment. The primary outcome assessed was association of drug levels with treatment response. The secondary outcomes assessed were association of drug levels with treatment duration/alteration, patient demographic profile, comorbidities and adverse effects. Patients were followed-up till treatment completion. Results A total of 40 patients with TBM were recruited. All received daily weight-based doses of anti TB drugs. Low Cmax of INH and rifampicin in plasma were observed in 60.5% &amp; 42.1% of observations respectively. In CSF, low Cmax of INH and rifampicin were observed in 77.6% &amp; 82.9% of observations respectively. The concentrations of INH (4 hours after drug intake) during follow up were significantly lower among patients with poor response, at 1 month (p=0.008) &amp; 6 months (p=0.009). Similarly, low Cmax &amp; CSF levels of INH at follow up sampling were significantly associated with poor response at 6 months of therapy (p= 0.022 &amp; 0.042 respectively). Conclusion Low plasma and CSF concentrations of isoniazid were associated with a poor response to treatment in patients with TBM. Therapeutic drug monitoring can guide dose modification of ATT to achieve target concentrations in patients with TBM and facilitate optimal treatment outcomes. Higher dose INH can be considered in TBM treatment regimen for better outcome. Disclosures All Authors: No reported disclosures

Evaluation of the clinical and quantitative performance of a practical HPLC-UV platform for in-hospital routine therapeutic drug monitoring of multiple drugs

BackgroundIn-hospital therapeutic drug monitoring (TDM) requires a suitable quantification method for target drugs from the viewpoint of precision, throughput, and testing costs. We previously developed a practical HPLC-UV platform for quantification of serum levels of various drugs. In this report, the platform was effectively applied to the quantification of patient serum levels of five different drugs by clinical professionals in our hospital during their daily work.MethodsThe residual sera of patients receiving carbamazepine (CBZ), phenytoin (PHT), lamotrigine (LTG), vancomycin (VCM), or voriconazole (VRCZ) were used in the present clinical study. The quantification method for each drug consisted of rapid solid-phase extraction (SPE) of each drug in the patient serum, followed by optimized HPLC-UV analysis of the drug in the SPE eluate. Furthermore, patient serum levels of PHT, CBZ, and VCM were also measured by ligand-binding assay using a cobas® analyzer in our hospital, and those of LTG and VRCZ were measured by HPLC-MS/MS at an outsourced provider. Passing–Bablok regression analysis and Bland–Altman analysis were employed to analyze the agreement of drug levels in patient sera, which was separately quantified using two different methods—our HPLC-UV platform and the cobas analyzer, or HPLC-UV and HPLC-MS/MS.ResultsAll analytical conditions of the present method using our HPLC-UV platform were well optimized for each target drug quantification in the patient’s serum, and the quantification method for each drug was fully validated for accuracy, precision and reproducibility. Furthermore, Passing–Bablok regression analysis and Bland–Altman analysis revealed that patient serum levels of PHT, CBZ, and VCM quantified by our HPLC-UV platform were closely correlated with those quantified by the cobas® analyzer, and the levels of LTG and VRCZ quantified by our HPLC-UV platform were also correlated with those quantified by HPLC-MS/MS.ConclusionsOur HPLC-UV platform can be performed without requiring special analytical techniques. This platform is expected to be used for the measurement of blood levels of multiple drugs for in-hospital routine TDM.

The effect of subthreshold depressive symptoms on cognitive functions and peripheral biomarkers in bipolar disorder

Objective A global approach to factors responsible for functional impairment in patients with BD is necessary. Method Ninety-three euthymic patients with BD [49 patients with SD (subthreshold depression) and 44 patients without SD] and 48 healthy controls were invited for evaluation of demographic, clinical, and cognitive characteristics. To define SD, the lower limit was HDRS ≥4 points and the upper limit was HDRS <9 points. Stroop test, California verbal learning test, digit-span test, controlled word association test, and clock drawing test were performed. Serum BDNF levels were measured. Additionally in the BD group; blood drug (lithium, valproic acid), leukocyte, C-reactive protein (CRP), TSH, and vitamin B12 levels were measured. Results We found no difference between serum BDNF levels of BD (n = 93) and controls. The cognitive performances of the BD group were worse than the control group (p < 0.001). Attention, working memory, and stroop performance of patients with SD were worse than patients without SD (p < 0.05). Verbal fluency, stroop test, and planning performance decreased as serum CRP level increased in patients with BD (p < 0.05). Conclusions Although the patient group with SD was in euthymia, their cognitive performance was worse than the group without SD. Poor cognitive performance in BD was associated with serum CRP levels.

Effect of Omeprazole Administration on the Pharmacokinetics of Oral Extended-Release Nifedipine in Healthy Subjects.

Oral extended-release (ER) dosage forms have been used to sustain blood drug levels, reduce adverse events, and improve patient compliance. We investigated potential effects of comedication on pharmacokinetic exposure of nifedipine ER products with different formulation designs and manufacturing processes. A clinical study compared a generic version of nifedipine ER tablet with pH-dependent dissolution behavior with an osmotic pump product with pH independent drug release under fasting condition. In this study, two nifedipine tablet products were tested with or without short-term omeprazole comedication in healthy subjects. Seven-day administration of omeprazole before nifedipine dosing significantly increased the gastric pH, and subsequently increased the geometric least square (LS) means of area under the concentration-time curve from time zero to the last measurable timepoint (AUC0-t ) and maximum plasma concentration (Cmax ) of nifedipine to 132.6% (90% confidence interval (CI): 120.6-145.7%) and 112.8% (90% CI: 100.8-126.3%) for pH-dependent ER tablets, and 120.6% (90% CI: 109.7-132.5%) and 122.5% (90% CI: 113.7-131.9%) for the pH-independent ER tablets, respectively. Similar extent of increase in AUC0-t and Cmax was confirmed in the subpopulations whose gastric pH was ≥ 4 or ≤ 3 in subjects with or without omeprazole administration. Given that similar increases in drug exposures were observed for both pH-dependent and pH-independent nifedipine formulations and the geometric LS mean ratios were between 112% and 133% with and without short-term omeprazole comedication, the gastric pH may have limited effects on omeprazole-induced nifedipine PK changes on the tested formulations. The inhibition of cytochrome P450 3A4 activity may play a significant role causing nifedipine exposure changes for both formulations, which would warrant additional assessment.

Leveraging psychedelic therapies for binge eating disorder

Leveraging psychedelic therapies for binge eating disorder Here Tryp Therapeutics examine the viability of using psychedelic therapies for Binge Eating Disorder and the potential results that using psychedelic-assisted psychotherapy could have on different eating disorders. Tryp Therapeutics is a clinical-stage biotechnology company dedicated to the development of exclusive and innovative formulations for administering psilocin in conjunction with psychotherapy, aiming to address unmet medical needs in various diseases. Our primary focus is on our lead program, TRP-8803, which represents a proprietary formulation of intravenous (IV) infused psilocin, the active metabolite of psilocybin. This formulation overcomes several limitations associated with oral psilocybin administration. By directly administering psilocin via the intravenous route, we achieve the most precise form of dosing, ensuring the reproducibility of blood levels necessary for clinical efficacy while preserving safety. In contrast, oral administration of psilocybin relies on enzymatic conversion of psilocybin to psilocin, resulting in substantial variability in drug blood levels among patients, potentially confounding the planned outcome of clinical studies.