Drug Monitoring Research Articles

Simultaneous determination of three tyrosine kinase inhibitors and three triazoles in human plasma by LC-MS/MS: applications to therapeutic drug monitoring and drug-drug interaction studies

Tyrosine kinase inhibitors (TKIs) and triazole antifungals are the first-line drugs for treating chronic myeloid leukemia (CML) and fungal infections, respectively, but both suffer from large exposure differences and narrow therapeutic windows. Moreover, these two types of drugs are commonly used together in CML patients with fungal infections. Multiple studies and guidelines have suggested the importance of therapeutic drug monitoring (TDM) of TKIs and triazoles. Currently, methods for the simultaneous determination of both types of drugs are limited. We developed a simple, rapid, and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous quantification of three commonly used TKIs (imatinib, dasatinib, and nilotinib) and three commonly used triazoles (voriconazole, itraconazole, and posaconazole) in human plasma. The analytes were eluted on a Welch XB-C18 analytical column (50 × 2.1 mm, 5 µm) at 0.7 mL/min, using a gradient elution of 10 mM ammonium formate (A) and methanol–acetonitrile-isopropanol (80:10:10, v/v/v) containing 0.2 % formic acid (B) with a total analysis time of 3.5 min. The calibration curves were linear over the range from 20 to 4000 ng/mL for imatinib and nilotinib, from 2 to 400 ng/mL for dasatinib, and from 50 to 10,000 ng/mL for voriconazole, itraconazole, and posaconazole. Selectivity, accuracy, precision, recovery, matrix effect, and stability all met the validation requirements. The method was successfully used for TDM in CML patients who co-treated with both TKIs and triazoles. Drug-drug interaction analysis between TKIs and triazoles showed that a significant positive correlation was observed between imatinib and voriconazole, as well as dasatinib and voriconazole. Therefore, this method can be well applied in clinical TDM for patients receiving TKIs, triazoles, or both simultaneously.

Addressing stability issues of vildagliptin: Method optimization and validation for accurate analysis in human plasma.

This research paper introduces novel strategies to address the stability issues arising with vildagliptin, marking the first attempt to tackle this challenge comprehensively. The study incorporates malic acid into the human plasma, a crucial step in stabilizing vildagliptin and preventing its degradation. Additionally, optimization of the elution process on a C18 Asentis Express column, fine-tuned with a combination of acetonitrile and ammonium trifluoroacetate 5mM, ensures optimal chromatographic conditions. For detection and quantification, electrospray ionization (ESI) is employed, monitoring multiple reactions for vildagliptin (304.2 → 154.2) and vildagliptin D7 (311.1 → 161.2). Meticulous validation of the method demonstrates high accuracy (97.30%-104.15%) and precision [(0.32%-3.09% coefficient of variance (CV)] for vildagliptin calibration curve standards (CC STD), establishing its sensitivity and reliability in measuring vildagliptin levels. This refined methodology offers numerous advantages, including the elimination of stability concerns, reduced human plasma sample volume (100 μL), exceptional reproducibility, shortened run time (~2.2min), and a wide concentration range (1.00 to 851.81 ng/mL). These attributes make it exceptionally well-suited for diverse research applications, spanning from extensive sampling in therapeutic drug monitoring units to bioequivalence and bioavailability studies, as well as pharmacokinetic investigations of vildagliptin.

Budget impact of resmetirom for the treatment of adults with non-cirrhotic non-alcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis)

Aims This study assessed the budget impact of resmetirom as a treatment for adults with non-cirrhotic non-alcoholic steatohepatitis (NASH) with moderate-to-advanced liver fibrosis and estimated total costs for a hypothetical private payer in the United States. Materials and methods A three-year budget impact analysis based on an open cohort state transition model was developed for a hypothetical one-million-member private health plan. The comparator was Standard of Care (SOC), defined as routine care for non-cirrhotic NASH patients with moderate-to-advanced liver fibrosis. Each year, the number of resmetirom treatment-eligible patients was estimated through prevalent, incident, and diagnostic rate estimates. Costs included resources incurred by the medical and pharmacy benefits of private payers, including resmetirom drug acquisition costs, diagnosis and monitoring, other medical and other prescription costs stratified by disease progression status (i.e. non-cirrhotic vs. cirrhotic/advanced liver diseases). Resmetirom adverse event management costs were included in sensitivity analysis. Drug costs were estimated based on the average wholesale acquisition cost as of March 2024. Other costs were based on published sources and inflated to 2023 US dollars. Budget impact outcomes were presented in aggregate, net, and on a per-member per-month (PMPM) basis. Results Compared with a scenario without resmetirom, the introduction of resmetirom yielded results ranging from 50 to 238 treated patients, net budget impact of $2.2 to $9.5 million, and PMPM from $0.19 to $0.80 over years one and three. Net costs excluding resmetirom declined over time. In sensitivity analyses, results were most sensitive to diagnostic and epidemiologic inputs. Limitations Market shares are based on internal forecasts, a short time horizon, average treatment effects, and other limitations common to BIMs. Conclusion The adoption of resmetirom on the formulary for the treatment of non-cirrhotic NASH with moderate-to-advanced liver fibrosis resulted in a moderate increase in budget impact with declining costs related to NASH progression.

An innovative population pharmacokinetic/pharmacodynamic strategy for attaining aggressive joint PK/PD target of continuous infusion ceftazidime/avibactam against KPC- and OXA-48- producing Enterobacterales and preventing resistance development in critically ill patients.

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. 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. 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. 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.

Decreased Kidney Function Explains Higher Vancomycin Exposure in Older Adults.

Older adults face a higher risk of vancomycin-related toxicity given their (patho)-physiological changes, making early management of supratherapeutic exposure crucial. Yet, data on vancomycin exposure in older adults is scarce. This study aims to compare vancomycin concentrations between older and younger patients, emphasizing supratherapeutic concentrations and the effect of patient characteristics. This observational retrospective study was conducted in the University Hospital of Leuven (EC Research S65213). We analyzed early (first) vancomycin concentrations between older (≥ 75 years) and younger patients. Multivariable analyses were conducted to evaluate the association between baseline patient characteristics with supratherapeutic exposure (logistic regression), and dose-normalized concentrations (linear regression). We included 449 patients aged ≥ 75 years (median 80) and 1609 aged < 75 years (median 61). In univariable analysis, the first-measured vancomycin concentrations were significantly higher in older adults (p < 0.001), who more frequently reached supratherapeutic concentrations (30.7% versus 21%; p < 0.001). In multivariable analysis, factors associated with supratherapeutic concentrations were decreased the estimated glomerular filtration rate calculated by using the Chronic Kidney Disease Epidemiology Collaboration equation (eGFRCKD-EPI) [odds ratio (OR) of 0.98, confidence interval (CI) 0.97-0.98]. Supratherapeutic concentrations had inverse association with giving lower loading dose (OR of 0.59, CI 0.39-0.90), and lower maintenance dose (OR of 0.45, CI 0.26-0.77). Factors that predicted increased dose-normalized concentrations included decreased eGFRCKD-EPI (coefficient of -0.05, CI -0.06 to -0.04), lower body weight (coefficient of -0.04, CI -0.05 to -0.03), increased blood urea nitrogen (coefficient of 0.02, CI 0.01-0.03), and delayed time to therapeutic drug monitoring (TDM) sampling (coefficient of 0.08, CI 0.06-0.09). The absence of age as a significant factor in the multivariable analysis suggests that eGFRCKD-EPI mediated the relationship between age and vancomycin exposure. Older adults may benefit more from vancomycin TDM.

A factorial-design/assisted HPLC method for simultaneous monitoring of phenytoin, trimethoprim, and sulphamethoxazole in plasma samples to optimize therapy and mitigate toxicity risks

Phenytoin, an anticonvulsant drug, has a narrow therapeutic index and exhibits significant affinity to plasma proteins, mainly albumin. It is mainly metabolized by cytochrome P450 enzymes 2C9, 2C8, and 2C19. The potential for increased phenytoin toxicity may arise when a drug with enzyme-blocking properties are concurrently administered. The co-administration of trimethoprim is reported to decrease phenytoin clearance by 30 %, therefore, monitoring its plasma concentrations is recommended to minimize the risk of its toxicity and optimize its therapeutic efficacy. This study involves development of a novel and simple HPLC method for concurrent measurement of trimethoprim, sulphamethoxazole and phenytoin in plasma samples. The proposed method was optimized using full factorial design to optimize the variable factors affecting chromatographic responses. The separation was performed via isocratic elution on HyperClone C8 column, using a mobile phase consisting of 30: 38.5: 31.5 (v/v/v) of acetonitrile: 3.3 mM heptane-1-sulphonic acid sodium salt: 0.05 M phosphate buffer containing 0.1 % triethylamine at pH 3.7. The mobile phase was delivered at a flow rate of 1 mL/min with UV detection at 210 nm. The method was validated to verify agreement to the criteria set by the International Council for Harmonization (ICH) and Bioanalytical Methods validation. The results showed excellent linearity over the concentration ranges of 0.5–20.0, 1.0–25.0 and 1.0–20.0 µg/mL with detection limits of 0.41, 0.82 and 0.92 µg/mL for trimethoprim, sulphamethoxazole and phenytoin, respectively.The proposed method was extended for the assessment and of the studied drugs in spiked human plasma samples with % recoveries ranging from 92.60 to 105.30 %, indicating bioanalytical applicability. The proposed method can be utilized to study drug-drug interactions for in-patients therapeutic drug monitoring.

Unlocking the potential of advanced large language models in medication review and reconciliation: A proof-of-concept investigation

BackgroundMedication review and reconciliation is essential for optimizing drug therapy and minimizing medication errors. Large language models (LLMs) have been recently shown to possess a lot of potential applications in healthcare field due to their abilities of deductive, abductive, and logical reasoning. The present study assessed the abilities of LLMs in medication review and medication reconciliation processes. MethodsFour LLMs were prompted with appropriate queries related to dosing regimen errors, drug-drug interactions, therapeutic drug monitoring, and genomics-based decision-making process. The veracity of the LLM outputs were verified from validated sources using pre-validated criteria (accuracy, relevancy, risk management, hallucination mitigation, and citations and guidelines). The impacts of the erroneous responses on the patients' safety were categorized either as major or minor. ResultsIn the assessment of four LLMs regarding dosing regimen errors, drug-drug interactions, and suggestions for dosing regimen adjustments based on therapeutic drug monitoring and genomics-based individualization of drug therapy, responses were generally consistent across prompts with no clear pattern in response quality among the LLMs. For identification of dosage regimen errors, ChatGPT performed well overall, except for the query related to simvastatin. In terms of potential drug-drug interactions, all LLMs recognized interactions with warfarin but missed the interaction between metoprolol and verapamil. Regarding dosage modifications based on therapeutic drug monitoring, Claude-Instant provided appropriate suggestions for two scenarios and nearly appropriate suggestions for the other two. Similarly, for genomics-based decision-making, Claude-Instant offered satisfactory responses for four scenarios, followed by Gemini for three. Notably, Gemini stood out by providing references to guidelines or citations even without prompting, demonstrating a commitment to accuracy and reliability in its responses. Minor impacts were noted in identifying appropriate dosing regimens and therapeutic drug monitoring, while major impacts were found in identifying drug interactions and making pharmacogenomic-based therapeutic decisions. ConclusionAdvanced LLMs hold significant promise in revolutionizing the medication review and reconciliation process in healthcare. Diverse impacts on patient safety were observed. Integrating and validating LLMs within electronic health records and prescription systems is essential to harness their full potential and enhance patient safety and care quality.

Therapeutic drug monitoring for valproate: deriving a novel formula for calculation of free concentration

BackgroundMonitoring 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.MethodsA 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.ResultsFree 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.ConclusionThis study proposes that the novel formula for calculating free valproate enables more accurate prediction.

Substance Use Disorder, Opioid Use Disorder, and Symptom Management in Palliative Care: A Rapid Review of Evidence.

Substance use disorder (SUD) affects more than 1 in 6 Americans older than 12 years and has become an increasingly relevant topic in palliative care. Lack of clear guidelines and fragmented care results in patient safety concerns and poor outcomes. This rapid review aims to present the current literature on opioid contracts/agreements, prescription drug monitoring database access, opioid risk assessment tools, and urine drug screening in the palliative care setting. Through a systematic process, we identified 19 articles published between 2018 and 2023 that pertained to substance use disorder and palliative care. Current risk mitigation strategies include prescription drug monitoring, opioid use agreements, risk assessment tools, urine drug screening, and the use of buprenorphine to manage pain. Prescription drug monitoring programs are state-based electronic databases that track controlled substances, and there are numerous risk assessment tools. Urine drug screening involves the use of both immunoassay and confirmatory chromatography to determine the presence or absence of either the prescribed controlled substance or unexpected findings including illicit drugs or prescription-controlled substances that are not prescribed to the patient. The goal of mitigating risk and reducing harm while providing expert symptom management is the challenge that palliative care transdisciplinary teams face as they continue to care for patients with substance use disorder. This review points to the need for further research on how to incorporate these harm-reducing strategies into clinical practice.

Population Pharmacokinetics of Trimethoprim/Sulfamethoxazole: Dosage Optimization for Patients with Renal Insufficiency or Receiving Continuous Renal Replacement Therapy.

The goal of the study was to describe the population pharmacokinetics of trimethoprim, sulfamethoxazole, and N-acetyl sulfamethoxazole in hospitalized patients. Furthermore, this study used the model to optimize dosing regimens of cotrimoxazole for Pneumocystis jirovecii pneumonia and in patients with renal insufficiency or with continuous renal replacement therapy (CRRT). This was a retrospective multicenter observational cohort study based on therapeutic drug monitoring (TDM) data from hospitalized patients treated with cotrimoxazole. We developed two population pharmacokinetic (POPPK) models: a model of trimethoprim and an integrated model with both sulfamethoxazole and N-acetyl sulfamethoxazole concentrations. Monte Carlo simulations were performed to determine the optimal dosing regimen. A total of 348 measurements from 168 patients were available. The estimated glomerular filtration rate (eGFR) and CRRT were included as covariates on the clearance of all three compounds. Cotrimoxazole TID 1,920 mg and b.i.d. 2,400 mg led to sufficient exposure for infections with P. jirovecii in patients without renal insufficiency. To reach equivalent exposure, a dose reduction of 33.3% is needed in patients with an eGFR of 10 mL/minute/1.73 m2 and of 16.7% for an eGFR of 30 mL/minute/1.73 m2. N-acetyl sulfamethoxazole accumulates in patients with a reduced eGFR. CRRT increased the clearance of sulfamethoxazole, but not trimethoprim or N-acetyl sulfamethoxazole, compared with the median clearance in the population. Doubling the sulfamethoxazole dose is needed for patients on CRRT to reach equivalent exposure.

Harnessing Biopolymer Gels for Theranostic Applications: Imaging Agent Integration and Real-Time Monitoring of Drug Delivery.

Biopolymer gels have gained tremendous potential for therapeutic applications due to their biocompatibility, biodegradability, and ability to adsorb and bind biological fluids, making them attractive for drug delivery and therapy. In this study, the versatility of biopolymer gels is explored in theranostic backgrounds, with a focus on integrating imaging features and facilitating real-time monitoring of drug delivery. Different methods of delivery are explored for incorporating imaging agents into biopolymer gels, including encapsulation, surface functionalization, nanoparticle encapsulation, and layer-by-layer assembly techniques. These methods exhibit the integration of agents and real-time monitoring drug delivery. We summarize the synthesis methods, general properties, and functional mechanisms of biopolymer gels, demonstrating their broad applications as multimodal systems for imaging-based therapeutics. These techniques not only enable multiple imaging but also provide signal enhancement and facilitate imaging targets, increasing the diagnostic accuracy and therapeutic efficacy. In addition, current techniques for incorporating imaging agents into biopolymer gels are discussed, as well as their role in precise drug delivery and monitoring.

Biomolecule‐responsive polymers and their bio‐applications

AbstractPrecise recognition and specific interactions between biomolecules are key prerequisites for ensuring the performance of all actives within living organisms. The convergence of biomolecular recognition systems into synthetic materials could endow the materials with high specificity and biological sensitivity; this, in turn, enables precise drug release, monitoring or detection of important biomolecules, and cell manipulation through targeted capture or release of specific biomolecules. Meanwhile, from the perspective of materials science, the application of conventional polymers in practical biological systems poses several challenges, such as low responsiveness and sensitivity, inadequate targetability, insufficient anti‐interference capacities, and unsatisfactory biocompatibility. These problems could be partly attributed to the polymers' weak discrimination abilities toward target biomolecules in the presence of interfering substances with high abundance. In particular, the proposition of “precision medicine” project raises higher demands for the design of biomaterials in terms of their precision and targetability. Therefore, there is an urgent demand for the development of new‐generation biomaterials with precise recognition and sensitive responsiveness comparable to biomacromolecules. This promotes a new research direction of biomolecule‐responsive polymers and their diverse applications. This review focuses on the origin and construction of biomolecule‐responsive polymers, as well as their attractive applications in drug delivery systems, bio‐detection, bio‐sensing, separation, and enrichment, as well as regulating cell adhesion.

An Integrated Nanoplatform via Dual Channel Excitation for Both Precise Fluorescence Imaging and Photodynamic Therapy of Orthotopic Breast Tumor in NIR-II Region.

Although research on photodynamic therapy (PDT) of malignant tumor has made considerable progress in recent years, it is a remaining challenge to extend PDT to the second near-infrared window (NIR-II) along with real-time and accurate NIR-II fluorescence imaging to determine drug enrichment status and achieve high treatment efficacy. In this work, lanthanide nanoparticles (Ln NPs)-based nanoplatform (LCR) equipped with photosensitizerChlorin e6 (Ce6) and targeting molecular NH2-PEG1000-cRGDfK aredeveloped, which can achieve NIR-II photodynamic therapy (PDT) and NIR-II fluorescence imaging by dual channel excitation. Under 808nm excitation, Nd3+ in the outer layer can absorb the energy and transfer inward to emit strong NIR-II emissions (1064 and 1525nm). Due to the low background noise of NIR-II light and the targeting effect of NH2-PEG1000-cRGDfK, LCR can recognize tiny tumor tissue (≈3mm) and monitor drug distribution in vivo. Under 1530nm excitation, internal Er3+ can be self-sensitized, generating intense upconversion emission (662nm) that can effectively activate Ce6 for in vivo PDT due to the deep tissue penetration of NIR-II light. This study provides a paradigm of theranostic nanoplatform for both real-time fluorescence imaging and PDT of orthotopic breast tumor in NIR-II window.

Predictive performance of multi-model approaches for model-informed precision dosing of piperacillin in critically ill patients

ObjectivesPiperacillin (PIP)/tazobactam is a frequently prescribed antibiotic; however, over- or underdosing may contribute to toxicity, therapeutic failure, and development of antimicrobial resistance. An external evaluation of 24 published PIP-models demonstrated that model-informed precision dosing (MIPD) can enhance target attainment. Employing various candidate models, this study aimed to assess the predictive performance of different MIPD-approaches comparing (i) a single-model approach, (ii) a model selection algorithm (MSA) and (iii) a model averaging algorithm (MAA). MethodsPrecision, accuracy and expected target attainment, considering either initial (B1) or initial and secondary (B2) therapeutic drug monitoring (TDM)-samples per patient, were assessed in a multicentre dataset (561 patients, 11 German centres, 3654 TDM-samples). ResultsThe results demonstrated a slight superiority in predictive performance using MAA in B1, regardless of the candidate models, compared to MSA and the best single models (MAA, MSA, best single models: inaccuracy ±3%, ±10%, ±8%; imprecision: <25%, <31%, <28%; expected target attainment >77%, >71%, >73%). The inclusion of a second TDM-sample notably improved precision and target attainment for all MIPD-approaches, particularly within the context of MSA and most of the single models. The expected target attainment is maximized (up to >90%) when the TDM-sample is integrated within 24 h. ConclusionsIn conclusion, MAA streamlines MIPD by reducing the risk of selecting an inappropriate model for specific patients. Therefore, MIPD of PIP using MAA implicates further optimisation of antibiotic exposure in critically ill patients, by improving predictive performance with only one sample available for Bayesian forecasting, safety, and usability in clinical practice.

Potential Convergence to Accommodate Pathogenicity Determinants and Antibiotic Resistance Revealed in Salmonella Mbandaka.

Salmonella species are causal pathogens instrumental in human food-borne diseases. The pandemic survey related to multidrug resistant (MDR) Salmonella genomics enables the prevention and control of their dissemination. Currently, serotype Mbandaka is notorious as a multiple host-adapted non-typhoid Salmonella. However, its epidemic and MDR properties are still obscure, especially its genetic determinants accounting for virulence and MD resistance. Here, we aim to characterize the genetic features of a strain SMEH pertaining to Salmonella Mbandaka (S. Mbandaka), isolated from the patient's hydropericardium, using cell infections, a mouse model, antibiotic susceptibility test and comparative genomics. The antibiotic susceptibility testing showed that it could tolerate four antibiotics, including chloramphenicol, tetracycline, fisiopen and doxycycline by Kirby-Bauer (K-B) testing interpreted according to the Clinical and Laboratory Standards Institute (CLSI). Both the reproducibility in RAW 264.7 macrophages and invasion ability to infect HeLa cells with strain SMEH were higher than those of S. Typhimurium strain 14028S. In contrast, its attenuated virulence was determined in the survival assay using a mouse model. As a result, the candidate genetic determinants responsible for antimicrobial resistance, colonization/adaptability and their transferability were comparatively investigated, such as bacterial secretion systems and pathogenicity islands (SPI-1, SPI-2 and SPI-6). Moreover, collective efforts were made to reveal a potential role of the plasmid architectures in S. Mbandaka as the genetic reservoir to transfer or accommodate drug-resistance genes. Our findings highlight the essentiality of antibiotic resistance and risk assessment in S. Mbandaka. In addition, genomic surveillance is an efficient method to detect pathogens and monitor drug resistance. The genetic determinants accounting for virulence and antimicrobial resistance underscore the increasing clinical challenge of emerging MDR Mbandaka isolates, and provide insights into their prevention and treatment.

Varying concentrations of tyrosine kinase inhibitors in chronic myeloid leukemia patients following bariatric surgery: a case series.

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.

Assessment of Dried Serum Spots (DSS) and Volumetric-Absorptive Microsampling (VAMS) Techniques in Therapeutic Drug Monitoring of (Val)Ganciclovir-Comparative Study in Analytical and Clinical Practice.

Ganciclovir (GCV) and its prodrug valganciclovir (VGCV) are antiviral medications primarily used to treat infections caused by cytomegalovirus (CMV), particularly in immunocompromised individuals such as solid organ transplant (SOT) recipients. Therapy with GCV is associated with significant side effects, including bone marrow suppression. Therefore, therapeutic drug monitoring (TDM) is mandatory for an appropriate balance between subtherapeutic and toxic drug levels. This study aimed to develop and validate three novel methods based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) for GCV determination in serum (reference methodology), dried serum spots (DSS), and VAMS-Mitra™ devices. The methods were optimized and validated in the 0.1-25 mg/L calibration range. The obtained results fulfilled the EMA acceptance criteria for bioanalytical method validation. Assessment of DSS and VAMS techniques extended GCV stability to serum for up to a minimum of 49 days (at room temperature, with desiccant). Developed methods were effectively evaluated using 80 clinical serum samples from pediatric renal transplant recipients. Obtained samples were used for DSS, and dried serum VAMS samples were manually generated in the laboratory. The results of GCV determination using serum-, DSS- and VAMS-LC-MS/MS methods were compared using regression analysis and bias evaluation. The conducted statistical analysis confirmed the interchangeability between developed assays. The DSS and VAMS samples are more accessible and stable during storage, transport and shipment than classic serum samples.

(Invited) Analytical Validation of Aptamer-Based Blood Drug Measurements Against Clinical Benchmark Methods

The practice of monitoring therapeutic drug concentrations in patient biofluids can significantly improve clinical outcomes while simultaneously minimizing adverse side effects. Although undeniably important to achieve effectiveness, therapeutic drug monitoring remains inconvenient in practice, due primarily to the lengthy process of sample collection, transport to a centralized facility, and analysis using costly instrumentation. Adding to this workflow is the possibility of backlogs at centralized clinical laboratories, which is not uncommon and may result in additional delays between biofluid sampling and concentration measurement, which can negatively affect clinical outcomes. In this talk I explore the possibility of using point-of-care, aptamer-based sensors to minimize the time delay between biofluid sampling and drug measurement. I will discuss analytical validations of aptamer-based blood measurements for two drugs, the antibiotic vancomycin and the antiretroviral drug emtricitabine. We conducted clinical agreement studies comparing the measurement outcomes of electrochemical and optical aptamer-based sensors to the benchmark (1) automated competitive immunoassays for vancomycin monitoring in serum, and (2) liquid chromatography coupled to mass spectrometry detection (LC-MS) for plasma emtricitabine. Our results demonstrate that aptamer-based sensors are selective for the free form of these drugs, and can achieve up to 95% positive correlation and 100% negative correlation with the benchmark assays. Given these results, aptamer sensors offer a promising path for point-of-care drug monitoring that is instantaneous and overcomes current barriers for broad implementation of drug monitoring in clinical settings.

Wearable Microneedle Biosensor for Real-Time I-Situ Antibiotic Monitoring

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 localized medical laboratories where sample processing and analysis are performed. To enable real-time and minimally invasive TDM, we have developed a microneedle (MN) biosensor to monitor the levels of two important antibiotics, vancomycin (VAN) and gentamicin (GEN). 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 has been validated in-vitro using skin models as well as in-vivo in live rat animal models. Furthermore, we leveraged data from the HMN-Flex system to construct pharmacokinetic profiles for VAN and GEN and compared these profiles with conventional blood-based measurements.

Pharmacokinetic variability of everolimus and impact of concomitant antiseizure medications in patients with tuberous sclerosis complex: A retrospective study of therapeutic drug monitoring data in Denmark and Norway.

The mTOR-inhibitor everolimus is a precision drug with antiepileptogenic properties approved for treatment of epilepsy in persons with tuberous sclerosis complex (TSC) in combination with other antiseizure medications (ASMs). However, the pharmacokinetic variability of everolimus is scarcely described, and the available information on pharmacokinetic interactions is scarce. The purpose of this study was to investigate pharmacokinetic variability of everolimus in patients with TSC, and the impact of age, sex and comedication. In this retrospective observational study we used anonymized data from medical records of patients with TSC using everolimus in Norway and Denmark, 2012 to 2020. Long-term therapeutic drug monitoring (TDM) identified inter-patient and intra-patient variability. The study included 59 patients, (36 females (61%)), median age 22 (range 3-59 years). Polytherapy was used in 50 patients (85%). The most frequently used ASMs were lamotrigine (n = 21), valproate (n = 17), and levetiracetam (n = 13). Blood concentrations of everolimus were measured in all patients. Pharmacokinetic variability of everolimus between patients was extensive, as demonstrated by a 24-fold variability from minimum-maximum concentration/dose (C/D)-ratios. The coefficient of variation (CV) for intra-patient (n = 59) and inter-patient variability (n = 47, ≥3 measurements) was 40% and 43%, respectively. The C/D-ratio of everolimus was 50% lower in 13 patients (22%) using enzyme-inducing ASMs compared to the 30 patients who did not (0.7 vs 1.4 ng/mL mg, P < .05). Age and sex were not significantly associated with changes in C/D-ratios of everolimus. Long-term TDM identified extensive variability in concentrations over time for everolimus both within and between patients, where comedication with enzyme-inducing ASMs was an important contributing factor. The findings suggest a need for TDM in patients with TSC treated with everolimus.