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Direct oral anticoagulants (DOACs) exert anticoagulation effect by directly inhibiting Factor Xa (rivaroxaban, apixaban, and edoxaban) or thrombin (dabigatran). Though DOACs are characterized by fixed-dose prescribing and generally do not require routine laboratory drug-level monitoring (DLM), circumstances may arise where the DLM may aid in clinical decision-making, including DOAC dose adjustment, anticoagulant class change, or decisions to withhold or administer reversal agents. We review the current literature that describes high-risk patient groups in which DLM may be beneficial for improved patient anticoagulation management and stewardship. The review also summarizes the limitations of conventional coagulation testing and discuss the emerging utility of quantitative methods for routine and rapid emergent evaluation of DOAC drug levels-in particular, the Anti-Xa activity to detect Factor Xa Inhibitors (rivaroxaban, apixaban, and edoxaban). Both technical and regulatory barriers to widespread DLM implementation are limiting factors to further clinical research that must be overcome, in order to propose universal DOAC DLM strategies and provide clinical-laboratory correlation to formally classify high-risk patient groups.

The four cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators, ivacaftor, lumacaftor, tezacaftor, and elexacaftor, have revolutionised the treatment of CF by direct action on the protein target behind the disease's development. The aim was to develop and validate a quantification method for these CFTR modulators in plasma and breast milk to better understand inter-patient variability in pharmacokinetics and treatment outcome, including the risk of adverse drug reactions. The ability to monitor CFTR modulators in breast milk enables the estimation of the exposure of breastfed infant, with a potential concern for CFTR modulator-induced liver injury. The analysis was performed on a Thermo Vanquish Flex Binary UHPLC system coupled to a high-resolution mass spectrometer (HRMS), Thermo Q Exactive. The analytes were detected using positive electrospray ionisation in full scan mode. After sample preparation by protein precipitation, the supernatant was injected onto the LC system and the analytes were separated using a Zorbax SB-C18 Rapid Res HPLC column (3.5 µm, 4.6 × 75 mm). This is the first published method for CFTR modulators in breast milk. The validated quantification range for ivacaftor is 0.0050–10 µg/mL with a coefficient of variation < 6% and a mean accuracy of 97–106%; for lumacaftor, tezacaftor, and elexacaftor, the validated quantification range is 0.050–100 µg/mL with a coefficient of variation < 8% and a mean accuracy 93–106%. A simple and sensitive quantification method for CFTR modulators has been developed and used for routine analysis of human plasma and breast milk samples since 2022. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusion Patients undergoing haemodialysis (HD) are at greater risk of methicillin‐resistant Staphylococcus aureus infections requiring intravenous vancomycin. Close vancomycin therapeutic drug monitoring is warranted in HD patients as renal clearance is the primary elimination pathway. Clinically, population pharmacokinetics (popPK) model‐informed dosing is commonly used. This study aimed to perform an external evaluation of published vancomycin popPK models developed for adults undergoing high‐flux intermittent HD, and to create a dosing nomogram derived from the model that performed best.A literature review was conducted through PubMed and EMBASE to identify relevant popPK models. an external dataset was collected retrospectively from patients of 2 healthcare centres in Quebec, Canada. Selected models were implemented in NONMEM (v7.5; ICON Development Solutions). Predictive performance was assessed through prediction and simulation‐based diagnostics.In total, 2386 vancomycin concentrations were collected from 274 patients and 476 antibiotic courses. Four vancomycin popPK models were selected for evaluation. None of the models demonstrated overall satisfactory or clinically acceptable predictive performance. Nonetheless, Bae et al.’s model performed best with a median prediction error of 16.25% and median absolute prediction error of 34.66%. Different predictive performance was also observed for vancomycin concentrations from samples collected during and between HD sessions.All evaluated models presented poor overall predictive performance. Further studies are required, through existing popPK model parameter re‐estimation or new model development, to adequately describe vancomycin pharmacokinetics for our high‐flux intermittent HD patient cohort. [ABSTRACT FROM AUTHOR]

Current methods for therapeutic drug monitoring (TDM) have a long turnaround time as they involve collecting patients' blood samples followed by transferring the samples to medical laboratories where sample processing and analysis are performed. To enable real‐time and minimally invasive TDM, a microneedle (MN) biosensor to monitor the levels of two important antibiotics, vancomycin (VAN) and gentamicin (GEN) is developed. The MN biosensor is composed of a hydrogel MN (HMN), and an aptamer‐functionalized flexible (Flex) electrode, named HMN‐Flex. The HMN extracts dermal interstitial fluid (ISF) and transfers it to the Flex electrode where sensing of the target antibiotics happens. The HMN‐Flex performance is validated ex vivo using skin models as well as in vivo in live rat animal models. Data is leveraged from the HMN‐Flex system to construct pharmacokinetic profiles for VAN and GEN and compare these profiles with conventional blood‐based measurements. Additionally, to track pH and monitor patient's response during antibiotic treatment, an HMN is developed that employs a colorimetric method to detect changes in the pH, named HMN‐pH assay, whose performance has been validated both in vitro and in vivo. Further, multiplexed antibiotic and pH detection is achieved by simultaneously employing the HMN‐pH and HMN‐Flex on live animals. [ABSTRACT FROM AUTHOR]

AbstractFor fixed-duration therapies against chronic lymphocytic leukemia (CLL), undetectable measurable residual disease (MRD) predicts overall and progression-free survival more accurately than complete remission. For indefinite therapies, MRD status can direct discontinuation of treatment. We systematically reviewed the relationship between antineoplastic drug exposures and undetectable MRD in CLL. Seventeen trials from MEDLINE and EMBASE met the inclusion criteria; four of which evaluated drug exposures in relation to MRD status. Undetectable MRD was associated with higher trough concentrations of ofatumumab and alemtuzumab, as well as increased maximum concentration and area under the plasma concentration curve (AUC) of ibrutinib. One study found an association between high rituximab AUC and undetectable MRD until adjusting for tumor burden. The limited studies, lack of exposure measurements of concomitant drugs, and high heterogeneity in designs limit the results’ generalizability. Further research is needed to explore the exposure–MRD relationship and the possibility for therapeutic drug monitoring in CLL. [ABSTRACT FROM AUTHOR]

Objectives: We evaluated the impact of polypharmacy on the health of community-dwelling older adults. Methods: We prospectively analyzed 5,631 individuals from the Moli-sani study (51% men, aged ≥65 years, recruitment 2005–2010, follow-up 2005–2020). Exposure was categorized as chronic polypharmacy therapy (C-PT; ≥5 therapeutic groups and >2 defined daily doses (DDDs)) or non-chronic polypharmacy therapy (NC-PT; polypharmacy but ≤2 DDDs). Hospitalization and mortality were the main outcomes. The mediating role of potentially inappropriate prescriptions (PIP) was examined. Results: Compared to individuals not on polypharmacy, those in NC-PT and C-PT had higher hazards of mortality [21% (95% CI 7%–37%) and 30% (16%–46%), respectively] and hospitalization [39% (28%–51%) and 61% (49%–75%), respectively]. Similar results were found for cardiovascular outcomes. PIP mediated the association between polypharmacy and outcomes, with mediation effects ranging from 13.6% for mortality to 6.0% for hospitalization. Older adults without multimorbidity experienced the same harm from multiple medications as those with multimorbidity. Conclusion: Polypharmacy is associated with a higher hazard of mortality and hospitalization, with PIP playing an important role. Addressing "medication without harm" requires assessing the appropriateness of drug prescriptions and monitoring for adverse effects. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Changes in gastrointestinal physiology following bariatric surgery may affect the pharmacokinetics of drugs. Data on the impact of bariatric surgery on drugs used for attention‐deficit/hyperactivity disorder (ADHD) are limited.In patients treated with ADHD medication and undergoing bariatric surgery, serial drug concentrations were measured for 24 h preoperatively and one, six and 12 months postoperatively. Primary outcome was change in area under the concentration‐time curve from 0 to 24 h (AUC0–24), with other pharmacokinetic variables as secondary outcomes.Eight patients treated with lisdexamphetamine (n = 4), dexamphetamine (n = 1), methylphenidate (n = 1) and atomoxetine (n = 2) were included. In total, 409 samples were analysed. Patients underwent sleeve gastrectomy (n = 5) and Roux‐en‐Y gastric bypass (n = 3). AUC0–24 and Cmax of dexamphetamine increased after surgery in those using the prodrug lisdexamphetamine. There was no clear‐cut reduction in tmax postoperatively. For ritalinic acid and atomoxetine, no changes in AUC0–24 were observed, but for atomoxetine, a higher Cmax and a shorter tmax were observed postoperatively.Bariatric surgery may increase the systemic exposure of dexamphetamine after intake of lisdexamphetamine. Patients using lisdexamphetamine should be followed with regard to adverse drug reactions after bariatric surgery, and, if available, therapeutic drug monitoring should be considered. [ABSTRACT FROM AUTHOR]

Background: Bacterial peritonitis is a common complication of peritoneal dialysis. In the absence of systemic signs of infection, adult guidelines recommend treatment with intraperitoneal vancomycin either as empiric coverage of gram‐positive organisms or as targeted therapy. However, there is no guidance on how to administer vancomycin in children on automated peritoneal dialysis. Case Report: We report vancomycin pharmacokinetics upon intraperitoneal administration for the treatment of a Staphylococcus hominis peritonitis in an 11‐year‐old patient on automated nocturnal intermittent peritoneal dialysis. While the patient was hospitalized, vancomycin was administered intraperitoneally as a continuous treatment. After hospital discharge, the nocturnal peritoneal dialysis was resumed. In the absence of treatment guidelines, intraperitoneal vancomycin was initially administered empirically only during the nocturnal dialysis exchanges which led to repetitive subtherapeutic vancomycin plasma concentrations and the persistence of S. hominis in dialysate cultures. Based on studies in adults, the dosing strategy was subsequently modified to administer vancomycin at a dosage of 15 mg kg−1 in the dialysate with a 6‐h dwell period prior to the nocturnal dialysis thereby allowing to reach optimal peak concentrations. The dosing interval was subsequently individualized using therapeutic drug monitoring to ensure residual vancomycin concentrations > 10 mg L−1 thereby leading to clinical and microbiological recovery. Conclusions: This case presents a dosing strategy based on a comprehensive review of the literature and highlights that a sufficient dwell period is critical when treating pediatric patients on automated peritoneal dialysis in order to allow vancomycin distribution and equilibration between the dialysate and the plasma. [ABSTRACT FROM AUTHOR]

Bioanalytical methods are used to quantify drugs and their metabolites in biological samples in order to determine bioequivalence, perform pharmacokinetic and bioavailability studies, and complete therapeutic drug monitoring. The objective of this review paper is to describe bioanalytical methods based on Liquid Chromatography that are used to quantify antitubercular drugs and their metabolites in different biological samples, utilizing scientific literature from 1992 to 2021. [ABSTRACT FROM AUTHOR]

Objectives To assess the impact of baseline RF level on drug concentrations and efficacy of certolizumab pegol [CZP; TNF inhibitor (TNFi) without a crystallizable fragment (Fc)] and adalimumab (ADA; Fc-containing TNFi) in patients with RA. Methods The phase 4 EXXELERATE study (NCT01500278) was a 104-week, randomized, single-blind (double-blind until week 12; investigator-blind thereafter), head-to-head study of CZP vs ADA in patients with RA. In this post hoc analysis, we report drug concentration and efficacy outcomes stratified by baseline RF quartile (≤Q3 or >Q3). Results Baseline data by RF quartiles were available for 453 CZP-randomized and 454 ADA-randomized patients (≤Q3: ≤204 IU/ml; >Q3: >204 IU/ml). From week 12, the area under the curve (AUC) of ADA concentration was lower in patients with RF >204 IU/ml vs patients with RF ≤204 IU/ml; the AUC of CZP concentration was similar in patients with RF ≤204 IU/ml and >204 IU/ml. For patients with RF ≤204 IU/ml, disease activity score (DAS28)-CRP was similar between CZP- and ADA-treated patients through week 104. For patients with RF >204 IU/ml, mean DAS28-CRP was lower in CZP- vs ADA-treated patients at week 104. The proportion of patients with RF >204 IU/ml achieving DAS28-CRP low disease activity at week 104 was greater in CZP- vs ADA-treated patients. Conclusion CZP was associated with maintained drug concentration and efficacy in patients with RA and high RF and may therefore be a more suitable therapeutic option than TNFis with an Fc fragment in these patients. Trial registration Clinicaltrials.gov, http://clinicaltrials.gov , NCT01500278 [ABSTRACT FROM AUTHOR]

Bariatric surgery is increasingly performed to treat severe obesity. As a result of anatomical and physiological changes in the gastrointestinal tract, the pharmacokinetics (PK) of oral drugs can be altered, affecting their efficacy and safety. This includes the class of tyrosine kinase inhibitors (TKIs) which are used to treat chronic myeloid leukemia (CML). This case series describes the clinical course of four CML cases with a history of bariatric surgery. The patients used various TKIs (nilotinib, dasatinib, bosutinib, ponatinib, and imatinib) for which 15 drug levels were measured. The measured TKI concentrations were in part subtherapeutic, and highly variable when compared to mean levels measured in the general population. Multiple drug levels were measured in these patients, as the clinicians were aware of the possible impact of bariatric surgery. The drug levels were used as additional input for clinical decision-making. All four patients required TKI switches and/or dose modifications to achieve an effective and tolerable treatment. Eventually, adequate clinical and molecular remissions were achieved in all cases. In summary, TKI concentrations of patients undergoing bariatric surgery may be subtherapeutic. Moreover, there is substantial interindividual and intraindividual variation, which may be explained by the complex interference of bariatric surgery and associated weight loss. For clinical practice, therapeutic drug monitoring is advised in patients with a history of bariatric surgery in case of suboptimal response or loss of response. [ABSTRACT FROM AUTHOR]

Background Drug-resistant tuberculosis (DR-TB) is one of the challenging forms of TB to treat, not only in adults but also in children and adolescents. Further, there is a void in the treatment strategy exclusively for children due to various reasons, including paucity of pharmacokinetic (PK) data on anti-TB drugs across the globe. In this context, the present study aimed at assessing the PK of some of the anti-TB drugs used in DR-TB treatment regimens. Method A multicentre observational study was conducted among DR-TB children and adolescents (n  = 200) aged 1–18 years (median: 12 years; IQR: 9–14) treated under programmatic settings in India. Steady-state PK (intensive: n  = 89; and sparse: n  = 111) evaluation of moxifloxacin, levofloxacin, cycloserine, ethionamide, rifampicin, isoniazid and pyrazinamide was carried out by measuring plasma levels using HPLC methods. Results In the study population, the frequency of achieving peak plasma concentrations ranged between 13% (for rifampicin) to 82% (for pyrazinamide), whereas the frequency of suboptimal peak concentration for pyrazinamide, cycloserine, moxifloxacin, levofloxacin and rifampicin was 15%, 19%, 29%, 41% and 74%, respectively. Further, the frequency of supratherapeutic levels among patients varied between 3% for pyrazinamide and 60% for isoniazid. In the below-12 years age category, the median plasma maximum concentration and 12 h exposure of moxifloxacin were significantly lower than that of the above-12 years category despite similar weight-adjusted dosing. Conclusions Age significantly impacted the plasma concentration and exposure of moxifloxacin. The observed frequencies of suboptimal and supratherapeutic concentrations underscore the necessity for dose optimization and therapeutic drug monitoring in children and adolescents undergoing DR-TB treatment. [ABSTRACT FROM AUTHOR]

Objectives Ceftazidime/avibactam is a key antibiotic for carbapenemase-producing Enterobacterales (CPE) Gram-negative infections, but current dosing may be suboptimal to grant activity. This study explores the population pharmacokinetics/pharmacodynamics (PK/PD) of continuous infusion (CI) ceftazidime/avibactam for maximizing treatment efficacy in critically ill patients. Methods A retrospective analysis of adult patients receiving CI ceftazidime/avibactam and therapeutic drug monitoring (TDM) of both compounds was performed. Population PK/PD modelling identified the most accurate method for estimating ceftazidime/avibactam clearance based on kidney function and Monte Carlo simulations investigated the relationship between various CI dosing regimens and aggressive joint PK/PD target attainment of ceftazidime/avibactam. Results The European Kidney Function Consortium (EKFC) equation best described kidney function for ceftazidime/avibactam clearance. The findings challenge the current approach of only reducing the ceftazidime/avibactam dose based on kidney function by identifying dose adjustments in patients with augmented kidney function. Our CI ceftazidime/avibactam dosing strategies, adjusted by TDM, showed promise for achieving optimal aggressive joint PK/PD targets and potentially improving clinical/microbiological outcomes against KPC- and OXA-48-producing Enterobacterales. The risk of neurotoxicity associated with these strategies appears acceptable. Conclusions This study suggests that adjusting ceftazidime/avibactam dosing regimen based solely on eCLcr might be suboptimal for critically ill patients. Higher daily doses delivered by CI and adjusted based on TDM have the potential to improve aggressive joint PK/PD target attainment and potentially clinical/microbiological outcomes. Further investigations are warranted to confirm these findings and establish optimal TDM-guided dosing strategies for ceftazidime/avibactam in clinical practice. [ABSTRACT FROM AUTHOR]

Apixaban is a widely used direct oral anticoagulant that is recommended over warfarin therapy for many clinical indications. In patients with atrial fibrillation, dose reductions are recommended for patients with advanced age (≥80 years), low weight (≤60 kg) or elevated serum creatinine (≥1.5 mg/dL), but there is no routine laboratory monitoring necessary for long term‐use. Furthermore, apixaban dose reductions due to renal dysfunction are not recommended when treating acute venous thromboembolism. Apixaban‐calibrated anti‐Xa assays are readily available at some medical centres, and they may be of clinical utility in certain circumstances such as in patients with renal insufficiency, medication adherence assessment, periprocedural planning, extremes in body weight and advanced age. Here, we describe the case of an elderly patient with chronic kidney disease taking apixaban for acute pulmonary embolism. The patient had an unanticipated prolonged apixaban half‐life, with detectable apixaban‐calibrated anti‐Xa levels for >10 days after the last administered dose, which delayed a necessary surgical intervention by >1 week. This case is an example of appropriately using apixaban‐calibrated anti‐Xa levels to guide therapeutic decision making in perioperative planning. [ABSTRACT FROM AUTHOR]

Aims: Dried blood volumetric absorptive microsamples (VAMS) may facilitate home‐based sampling to enhance therapeutic drug monitoring after transplantation. This study aimed to clinically validate a liquid chromatography–tandem mass spectrometry assay using 2 VAMS devices with different sampling locations (Tasso‐M20 for the upper arm and Mitra for the finger). Patient preferences were also evaluated. Methods: Clinical validation was performed for tacrolimus and mycophenolic acid by comparison of paired VAMS and venipuncture samples using Passing–Bablok regression and Bland–Altman analysis. Conversion of mycophenolic acid VAMS to serum concentrations was evaluated using haematocrit‐dependent formulas and fixed correction factors defined a priori. Patients' perspectives, including useability, acceptability and feasibility, were also investigated using established questionnaires. Results: Paired samples (n = 50) were collected from 25 kidney transplant recipients. Differences for tacrolimus whole‐blood concentration were within ±20% for 86 and 88% of samples from the upper arm and fingerstick, respectively. Using correction factors of 1.3 for the upper‐arm and 1.47 for finger‐prick samples, 84 and 76% of the paired samples, respectively, were within ±20% for mycophenolic acid serum concentration. Patient experience surveys demonstrated limited pain and acceptable useability of the upper‐arm device. Conclusions: Tacrolimus and mycophenolic acid can be measured using 2 common VAMS devices with similar analytical performance. Patients are supportive of home‐based monitoring with a preference for the Tasso‐M20 device. [ABSTRACT FROM AUTHOR]

Aims: Metamizole is quite an old drug with analgesic, antipyretic and spasmolytic properties. Recent findings have shown that it may induce several cytochrome P450 (CYP) enzymes, especially CYP3A4 and CYP2B6. The clinical relevance of these properties is uncertain. We aimed to unravel potential pharmacokinetic interactions between metamizole and the CYP3A4 substrate quetiapine. Methods: Plasma concentrations of quetiapine from a large therapeutic drug monitoring database were analysed. Two groups of 33 patients, either receiving quetiapine as a monotherapy (without CYP modulating comedications) or with concomitantly applied metamizole, were compared addressing a potential impact of metamizole on the metabolism of quetiapine being reflected in differences of plasma concentrations of quetiapine and dose‐adjusted plasma concentrations. Results: Patients comedicated with metamizole showed >50% lower plasma concentrations of quetiapine (median 45.2 ng/mL, Q1 = 15.5; Q3 = 90.5 vs. 92.0 ng/mL, Q1 = 52.3; Q3 = 203.8, P =.003). The dose‐adjusted plasma concentrations were 69% lower in the comedication group (P =.001). Subgroup analyses did not suggest a dose dependency of the metamizole effect or an influence of quetiapine formulation (immediate vs. extended release). Finally, the comedication group exhibited a significantly higher proportion of patients whose quetiapine concentrations were below the therapeutic reference range (78.8% in the metamizole group vs. 54.4% in the control group, P =.037) indicating therapeutically insufficient drug concentrations. Conclusion: The combination of metamizole and quetiapine leads to significantly lower drug concentrations of quetiapine, probably via an induction of CYP3A4. Clinicians must consider the risk of adverse drug reactions, especially treatment failure under quetiapine when adding metamizole. [ABSTRACT FROM AUTHOR]

Extracorporeal membrane oxygenation (ECMO) support of critically ill pediatric patients is associated with increased risk of thromboembolic events, and unfractionated heparin is used commonly for anticoagulation. Given reports of acquired antithrombin (AT) deficiency in this patient population and associated concern for heparin resistance, AT activity measurement and off‐label AT replacement have become common in pediatric ECMO centers despite limited optimal dosing regimens. We conducted a retrospective cohort study of pediatric ECMO patients (0 to <18 years) at a single academic center to characterize the pharmacokinetics (PK) of human plasma‐derived AT. We demonstrated that a two‐compartment turnover model appropriately described the PK of AT, and the parameter estimates for clearance, central volume, intercompartmental clearance, peripheral volume, and basal AT input under non‐ECMO conditions were 0.338 dL/h/70 kg, 38.5 dL/70 kg, 1.16 dL/h/70 kg, 40.0 dL/70 kg, and 30.4 units/h/70 kg, respectively. Also, ECMO could reduce bioavailable AT by 50% resulting in 2‐fold increase of clearance and volume of distribution. To prevent AT activity from falling below predetermined thresholds of 50% activity in neonates and 80% activity in older infants and children, we proposed potential replacement regimens for each age group, accompanied by therapeutic drug monitoring. [ABSTRACT FROM AUTHOR]

Objectives. To investigate characteristics of data reported in US medical cannabis registries across states. Methods. Data included 2021 medical cannabis registry reports from 34 states, Puerto Rico, and the District of Columbia (hereafter, states) with active medical cannabis programs. The data from the reports were manually coded into domains and subcategories, including information related to patients (e.g., number, demographics), authorizing clinicians, sales (e.g., content, revenue), license tracking, and health and safety outcomes. Results. Among 36 states, 97% reported total patient number and 75% reported number of authorizing clinicians. Least reported subcategories included patient race/ethnicity (8%), adverse events (11%), therapeutic benefits (6%), and product recalls (6%). States that recently legalized medical cannabis (2013–2018) reported a higher number of subcategories overall, with a median of 11 versus 8 for early adopting states (1996–2012). More medical-use states reported data on authorizing clinicians compared with nonmedical adult-use states but were otherwise similar. Conclusions. Medical cannabis state registries generally reported data on consumers, clinicians, and sales rather than health and safety outcomes. More comprehensive and uniform medical cannabis public health surveillance is needed. (Am J Public Health. 2024;114(S8):S685–S693. https://doi.org/10.2105/AJPH.2024.307728) [ABSTRACT FROM AUTHOR]

Background: For psychotic disorders (i.e. schizophrenia), pharmacotherapy plays a key role in controlling acute and long-term symptoms. To find the optimal individual dose and dosage strategy, specialised tools are used. Three tools have been proven useful to personalise drug treatments: therapeutic drug monitoring (TDM) of drug levels, pharmacogenetic testing (PG), and molecular neuroimaging. Methods: In these Guidelines, we provide an in-depth review of pharmacokinetics, pharmacodynamics, and pharmacogenetics for 45 antipsychotics. Over 30 international experts in psychiatry selected studies that have measured drug concentrations in the blood (TDM), gene polymorphisms of enzymes involved in drug metabolism, or receptor/transporter occupancies in the brain (positron emission tomography (PET)). Results: Study results strongly support the use of TDM and the cytochrome P450 (CYP) genotyping and/or phenotyping to guide drug therapies. Evidence-based target ranges are available for titrating drug doses that are often supported by PET findings. Conclusion: All three tools discussed in these Guidelines are essential for drug treatment. TDM goes well beyond typical indications such as unclear compliance and polypharmacy. Despite its enormous potential to optimise treatment effects, minimise side effects and ultimately reduce the global burden of diseases, personalised drug treatment has not yet become the standard of care in psychiatry. [ABSTRACT FROM AUTHOR]

Introduction: Individualized heparin and protamine management is increasingly used as a strategy to reduce coagulation activation and bleeding complications. While it is associated with increased heparin requirements during Cardiopulmonary Bypass (CPB), the impact on protamine administration remains controversial. We aim to investigate the effect of heparin level-guided monitoring on protamine dosing during cardiac surgery where low-anticoagulation protocols are implemented. Methods: This is a prospective, randomized, controlled trial. A total of 132 patients undergoing elective full-spectrum cardiac surgery with Minimal Invasive Extracorporeal Circulation (MiECC) were recruited. All patients were managed by the same anaesthetic, surgical and perfusion team. Patients were randomly allocated in two groups; the individualized heparin-protamine titration (IHPT) group and the conventional heparinization and reversal group by using ACT (cACT) with a 0.75:1, protamine: heparin ratio. Titration was accomplished with the Hepcon HMS Plus (Medtronic, Minneapolis, MN) system. The primary outcome of the study was the total protamine dose used. Secondary outcomes comprised of the total heparin dose, the percentage of patients achieving target ACT, 24-h transfusion requirements, postoperative bleeding, duration of mechanical ventilation, major morbidity and length of hospital stay. Patients in each group were divided in two subgroups according to the target ACT; those operated for coronary artery bypass grafting (CABG) using a target ACT >300 s and the rest (non-CABG) patients operated with a target ACT >400 s, respectively. Results: Protamine requirements were significantly reduced when IHPT was implemented; CABG (118 ± 24 mg vs 163 ± 61 mg; p < 0.001) and non-CABG cases (151 ± 46 mg vs 197 ± 45 mg; p < 0.001). Moreover, heparin requirements were significantly higher in the non-CABG subgroup managed with IHPT (34,539 ± 7658 IU vs 29,893 ± 9037 IU; p = 0.02). In overall, no significant differences were detected with respect to postoperative bleeding, transfusion of RBC or other blood products. Conclusions: Individualized heparin monitoring and management reduces protamine requirements in cardiac surgery with MiECC implementing reduced anticoagulation strategy. Trial registration: clinicaltrials.gov; NCT04215588. [ABSTRACT FROM AUTHOR]

Clozapine (CLZ) -related accidents or crimes are common in the world. Oral fluid drug detection is a convenient measure of dealing with things like that. There has not been any literature reported detailedly the representation rule of clozapine and its metabolites in oral fluid so far. The study aimed to describe the pharmacokinetics of CLZ and its metabolites N-desmethylclozapine and clozapine-N-oxide in human oral fluid after a single 12.5 mg oral dose of CLZ. Twenty-nine volunteers, including 20 males and 9 females, were recruited, and 2 mL oral fluid was collected from each participant at post-consumption time-points of prior (zero), 0.5, 1.5, 3, 5, 8, 12, 24, 36, 51, 82, and 130 h, respectively. Analytes of interest were extracted with solid-phase extraction and analyzed with liquid chromatography tandem mass spectrometry method. Pharmacokinetic parameters were calculated using the pharmacokinetic software DAS according to the non-compartment model. The maximum concentration, the time of maximum concentration, oral clearance, and the elimination half-life of clozapine were 16.57 ± 9.63 ng/mL, 4.53 ± 3.61 h, 57.65 ± 23.77 L/h and 53.58 ± 52.28 h, respectively. The maximum concentration, the time of maximum concentration, and the elimination half-life of the metabolite N-desmethylclozapine were 3.08 ± 1.19 ng/mL, 9.38 ± 9.33 h and 62.67 ± 82.57 h, respectively; of clozapine-N-oxide were 1.15 ± 0.36 ng/mL, 4.53 ± 2.19 h and 19.15 ± 23.11 h, respectively. It was the first study on the pharmacokinetics of CLZ and its metabolites in the oral fluid of Chinese healthy volunteers, and it provided a basis for the therapeutic drug monitoring and toxicological interpretation in clozapine-related cases. [ABSTRACT FROM AUTHOR]

Summary: Background: There are a plethora of therapeutic options for the management of inflammatory bowel disease (IBD). Despite this, clinical outcomes with standard dosing often fall short of established targets. While efforts centre on developing novel therapies, there is an ongoing need to optimise the use of existing agents. Aims: To focus on strategies to optimise response to biologic (monoclonal antibody) therapies in IBD, including use of therapeutic drug monitoring (TDM). Methods: An extensive review of the published literature. Results: TDM is a strategy aimed at enhancing the effectiveness of drugs with variable exposure‐response relationships by measuring serum concentrations of biologic therapies and detecting neutralising antibodies. Reactive TDM is performed when therapeutic goals have not been achieved. Tumour necrosis factor alpha (TNF) inhibitors are the treatment class most frequently associated with immunogenicity and loss of response. Immunogenicity can be reduced through avoidance of low serum drug concentrations by dose optimisation or use of concomitant immunomodulator therapy. Subtherapeutic dosing in the absence of antidrug antibodies is best managed by dose escalation or dose interval reduction. Persistent neutralising drug antibodies necessitate switching to an alternative therapy. Proactively ensuring adequate serum trough levels might help sustain treatment durability and prevent loss of response. Newer non‐TNF inhibitors demonstrate less robust exposure‐response relationships, and TDM may not prove as beneficial. Conclusions: In the treat‐to‐target paradigm of IBD treatment, optimising treatment effect with dose optimisation, which may involve strategies including TDM, increases the likelihood of achieving clinical remission and may accomplish deeper levels of remission beyond symptom control. [ABSTRACT FROM AUTHOR]

Ruxolitinib (RUX), a Janus kinase 2 (JAK2) inhibitor, and lenalidomide (LEN), an immunomodulatory agent, have recently been proposed as a combined treatment for myelofibrosis (MF). This combination has demonstrated improved efficacy, safety, and tolerability compared to monotherapy. To further refine these findings, an efficient analytical tool is needed to simultaneously determine RUX and LEN concentrations in blood plasma. This tool would enable the study of their pharmacokinetics, drug-drug interactions, and therapeutic monitoring during MF therapy. Unfortunately, such a method has not been existed in the literature. This study presents the first HPLC method with UV detection for the simultaneous quantitation of RUX and LEN in plasma. The method was validated according to the ICH guidelines for bioanalytical method validation. It exhibited linearity in the concentration ranges of 10 to 3150 ng mL− 1 for RUX and 80 to 5200 ng mL− 1 for LEN. The limits of quantitation were determined to be 25 and 90 ng mL− 1 for RUX and LEN, respectively. All other validation parameters were satisfactory. The HPLC-UV method was successfully employed to study the pharmacokinetics and drug-drug interactions of RUX and LEN in rats following oral administration of single doses. The results demonstrated that the pharmacokinetics of both drugs were changed substantially by their coadministration. LEN exhibited synergistic effects on the maximum plasma concentration (Cmax) and total bioavailability of RUX, meanwhile it exhibited diminishing effect on the values of volume of distribution (Vd) and clearance (CL). Additionally, RUX decreased the Cmax and total bioavailability of LEN, meanwhile it increased its Vd and CL. These data suggest that the use of RUX, as a combination with LEN, is a better therapeutic approach for MF, compared with RUX as a monotherapy. The effects of LEN on the pharmacokinetics of RUX should be considered and can be useful in determining the appropriate RUX dosage and dosing regimen to achieve the desired therapeutic effect when used as a combination therapy with LEN. The method's environmental friendliness was confirmed through three comprehensive tools. This method represents a valuable tool for determining the appropriate dosage and dosing regimen of RUX in combination therapy with LEN to achieve the desired therapeutic effect. Furthermore, it can aid in predicting drug distribution in different patients and assessing the drug accumulation or insufficient drug levels in specific body compartments. [ABSTRACT FROM AUTHOR]

Purpose: Therapeutic drug monitoring (TDM) of voriconazole (VCZ) should be mandatory for all pediatric patients with invasive fungal infections (IFIs). The narrow therapeutic index, inter-individual variability in VCZ pharmacokinetics, and genetic polymorphisms cause achieving therapeutic concentration during therapy to be challenging in this population. Methods: The study included 44 children suffering from IFIs treated with VCZ. Trough concentrations (Ctrough) of VCZ ware determined by the HPLC-FLD method. Identification of the CYP2C19*2 and CYP2C19*17 genetic polymorphisms was performed by PCR–RFLP. The correlation between polymorphisms and VCZ Ctrough was analyzed. Moreover, the effect of factors such as dose, age, sex, route of administration, and drug interactions was investigated. Results: VCZ was administered orally and intravenously at a median maintenance dosage of 14.7 mg/kg/day for a median of 10 days. The VCZ Ctrough was highly variable and ranged from 0.1 to 6.8 mg/L. Only 45% of children reached the therapeutic range. There was no significant association between Ctrough and dosage, age, sex, route of administration, and concomitant medications. The frequencies of variant phenotype normal (NM), intermediate (IM), rapid (RM) and ultrarapid metabolizers (UM) were 41%, 18%, 28%, and 13%, respectively. Ctrough of VCZ were significantly higher in NM and IM groups compared with RM, and UM groups. Conclusion: The Ctrough of VCZ is characterized by inter-individual variability and a low rate of patients reaching the therapeutic range. The significant association exists in children between VCZ Ctrough and CYPC19 phenotype. The combination of repeated TDM and genotyping is necessary to ensure effective treatment. [ABSTRACT FROM AUTHOR]

Purpose: Therapeutic drug monitoring (TDM) is a standard clinical procedure that uses the pharmacokinetic and pharmacodynamic parameters of the drug in the body to determine the optimal dose. The pharmacokinetic variability of the drug(s) is a significant contributor to poor treatment outcomes, including the development of acquired drug resistance. TDM aids in dose optimization and improves outcomes while lessening drug toxicity. TDM is used to manage patients with tuberculosis (TB) who exhibit a slow response to therapy, despite good compliance and drug-susceptible organisms. Additional indications include patients at risk of malabsorption or delayed absorption of TB drugs and patients with drug-drug interaction and drug toxicity, which confirm compliance with therapy. TDM usually requires two blood samples: the 2 h and the 6 h post-dose. This narrative review will discuss the pharmacokinetics and pharmacodynamics of TB drugs, determinants of poor response to therapy, indications of TDM, methods of performing TDM, and its interpretations. Methods: This is a narrative review. We searched PubMed, Embase, and the CINAHL from inception to April 2024. We used the following search terms: tuberculosis, therapeutic drug monitoring, anti-TB drugs, pharmacokinetics, pharmacodynamics, limited sample strategies, diabetes and TB, HIV and TB, and multidrug-resistant TB. All types of articles were selected. Results: TDM is beneficial in managing TB, especially in patients with slow responses, drug-resistance TB, recurrent TB, and comorbidities such as diabetes mellitus and human immunodeficiency virus infection. Conclusion: TDM is beneficial for improving outcomes, reducing the risk of acquired drug resistance, and avoiding side effects. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to assess the predictive performance of published valproic acid (VPA) population pharmacokinetic (PPK) models using an external data set in Chinese adults with epilepsy or after neurosurgery. Methods: A total of 384 concentrations from 290 Chinese adults with epilepsy or after neurosurgery were used for external validation. Data on published VPA PPK models were extracted from the literature. Prediction-based diagnostics (such as F20 and F30), simulation-based diagnostics, and Bayesian forecasting were used to evaluate the predictability of models. Results: The results of prediction-based diagnostics of all models were unsatisfactory. Models B, F, and H showed the best prediction performance in simulation-based diagnostics and Bayesian forecasting, demonstrating superior precision and accuracy. Bayesian forecasting demonstrated significant improvements in the model predictability. Conclusion: The published PPK models showed extensive variation in predictive performance for extrapolation among Chinese adults with epilepsy or after neurosurgery patients. Fixed parameters of Vd and Ka in the PPK modeling of VPA might be the reason for the unsatisfied predictive performance. Bayesian forecasting significantly improved model predictability and may help to individualize VPA dosing. [ABSTRACT FROM AUTHOR]

Background: Monitoring free valproate concentrations, as with other highly protein-bound anticonvulsants, is essential in clinical situations where protein binding may be disrupted. Conversion of measured total concentrations to approximate free concentrations offers a cost-effective alternative. This study evaluated the relationship between total and free valproate concentrations for discordance and the impact of key determinants. A novel formula was devised that incorporates significant variables. Methods: A multicentre, cross-sectional observational analytical study included 101 subjects 18 years and older using valproate for 6 months or longer. Participants were recruited from private and public sector healthcare settings from primary to tertiary level in, South Africa, during 2017–2019. Results: Free valproate concentrations could be measured for 84 subjects. Discordance for concomitant total and free valproate concentrations was 79.1%. Among 19 participants with elevated free concentrations, 15 (78.9%) had total valproate concentrations within the recommended reference range. Calculations based on the study-derived formula were more accurate in predicting free valproate concentration than previously proposed methods. Conclusion: This study proposes that the novel formula for calculating free valproate enables more accurate prediction. [ABSTRACT FROM AUTHOR]

Objective: Medication is commonly used in anorexia nervosa (AN) despite largely missing high grade evidence. Olanzapine (OLZ) is the best‐evidenced substance used off‐label in this group, with conflicting outcome regarding BMI, clinical and safety parameters. Therefore, it is important to strictly assure quality of treatment with OLZ in AN by using 'Therapeutic Drug Monitoring' according to AGNP‐guidelines, including serum levels and adverse drug reactions (ADRs) to support safety for adolescents with AN and attempt to generate an initial age‐ and disorder‐specific therapeutic reference range. Method: Sixty‐five adolescents with AN (aged 10–18) treated with OLZ (98% female; 97.5% AN‐restricting‐type) were prospectively observed, ADRs reported, and correlations between dosage and serum levels measured at trough level were calculated, a preliminary therapeutic range defined. Results: Mean dosage of OLZ was 8.15 (SD: 2.91) mg and 0.19 (SD: 0.07) mg/kg respectively, average concentration was 26.57 (SD: 13.46) ng/mL. Correlation between daily dosage/dosage per kg and serum level was 0.72 (**p < 0.001)/0.65 (**p < 0.001), respectively. ADRs with impairment were rare (6.3%). 75% improved clinically (CGI). BMI increased significantly by 1.5 kg/m2 (t = 10.6, p < 0.001). A preliminary therapeutic reference range is 11.9 and 39.9 ng/mL. Conclusions: OLZ in the hands of specialists is a well‐tolerated and safe treatment adjunct for adolescents with AN. Highlights: Olanzapine in adolescents with anorexia nervosa is a safe and well‐tolerated adjunct to a multidisciplinary inpatient treatment approach using therapeutic drug monitoring.Correlations of dosage and serum levels are high.A preliminary disorder‐ and age‐specific reference range was successfully defined for the first time. [ABSTRACT FROM AUTHOR]

Adherence drives efficacy in PrEP clinical trials. We compared drug concentrations and self-reported adherence in HPTN069/ACTG5305, a double-blinded, randomized trial of the safety and tolerability of candidate PrEP regimens that included maraviroc (MVC), tenofovir (TDF), and emtricitabine (FTC). Plasma drug concentrations and self-reported adherence by computer-assisted self-interview (CASI) were assessed at study weeks 24 and 48. Descriptive statistics and a generalized linear model were used to assess the association between selected demographic factors, self-report of daily medication adherence and plasma drug concentrations consistent with daily adherence. Among 718 paired observations from 370 participants, 43% (306/718) reported daily adherence by CASI, 65% (467/718) had drug concentrations consistent with daily adherence and 11% (81/718) had CASI responses that reported daily adherence despite having drug concentrations consistent with less-than-daily adherence. In adjusted analyses, participants who were assigned male at birth (aOR 1.42 [95% CI 1.02, 1.97]), older (5-year increments aOR 1.10 [95% CI 1.09, 1.11]), White (aOR 2.2 [95% CI 1.88, 2.56]), had advanced education (aOR 3.89 [95% CI 2.97, 5.09]), were employed (aOR 1.89 [95% CI 1.50, 2.40]), or partnered/married (aOR 2 [95% CI 1.72, 2.32]) were more likely to have drug concentrations consistent with daily adherence. Participants who were not employed (aOR 2.7 [95% CI 1.31, 5.55]) or who were single/not partnered (aOR 2.33 [CI 95% 1.25, 4.34]) were more likely to have drug concentrations that did not reflect daily adherence despite self-reported PrEP adherence. These findings support the need for ongoing adherence counseling in clinical trials of new PrEP regimens. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusions Therapeutic drug monitoring for astronauts faces limitations in conventional blood sampling and sample management onboard the international space station. Here, we explore the feasibility of dried blood spot (DBS) collection during parabolic flights (PF) to overcome these constraints.We assessed the feasibility of blood deposition on blotting paper for preanalytical aspects in a PF using synthetic blood. Subsequently, DBS sampling validation was carried out in another PF campaign. Twenty volunteers participated in a pharmacokinetic study on caffeine and its metabolite, paraxanthine, conducted during parabolic flights. After >18 h caffeine washout, coffee (115 mg), tea (30 mg) or dark chocolate (11 mg) were ingested by the participants. DBS samples were collected at baseline, during weightlessness and post‐flight. Caffeine and paraxanthine were analysed using liquid chromatography–tandem mass spectrometry (LC‐MS/MS). Genotyping for cytochrome P450‐1A2 (CYP1A2) was performed and a metabolic ratio by area under the curve for caffeine and paraxanthine (AUCPAX/AUCCAF) for CYP1A2 was determined. A user experience survey was also conducted.Full in‐flight pharmacokinetic study was feasible in seventeen volunteers with three unable to perform the sampling due to motion sickness. Nineteen participants (twelve males and seven females) completed pharmacokinetic profiles, with repeated pharmacokinetic studies for six participants. CYP1A2 genotyping resulted in eight ultrarapid, eleven intermediate, and one poor metabolizer. Among the women, four were on oestrogen contraceptives, a known inhibitor of CYP1A2, and were considered as poor metabolizers. Expected differences in kinetic profiles, consistent with consumption habits, the ingested dose and the genotypic/phenotypic information, were observed. The mean caffeine AUC for coffee, tea and chocolate were 9419 ng.h.mL−1 (95% confidence interval [CI]: 6222–12 616, n = 10), 6917 ng.h.mL−1 (95% CI: 2729–11 105), n = 7) and 3039 ng.h.mL−1 (95% CI: 1614–4142, n = 12), respectively. The mean paraxanthine AUC were 10 566 ng.h.mL−1 (95% CI: 6242–14 890, n = 10), 4011 ng.h.mL−1 (95% CI: 2305–5716, n = 7) and 3638 ng.h.mL−1 (95% CI: 1589–40 859, n = 12), respectively. The mean metabolic ratio in oestrogen‐treated women was 0.53 (95% CI: 0.35–0.71) compared to 1.19 (95% CI: 0.99–1.33) in others. The mean metabolic ratio was 1.02 (95% CI: 0.81–1.23, n = 15) on the ground and 1.10 (95% CI: 0.70–1.41, n = 13) during the parabolic flights, with no significant difference observed between the two conditions. Overall participants were satisfied with the usability of the method.DBS collection was safe, stable, feasible and well accepted in weightlessness. This method would offer valuable insights into human metabolism adaptation during long‐term spaceflight, addressing space pharmacology challenges. [ABSTRACT FROM AUTHOR]

Background: Cyclosporine A (CsA) is used as a steroid-sparing or alternative immunosuppressing agent in cats with various immune-mediated diseases such as immune-mediated hemolytic anemia. Daily treatment dosages of 5–20  mg/ kg have been described. Interindividual variations in CsA blood levels are known to occur. To determine when steady-state conditions are reached and thus the earliest advisable time for monitoring CsA blood levels during the course of treatment, a prospective experimental study was conducted in six healthy adult Domestic Shorthair cats. Materials and methods: Cats were treated with an oral dosage of 7  mg/kg CsA q 12  h for 10  days. On days 1, 2, 3, 5, 7, and 10 after the start of CsA administration (i.e., after 1, 3, 5, 9, 13, and 19 CsA administrations), EDTA blood was collected to measure the CsA level 12  h after the CsA administration (trough values) using high-performance liquid chromatography coupled to mass spectrometry (HPLC-MS/MS). Results: Statistical analysis revealed a significant increase in mean CsA blood levels up to day 5 (2,050  ±  964.2  ng/mL [mean  ±  SD], 832–3,203  ng/mL [minimum–maximum]; repeated-measures ANOVA: p  =  0.0021), while values on days 5 and 7 did not differ significantly from CsA concentrations on day 10. CsA concentrations showed markedly interindividual variability. Conclusion: Cyclosporine A blood levels reached a steady state on day 5 of high dosages of CsA q 12  h (i.e., after nine CsA administrations), indicating that this time point is suitable for monitoring blood levels in clinical patients. Results confirmed the well-known remarkable interindividual variability of CsA, indicating the need for treatment monitoring. The assessed treatment regime resulted in significantly higher mean CsA trough levels than the target range for immunosuppressive therapy (200–600  ng/mL). [ABSTRACT FROM AUTHOR]

This simulation-based study presented a novel hybrid RF antenna array designed for neck cancer treatment within a 7T MRI system. The proposed design aimed to provide microwave hyperthermia to release 19F-labeled anticancer drugs from thermosensitive liposomes, facilitating drug concentration monitoring through 19F imaging and enabling 1H anatomical imaging and MR thermometry for temperature control. The design featured a bidirectional microstrip for generating the magnetic |B1|-fields required for 1H and 19F MR imaging, along with a patch antenna for localized RF heating. The bidirectional microstrip was operated at 300 MHz and 280 MHz through the placement of excitation ports at the ends of the antenna and an asymmetric structure along the antenna. Additionally, a patch antenna was positioned at the center. Based on this setup, an array of six antennas was designed. Simulation results using a tissue-mimicking simulation model confirmed the intensity and uniformity of |B1|-fields for both 19F and 1H nuclei, demonstrating the suitability of the design for clinical imaging. RF heating from the patch antennas was effectively localized at the center of the cancer model. In simulations with a human model, average |B1|-fields were 0.21 μT for 19F and 0.12 μT for 1H, with normalized-absolute-average-deviation values of 81.75% and 87.74%, respectively. Hyperthermia treatment was applied at 120 W for 600 s, achieving an average temperature of 40.22°C in the cancer model with a perfusion rate of 1 ml/min/kg. This study demonstrated the potential of a hybrid antenna array for integrating 1H MR, 19F drug monitoring, and hyperthermia. [ABSTRACT FROM AUTHOR]

Objective: Pharmaceutical health literacy intervention (PHLI) plays a crucial role in influencing patients' medical decision-making, particularly concerning medication use. However, PHLI has not been widely implemented in China. This study aims to develop a novel PHLI model within a psychiatric hospital setting and evaluate its effectiveness. Methods: A PHLI model encompassing four modes—covering inpatients, outpatients, Internet+ and community—was established at The Affiliated Mental Health Center of Jiangnan University. The model's operation was detailed, and its performance data from 2022 and 2023 were evaluated. Results: In 2022 and 2023, a total of 636 PHLI cases were reported. Of these, 386 cases (60.69%) were identified through the inpatient mode. The proportion of PHLI delivered via inpatient and Internet information subscription modes gradually increased, while interventions through other methods decreased. The age group of 18–30 accounted for 21.97% of cases, with 116 instances reported. Various types of PHLI were provided, including adverse reactions (18.87%), dosage and administration (11.64%), and therapeutic drug monitoring (9.43%). In addition, intervention strategies primarily focused on adverse reaction identification (10.22%), interpretation of pharmaceutical reports (7.23%), and routine examination reminders (6.45%). Conclusion: The PHLI model developed at our hospital offers an effective approach to health literacy intervention and represents an innovation advancement in pharmaceutical health literacy management. It can also serve as a reference framework for other hospitals. [ABSTRACT FROM AUTHOR]

Introduction: Early administration of appropriate antibiotics has been shown to be among the most effective interventions to reduce mortality in septic patients. We evaluated the attainment of efficacy and safety targets at 24 h associated with the use of intensive beta‐lactam therapy in patients admitted to the intensive care unit for sepsis. Methods: This was a prospective study with patients who received beta‐lactams for sepsis or septic shock between February 2023 and September 2023. The antibiotic dose was unadjusted for renal function and administered by a loading dose followed by extended infusions, according to local practices. Blood samples were taken at the trough 24 h after the start of the beta‐lactam to obtain serum levels. These levels were compared to efficacy and innocuity thresholds found in the literature. Results: Among 36 included patients, all of them achieved serum concentrations above the minimum inhibitory concentration (MIC) for 100% of the therapeutic interval and 75% of them achieved serum concentrations above four times the MIC for 100% of the therapeutic interval. The predefined toxicity thresholds were reached by 8.3% of patients. Renal impairment was the factor most associated with the achievement of higher serum levels. Conclusion: Nonrenally adjusted doses of beta‐lactams administered by extended infusion showed good attainment of effective concentrations and few toxic concentrations in critically ill patients with sepsis or septic shock. Further studies are needed to better define the association between toxic concentrations and toxicity manifestations. [ABSTRACT FROM AUTHOR]

Introduction: Inflammatory factors released during severe coronavirus disease-19 (COVID-19) caused by acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are known to influence drug exposure, but data on the effect of mild infection are few. Here we describe for the first time an increase in plasma imatinib and norimatinib concentrations observed in a series of 5 patients treated with imatinib for gastrointestinal stromal tumor (GIST) after mild COVID-19. Methods: The patients were undergoing routine therapeutic drug monitoring (TDM) and pharmacogenetic (PGx) analyses of polymorphisms in genes involved in imatinib metabolism and transport (CYP3A4, CYP3A5, ABCB1, and ABCG2) when SARS-CoV-2 infection occurred. Imatinib and its active metabolite norimatinib concentrations were determined at Ctrough using a validated LCMS/MS method. PGx analyses were performed by KASP genotyping assays on a Real-Time PCR system. All patients received imatinib 400 mg/day. Case 1 was prospectively monitored. Cases 2-5 were identified retrospectively Results: On average, imatinib Ctrough increased significantly by 70% during COVID-19, whereas norimatinib showed a 44% increase compared with pre-COVID-19 levels. Elevated plasma imatinib concentrations persisted up to 6 months after infection remission. In 3 cases, this increase reflected the occurrence or worsening of imatinib side effects. Conclusion: This case-series highlights the clinical impact of SARS-CoV-2 infection on the management of patients with GIST treated with imatinib. [ABSTRACT FROM AUTHOR]

The development of simple, accurate, responsive, and selective antimicrobial drug analysis platforms is extremely important for biomedical research. Developing a novel electrode material that possesses low detection limit, high sensitivity, and stability continues to be a difficult undertaking. Here, vanadium tungstate nanostones (VWNs) were synthesized by utilizing facile sonochemical method with the aid of urea and ethylene glycol for application in electrochemical sensing of antibiotic drug nitrofurantoin (NFT). Using a distinct analytical methods, the structural and morphological characteristics of the as‐prepared transducer material were described. Further, electrochemical behaviour of modified electrode were analysed using cyclic voltammetry and liner sweep voltammetry. Under the optimal conditions VWNs/GCE electrode exhibited superior electrocatalytic activity towards NFT with linear range (20–160 μM), limit of detection (0.019 μM) with better sensitivity (0.69 μM−1 cm−2). The modified electrode demonstrated remarkable repeatability, reproducibility, and excellent stability, indicating its potential as an electrocatalyst. Ultimately, the suggested electrode was used to measure FLT in real samples like tap water and NFT capsule. [ABSTRACT FROM AUTHOR]

With the advantages of a high specificity, a long half-life, and a high safety, the use of antibody biologic drugs, including camrelizumab, has been rapidly increasing in clinical practice. Camrelizumab, an immune checkpoint inhibitor and humanized monoclonal antibody, is used to treat several advanced solid cancers. Measuring its concentration supports personalized dosage adjustments, influences treatment decisions for patients, strengthens the control of disease activity through therapeutic drug monitoring, and helps evaluate and prevent drug interactions in combination therapy. Because antibodies are present in complex biological matrices, quantifying monoclonal antibody drugs is challenging, and must rely on precise, selective, and reliable analytical methods. In this study, a quadrupole time-of-flight mass spectrometry TripleTOF 6600+ (AB SCIEX, Framingham, MA, USA) system equipped with a Turbo V ion source was used for the qualitative analysis of monoclonal antibodies using the data-dependent acquisition (IDA) MS/MS mode, followed by quantitative analysis using a targeted MRMHR workflow. This method showed a good linear relationship within the range of 4–160 μg/mL, with a correlation coefficient of R2 ≥ 0.996. It demonstrated an acceptable accuracy (88.95–101.18%) and precision (≤15%). Furthermore, the lower limit of quantification was found to be 4 μg/mL, with the lowest detection limit of 0.3217 μg/mL, indicating that this method is rapid, accurate, and reliable for the quantitative analysis of camrelizumab in human serum. [ABSTRACT FROM AUTHOR]

Successful antimicrobial therapy depends on achieving optimal drug concentrations within individual patients. Inter-patient variability in pharmacokinetics (PK) and differences in pathogen susceptibility (reflected in the minimum inhibitory concentration, [MIC]) necessitate personalised approaches. Dose individualisation strategies aim to address this challenge, improving treatment outcomes and minimising the risk of toxicity and antimicrobial resistance. Therapeutic drug monitoring (TDM), with the application of population pharmacokinetic (popPK) models, enables model-informed precision dosing (MIPD). PopPK models mathematically describe drug behaviour across populations and can be combined with patient-specific TDM data to optimise dosing regimens. The integration of machine learning (ML) techniques promises to further enhance dose individualisation by identifying complex patterns within extensive datasets. Implementing these approaches involves challenges, including rigorous model selection and validation to ensure suitability for target populations. Understanding the relationship between drug exposure and clinical outcomes is crucial, as is striking a balance between model complexity and clinical usability. Additionally, regulatory compliance, outcome measurement, and practical considerations for software implementation will be addressed. Emerging technologies, such as real-time biosensors, hold the potential for revolutionising TDM by enabling continuous monitoring, immediate and frequent dose adjustments, and near patient testing. The ongoing integration of TDM, advanced modelling techniques, and ML within the evolving digital health care landscape offers a potential for enhancing antimicrobial therapy. Careful attention to model development, validation, and ethical considerations of the applied techniques is paramount for successfully optimising antimicrobial treatment for the individual patient. [ABSTRACT FROM AUTHOR]

Malaria parasites are haploid within humans, but infections often contain genetically distinct groups of clonal parasites. When the per-infection number of genetically distinct clones (i.e., the multiplicity of infection, MOI) exceeds one, and per-infection genetic data are generated in bulk, important information are obfuscated. For example, the MOI, the phases of the haploid genotypes of genetically distinct clones (i.e., how the alleles concatenate into sequences), and their frequencies. This complicates many downstream analyses, including relatedness estimation. MOIs, parasite sequences, their frequencies, and degrees of relatedness are used ubiquitously in malaria studies: for example, to monitor anti-malarial drug resistance and to track changes in transmission. In this article, MrsFreqPhase methods designed to estimate statistically malaria parasite MOI, relatedness, frequency and phase are reviewed. An overview, a historical account of the literature, and a statistical description of contemporary software is provided for each method class. The article ends with a look towards future method development, needed to make best use of new data types generated by cutting-edge malaria studies reliant on MrsFreqPhase methods. [ABSTRACT FROM AUTHOR]

The article explores the use of physiologically based pharmacokinetic modeling to evaluate the impact of pathophysiological changes in neonates, addressing challenges in drug development for this population. It underscores the significance of comprehending pharmacokinetics and pharmacodynamics for safe and effective pharmacotherapy. The strengths and weaknesses of extrapolation tools like population pharmacokinetic modeling and physiologically based pharmacokinetic modeling are discussed, with a call for collaborative efforts among clinical researchers, data scientists, and modelers to refine these models for neonatal drug development. Recent research has shown progress in pharmacokinetics modeling for neonates, focusing on improving drug development and dose precision, particularly in therapeutic hypothermia, and predicting medicine concentrations in human milk using PBPK modeling for projects like ConcePTION. [Extracted from the article]

The article discusses the challenges and gaps in knowledge regarding the use of medicines during pregnancy. It highlights the need for a clinical pharmacology extrapolation framework based on model-informed drug development to support pregnancy drug development strategies. The article also addresses the regulatory landscape, emphasizing the importance of including pregnant and breastfeeding women in clinical trials to generate data supporting safe medication use during pregnancy. Additionally, it discusses the impact of pregnancy-related physiological changes on drug exposure and the importance of adapting pediatric extrapolation frameworks to pregnancy to optimize treatment strategies. [Extracted from the article]

Background : Vancomycin 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. Methods: Participants 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. Discussion: This trial will clarify the propagated benefits and provide new insights into how to optimally monitor vancomycin treatment in critically ill children. Trial registration: Eudract number: 2019–004538-40. Registered on 2020–09-08 ClinicalTrials.gov NCT046666948. Registered on 2020–11-28 [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusion Therapeutic drug monitoring of tacrolimus based on whole blood drug concentrations is routinely performed. The concentration of tacrolimus in peripheral blood mononuclear cells (PMBCs) is likely to better reflect drug exposure at the treatment target site. We aimed to describe the relationship between tacrolimus whole blood and PBMC concentrations, and the influence of patient characteristics on this relationship by developing a population pharmacokinetic model.We prospectively enrolled 63 stable adult kidney‐transplanted patients and collected dense (12‐h, n = 18) or sparse (4‐h, n = 45) pharmacokinetic profiles of tacrolimus. PBMCs were isolated from whole blood (Ficoll density gradient centrifugation), and drug concentrations in whole blood and PBMCs were analysed using liquid chromatography‐mass spectrometry. Patient genotype (CYP3A4/5, ABCB1, NR1I2) was assessed with PCR. Population pharmacokinetic modelling and statistical evaluation was performed using NONMEM.Tacrolimus whole blood concentrations were well described using a two‐compartment pharmacokinetic model with a lag‐time and first‐order absorption and elimination. Tacrolimus PBMC concentrations were best estimated from whole blood concentrations with the use of a scaling factor, the ratio of whole blood to PBMC concentrations (RC:PBMC), which was the extent of tacrolimus distribution into PBMC. CYP3A5*1 non‐expressors and NR1I2‐25 385T allele expressors demonstrated higher RC:PBMC ratios of 42.4% and 60.7%, respectively.Tacrolimus PBMC concentration could not be accurately predicted from whole blood concentrations and covariates because of significant residual unexplained variability in the distribution of tacrolimus into PBMCs and may need to be measured directly if required for future studies. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusion Linezolid is primarily used to treat of methicillin‐resistant Staphylococcus aureus and multidrug‐resistant tuberculosis infections. Thrombocytopenia due to linezolid usage is a concern, and therapeutic drug monitoring has been reported to be effective in its prevention. Plasma concentrations provide valuable information for treatment decisions; however, collecting plasma samples can be burdensome for both patients and healthcare providers. Therefore, there is interest in saliva as an alternative for monitoring, considering its potential to replace plasma samples.Patients hospitalized at Hokkaido University Hospital and Hokkaido Spinal Cord Injury Center between April 2022 and July 2024, who received oral or intravenous linezolid treatment, were enrolled. The concentrations of linezolid were simultaneously measured in plasma and saliva samples. We determined the concentration profiles of linezolid in the saliva and examined the correlation between saliva and plasma linezolid concentrations.Eighteen patients receiving linezolid were enrolled. The average of saliva/plasma (S/P) concentration ratios of linezolid were 1.018. A strong correlation was found between the salivary and plasma concentrations of linezolid (R = .833, P < .001). Notably, in patients receiving intravenous administration of linezolid, the correlation was even more pronounced (R = .885, P < .001). Additionally, when focusing on the S/P ratio of the trough concentrations in the morning and at night, the S/P ratios at night were much closer to 1.0.The concentrations of linezolid in plasma and saliva were similar, indicating their potential applicability in clinical settings. The monitoring of linezolid concentrations in saliva has been shown to be particularly suitable for patients receiving intravenous administration. [ABSTRACT FROM AUTHOR]

Bleeding events in patients receiving direct oral anticoagulation (DOAC) can be life-threatening even at therapeutic DOAC plasma concentrations, as anticoagulation impairs hemostasis and should therefore be identified immediately after hospital admission. The anticoagulatory effects of DOAC are typically not measurable in standard coagulation tests, such as PT or aPTT. Specific calibrated anti-FXa-tests allow specific drug monitoring, but they are too time-consuming for critical bleeding events and are commonly not available for 24 h/7 days in routine care. However, recent advances in point-of-care (POC) viscoelastic testing (VET) have shown a promising approach for rapid and quantitative detection of DOAC plasma concentrations using the Russell viper venom factor V activator (RVV for FXa-inhibitors) test or the ecarin clotting time (thrombin inhibitors). In acute bleeding situations, direct FXa inhibitors can be reversed by specific antidote andexanet alfa or hemostasis can be improved by prothrombin complex factor concentrates (PCCs). After reversal, confirmation of reversal efficacy is often requested, but no routine assays are currently available. Thus, the emergency management of bleeding DOAC patients is usually "blinded" with regard to reversal efficacy. POC VET laboratory assays might therefore also be helpful for measuring DOAC effects after reversal. We present a case series demonstrating the usefulness of RVV-clotting time post-DOAC reversal with andexanet alfa. [ABSTRACT FROM AUTHOR]

Background: Pharmacogenomic (PGx) factors significantly influence how patients respond to antipsychotic medications This systematic review was performed to synthesize the clinical utility of PGx-assisted treatment versus standard of care in schizophrenia. Methods: PubMed, Embase, and Cochrane CENTRAL databases were searched for randomized controlled trials (RCTs) from inception till June 2024 that had compared the clinical utility of PGx-assisted intervention as compared to the standard of care in schizophrenia. The primary outcome was safety, and the secondary outcomes were efficacy and medication adherence. Pooled standardized mean differences (SMD) along with a 95% confidence interval (CI) were calculated (random-effects model) wherever feasible. Results: A total of 18,821 studies were screened, and five were included for review. All the RCTs had a high risk of bias. Four studies included the commonly used antipsychotics. Three studies reported negative outcomes (safety, efficacy, and medication adherence) and two reported positive outcomes (safety) using different scales. In the meta-analysis, there were significant differences in the total Udvalg for Kliniske Undersogelser Side-Effect Rating scale score [SMD 0.95 (95% CI: 0.76–1.13), p < 0.001); I2 = 0%] and the total Positive and Negative Syndrome Scale score [SMD 10.65 (95% CI: 2.37–18.93), p = 0.01); I2 = 100%] between the PGx-assisted treatment and standard of care arms. However, the results were inconsistent, and the certainty of evidence (GRADE criteria) was very low. Conclusion: Current evidence on the clinical utility of PGx-assisted treatment in schizophrenia is limited and inconsistent and further evidence is required in this regard. [ABSTRACT FROM AUTHOR]

Catalytic therapies, such as chemodynamic therapy and ferroptosis, harness the tumor microenvironment to enhance the specificity and penetration of treatments, thus improving targeted tumor therapy. Despite these advancements, treatment effectiveness varies due to individual differences, making precise monitoring of drug activity and dosage essential to optimize therapy. Traditional imaging strategies, which monitor metal ion release or reactive oxygen species production, frequently fail to well correlate with therapeutic outcome. Herein, this study have developed an integrated self‐monitoring catalytic therapy platform that combines palladium‐ and manganese‐based nanoparticles (PdMn NPs) with caspase‐3 activated probe (Casp probe). Dual‐channel MRI and fluorescent probe, responsive to both low pH and caspase‐3 activity, significantly enhances the accuracy of real‐time therapeutic evaluations, allowing for early reporting treatment response (in 6 h), earlier than tumor volume reduction (8 days). This approach improves the assessment of therapeutic outcomes and aligns with the shift toward individualized cancer treatment protocols. [ABSTRACT FROM AUTHOR]

We explore an unsolved challenge in the era of evidence-based medicine (EBM): the recognition of the patient as an epistemic agent or ‘knower’. While patients are increasingly acknowledged as carriers of values and preferences, it seems more challenging to acknowledge them as carriers of important causal information. In contrast, the science of pharmacovigilance depends on patient testimonies as valuable sources of causal evidence. This incompatibility can give rise to cases of what has been called participatory epistemic injustice. We analyse the testimony of a chronic pain patient and co-author of this article, Christine. Christine gives an auto-ethnographic account of her interactions with healthcare professionals trying to find the right pharmacological treatment for her condition. Through the analysis of her own story, she identifies some relevant themes for the epistemic interaction between healthcare professionals and chronic pain patients. We argue that such epistemic interactions are increasingly shaped by EBM and its conception of causality, which devalues patient subjective testimonies and emphasises statistical evidence. We conclude that outlier patients face an inherent risk of being left vulnerable to participatory epistemic injustice, particularly regarding the discovery of novel, rare adverse effects of medicines. [ABSTRACT FROM AUTHOR]

Background: Compared to the general population, people living in prison are at an increased risk to experience negative (mental) health outcomes. Moreover, delinquency and drug use have many risk factors in common. A need exists for increasing the knowledge about health needs, drug use patterns and the coverage of drug-related interventions in prison within Europe. The current protocol describes the design of a study about wellbeing, drug use and related care in prison. Methods/design: A multicentre mixed method design is implemented in five European countries (Belgium, Cyprus, Greece, Lithuania and Luxembourg). Qualitative and quantitative data collection tools are combined in order to generate complementary and comprehensive results. First, a cross-sectional survey among people living in prison is conducted. This survey is based on a model questionnaire, the European Questionnaire on Drug use among people living in Prison, developed by the European Monitoring Centre for Drug and Drugs Addiction. Second, people living in prison and people who have been recently released from prison are involved in qualitative semi-structured face-to-face interviews. The main topics of interest are the use of drugs and other health related topics such as loneliness, anxiety, depression, infectious diseases, suicide and treatment. Third, data regarding health and social reintegration measures in prison is collected through a quantitative survey addressed to the prison authorities. Discussion: This study protocol presentes a European study which aims to assess drug use among people living in prison and recently released people who use drugs as well as the existing care services in prisons. Hereby, factors related to the prison environment and their needs, both inside and outside prison are taken into account. Importantly, this study protocol describes a methodology which is developed to be executed in different prison settings within different countries simultaneously. Accordingly, for each country the protocol is adjustable to specific national legal requirements, regional differences and distinct local regulations of prison administrations. However, extensive modularity inevitably comes with significant limitations of comparability and generalizability of the results. [ABSTRACT FROM AUTHOR]