Pharmacokinetic Monitoring Research Articles

Vancomycin dosing in high-intensity continuous renal replacement therapy: A retrospective cohort study.

An inverse relationship exists between vancomycin serum concentrations and the intensity of continuous renal replacement therapy (CRRT), reflected through the dialysate flow rate (DFR). There remains a lack of evidence to guide initial vancomycin dosing in the setting of high-intensity CRRT (i.e., DFR >30 mL/kg/h). Additionally, recommendations for pharmacokinetic monitoring of vancomycin have transitioned from a trough-based to area under the curve (AUC)-based dosing strategy to optimize efficacy and safety. Therefore, an improved understanding of the impact of CRRT intensity on AUC/MIC (minimum inhibitory concentration) has the potential to enhance vancomycin dosing in this patient population. The goal of this study is to evaluate current vancomycin dosing strategies and achievement of pharmacokinetic targets in patients on high-intensity CRRT. This was a single-center, retrospective cohort study of adult critically ill patients admitted to Houston Methodist Hospital between May 2019 and October 2021 and received vancomycin therapy while on high-intensity CRRT. High-intensity CRRT was defined by a DFR that was both ≥3 L/h and >30 mL/kg/h. Depending on the initial vancomycin dosing strategy, patients were stratified into either the traditional (15 mg/kg/day) or enhanced (≥15 mg/kg/day) dosing group. The primary outcome was the percent of patients who attained steady-state AUC24 /MIC ≥400 mg*h/L at the first obtained vancomycin level in the enhanced group compared with the traditional group. A total of 125 patients were included in the final analysis, 56 in the traditional and 69 in the enhanced dosing group. The primary end point occurred in 74% and 54% of patients in the enhanced and traditional dosing groups, respectively (p = 0.029). Therapeutic vancomycin trough levels (10-20 μg/mL) were more commonly achieved in the enhanced dosing group compared with the traditional dosing group (66.7% vs. 45%, p = 0.013). As DFR rose, increasingly higher doses of vancomycin, up to 27 mg/kg/day, were required to achieve the therapeutic targets. This is the first study to evaluate the influence of variable CRRT intensities on vancomycin AUC/MIC. Our findings suggest that vancomycin doses of ≥15 mg/kg/day are needed to achieve early therapeutic targets in patients on high-intensity CRRT.

Translated article] Consensus recommendations for the improvement of inter- and intra-centre care coordination in the management of hemophilia

ObjectiveDefine consensus recommendations to improve care coordination between Hospital Pharmacy, Hematology and Nursing, inter- and intra-center, in the care of hemophilia patients. MethodRecommendations for the improvement of care coordination in the management of hemophilia patients were identified and assessed by a multidisciplinary panel of professionals with experience in this field (Hospital Pharmacy, Hematology and Nursing) and supported by scientific evidence. The identified recommendations were assessed by Rand/UCLA consensus methodology (Delphi-adapted) based on their appropriateness and, subsequently, on their necessity. In both cases, it was used ordinal Likert scale. Data were statistically analyzed through different metrics. ResultsFifty-three recommendations for the improvement of care coordination between Hospital Pharmacy, Hematology and Nursing in the management of hemophilia patients were identified, grouped into eight areas of action: i) Hemophilia units, reference centers and multidisciplinary care; ii) Role of Hematology, Hospital Pharmacy and Nursing in the patient journey of hemophilia patients; iii) Telepharmacy and telemedicine; iv) Pharmacokinetic monitoring; v) Transition to adult patient regimen; vi) Patient health education; vii) Surgery, emergency room and hospital admission; and viii) Outcome evaluation. All recommendations were assessed as appropriate and necessary by the external expert panel. ConclusionsHemophilia patient journey is complex and depends on different variables. It also requires the involvement of different healthcare professionals who must act in a coordinated and integrated manner at all stages of the patient's life, adapted to their individual needs. On this matter, the identified and agreed recommendations may improve continuity and quality of care, as they facilitate the integration and coordination of the professionals involved in the management of this pathology, especially Hospital Pharmacy, Hematology and Nursing.

Current Role of Monoclonal Antibody Therapy in Pediatric IBD: A Special Focus on Therapeutic Drug Monitoring and Treat-to-Target Strategies

In the last two decades, biologicals have become essential in treating children and adolescents with inflammatory bowel disease. TNF-α inhibitors (infliximab, adalimumab and golimumab) are preferentially used. Recent studies suggest that early application of TNF-α inhibitors is beneficial to inducing disease remission and preventing complications such as development of penetrating ulcers and fistulas. However, treatment failure occurs in about one third of pediatric patients. Particularly, children and adolescents differ in drug clearance, emphasizing the importance of pharmacokinetic drug monitoring in the pediatric setting. Here, current data on the choice and effectiveness of biologicals and therapeutic drug monitoring strategies are reviewed.

A NOVEL RP-HPLC GRADIENT ELUTION TECHNIQUE FOR BIOANALYTICAL METHOD DEVELOPMENT AND VALIDATION FOR ESTIMATING GALLIC ACID IN WISTAR RAT PLASMA

Objective: Present study aimed to develop and validate a novel, unique, simple, quick, cost-effective, sensitive, specific, accurate, precise, rugged, and robust bioanalytical method for the quantification of gallic acid in rat plasma by reverse phase high-performance liquid chromatography (RP-HPLC) using gradient elution technique. Methods: The stationary phase was a Zorbax SB C18 5 µ (4.6*150) mm column, with the mobile phase being water with 0.1 percent formic acid (A): acetonitrile (ACN) with 0.08 percent formic acid (B). Gradient chromatographic method was used throughout this experiment from the point of view of the estimation of gallic acid from herbal formulations when present along with other phytoconstituents. So at the gradient method, all the present phytoconstituents has cleared off from the column and no any strongly adsorption of phytoconstituents occurred. The experiment was carried out at a flow rate of 1.0 ml/min at 30 °C utilising PDA detectors at 271 nm. The proposed method was validated for different parameters. Results: The approach was found to be linear in the concentration range of 0.5-100 µg/ml, with a r2 of 0.9998. There was not observed any interference of co-eluting peaks of endogenous compounds from the biological matrix at the same retention time (Rt) of gallic acid. The RSD (%) of intra and interday precision was found to be within acceptable limit. The overall % mean recovery was found to be 99.97%. LOD and LOQ were found to be 0.1 and 0.5 μg/ml, respectively. In terms of fluctuation in essential parameters and operating settings, the devised bioanalytical approach was shown to be rugged and resilient. Short-term, long-term, autosampler, bench-top, and freeze-thaw stability experiments revealed that gallic acid is stable. Conclusion: The developed method described in this report was found to be well within an acceptable range. Hence, in the future, this method can be used successfully for the estimation of gallic acid alone or in combination with another analyte or marker present in bulk or an extract containing various phytoconstituents in pharmacokinetic, bioequivalence, and therapeutic drug monitoring studies in clinical laboratories.

Pengembangan dan Validasi Metode Bioanalisis Trimetoprim dalam Sampel Plasma dan Urin Manusia Simulasi Menggunakan KCKT-PDA

To monitor trimethoprim levels (TMP) in humans, a validated, simple, and cost-efficient analytical method is needed to be applied regularly. However, most of the methods used to establish TMP levels in urine and plasma use complex instrumentation. Therefore, in this study, a simpler High-Performance Liquid Chromatography-based (HPLC) method was developed. The separation was carried out using a GIST® C18 column (150 × 4.6 mm, 5 μm) at a temperature of 35°C which was fed by a mobile phase in the form of an acetic acid solution pH 2.5: acetonitrile (87:13, v / v) at a speed of 1.4 ml/min. Detection was performed with Photodiode Array Detector (PDA) at wavelengths of 254 nm and 243 nm to quantify TMP in urine and plasma samples respectively. The preparation of urine and plasma sequentially was carried out by the liquid-liquid extraction (ECC) method using ethyl acetate and the protein precipitation using acetonitrile. This method proved to be selective, linear (R=0.997), accurate with %error ≤ 10.29% at LLOQ level and above LLOQ value %error ≤ 10.45%, precision with %RSD ≤ 11.79% at LLOQ level and %RSD ≤ 10.82% above LLOQ. In addition, this method is quite sensitive for pharmacokinetic studies in the urine and monitoring of TMP levels in the blood with LLOQ 5 mg/L in both urine and plasma. The stability of trimethoprim in solution, urine, and plasma was conducted to ensure storage time. The developed method is proven to be valid and can be applied in pharmacokinetic studies and monitoring of trimethoprim drug levels in urine and plasma.

Consenso de recomendaciones para la mejora de la coordinación asistencial inter e intra-centros en el abordaje de la hemofilia

ObjectiveDefine consensus recommendations to improve care coordination between Hospital Pharmacy, Haematology and Nursing, inter- and intra-center, in the care of haemophilia patients. MethodRecommendations for the improvement of care coordination in the management of haemophilia patients were identified and assessed by a multidisciplinary panel of professionals with experience in this field (Hospital Pharmacy, Haematology and Nursing) and supported by scientific evidence. The identified recommendations were assessed by Rand/UCLA consensus methodology (Delphi-adapted) based on their appropriateness and, subsequently, on their necessity. In both cases, it was used ordinal Likert scale. Data were statistically analysed through different metrics. ResultsFifty-three recommendations for the improvement of care coordination between Hospital Pharmacy, Haematology and Nursing in the management of haemophilia patients were identified, grouped into eight areas of action: i) Haemophilia units, reference centers and multidisciplinary care; ii) Role of Haematology, Hospital Pharmacy and Nursing in the patient journey of haemophilia patients; iii) Telepharmacy and telemedicine; iv) Pharmacokinetic monitoring; v) Transition to adult patient regimen; vi) Patient health education; vii) Surgery, emergency room and hospital admission; and viii) Outcome evaluation. All recommendations were assessed as appropriate and necessary by the external expert panel. ConclusionsHaemophilia patient journey is complex and depends on different variables. It also requires the involvement of different healthcare professionals who must act in a coordinated and integrated manner at all stages of the patient's life, adapted to their individual needs. On this matter, the identified and agreed recommendations may improve continuity and quality of care, as they facilitate the integration and coordination of the professionals involved in the management of this pathology, especially Hospital Pharmacy, Haematology and Nursing.

In vivo monitoring of brain pharmacokinetics and pharmacodynamics with cerebral open flow microperfusion.

In vivo investigation of brain pharmacokinetics and pharmacodynamics (PK/PD) is an integral part of neurological drug development. However, drugs intended to act in the brain may reach it at very low concentrations due to the protective effect of the blood-brain barrier (BBB). Consequently, very sensitive measurement methods are required to investigate PK/PD of drugs in the brain. Also, these methods must be capable of continuously assessing cerebral drug concentrations with verifiable intact BBB, as disrupted BBB may lead to compound efflux from blood into brain and to biased results. To date, only a few techniques are available that can sensitively measure drug concentrations in the brain over time; one of which is cerebral open flow microperfusion (cOFM). cOFM's key features are that it enables measurement of cerebral compound concentrations with intact BBB, induces only minor tissue reactions, and that no scar formation occurs around the probe. The membrane-free cOFM probes collect diluted cerebral interstitial fluid (ISF) samples that are containing the whole molecule spectrum of the ISF. Further, combining cOFM with an in vivo calibration protocol (e.g. Zero Flow Rate) enables absolute quantification of compounds in cerebral ISF. In general, three critical aspects have to be considered when measuring cerebral drug concentrations and recording PK/PD profiles with cOFM: (a) the BBB integrity during sampling, (b) the status of the brain tissue next to the cOFM probe during sampling, and (c) the strategy to absolutely quantify drugs in cerebral ISF. This work aims to review recent applications of cOFM for PK/PD assessment with a special focus on these critical aspects.

Vancomycin Flight Simulator: A Team-Based Learning Exercise

Team-based learning (TBL) encourages learners to think critically to solve problems they will face in practice. Pharmacokinetic dosing and monitoring are complex skills requiring the application of learned knowledge. The study sought to assess the impact of a TBL, vancomycin dosing activity in a Pharmaceutical Skills IV course measured with exam question performance during the second professional year. This retrospective, descriptive study relates a TBL activity, assigned to 85 students, which included an individual student pre-preparation quiz, assigned readings, in-class individual and team-based readiness assessments, small group application of a vancomycin patient case, and group discussion/feedback on clinical decisions with supportive reasoning. The class year before and class year of the TBL implementation were compared using the total percentage of points possible earned by the class years, by topic. To minimize potential confounding, the primary outcome was the change in topic performance by the rank difficulty (e.g., the largest possible benefit being the hardest topic becoming the easiest with no other variation in topic rank difficulty). In the year of implementation, the mean individual readiness assurance test (IRAT) performance was 5.5 ± 1.88 (10 points possible, 55%). The mean team readiness assurance test (TRAT) performance was 10 of 10 points possible (100%). The class exam item performance in the year before (n = 101) and year of (n = 84) TBL implementation showed a general decline in exam scores. However, the vancomycin topic difficultly went from fifth easiest, to second easiest, with less than 1% change in raw score. Implementation of a pharmacokinetic TBL activity appeared to moderately support the students' vancomycin learning. Additional studies are warranted on APPE readiness and performance.

Antipsychotic Safety in Liver Disease: A Narrative Review and Practical Guide for the Clinician.

Clinicians treating psychiatric disorders in medically ill patients need a comprehensive resource for comparing the risk and types of liver injury associated with antipsychotic therapy. We conducted a narrative review aimed at developing a comprehensive resource comparing antipsychotics with regard to risk of inducing or worsening liver injuries, types of liver injury, associated pharmacokinetic changes, dosing, monitoring, and patient counseling recommendations. We conducted database searches of LiverTox.nih.gov, DailyMed.nlm.nih.gov, and PubMed through June of 2022. Sources describing premarketing data, observational studies, case reports and case series of antipsychotic-induced liver injuries, types of hepatic dysfunction, interventions, recovery, and treatment for 15 antipsychotics were included. Duplicate reports were excluded. Antipsychotics were graded as low, low to moderate, moderate, moderate to high, or high risk for causing or worsening a liver disease. Of the 1861 publications, 21 papers met criteria and were included. Evidence shows antipsychotic-induced liver dysfunction is uncommon to rare. Chlorpromazine, clozapine, and olanzapine pose the greatest risk of hepatoxicity; quetiapine and risperidone pose a moderate risk with haloperidol considered to pose low to moderate risk. Paliperidone, aripiprazole, lurasidone, and loxapine are lower-risk agents with no reports of liver failure. Transaminitis that is mild and self-limiting is the most common antipsychotic-induced liver injury followed by hepatocellular disease, steatosis, and mixed liver injury. A careful risk-benefit analysis should guide the decision to discontinue the antipsychotic in cases of severe liver disease. Dose adjustments and careful monitoring are recommended for a mild to moderate disease when the benefits of treating psychosis outweigh the risks. Patients without an existing liver disease initiating a treatment with a higher-risk antipsychotic should be counseled to report symptoms of liver injuries along with regular lab monitoring. Antipsychotic selection, dosing, monitoring, and counseling should be individualized based on whether a patient has an existing liver disease and if they are receiving an agent that poses a higher risk of liver injury. The consultation-liaison psychiatry provider can guide the primary team in management through thoughtful integration of the known pathophysiologic changes in hepatic disease and risk-benefit analysis of antipsychotic safety profiles.

Review of Tobramycin Dosing in Pediatric Patients With Cystic Fibrosis.

An institution's tobramycin pharmacokinetics (PK) database was reviewed to evaluate the efficacy and safety of empiric tobramycin dosing and monitoring strategies used in pediatric patients with cystic fibrosis (CF). The relationship between patient age and tobramycin dosing needed to achieve the area under the curve (AUC) goal was investigated. Retrospective chart review was performed for patients who received tobramycin during a CF exacerbation from 2009 to 2019 who received PK monitoring by pediatric pharmacists. Tobramycin dosing needed to achieve an AUC of 100 mg·hr/L was calculated for each patient. Serum creatinine and concomitant nephrotoxin use were collected as surrogate nephrotoxicity endpoints to evaluate safety. Goal AUC (100 ± 15 mg·hr/L) was achieved based on initial or repeat PK calculations in 43.5% (95% CI, 37.7-49.3) of 85 unique patients across 326 encounters. Patients with calculated recommended doses of 9.5 to 11.9 mg/kg every 24 hours empirically achieved goal AUC in 77% (78/101) of encounters. The odds of achieving goal AUC were 56% higher for children aged 10 vs 5 years (OR = 1.56; 95% CI, 1.04-2.34; p = 0.033) and 32% higher for children aged 15 vs 10 years (OR = 1.32; 95% CI, 1.07-1.61; p = 0.008). Overall rates of acute kidney injury and concomitant nephrotoxin use were 10.8% (95% CI, 6.2-15.5) and 80.7% (95% CI, 74.3-87.1), respectively. Desired AUC was achieved by 43.5% of pediatric patients with CF using tobramycin 10 mg/kg every 24 hours. Older patient age was associated with higher initial AUC attainment and fewer dose modifications. Younger children may require higher weight-based dosing to meet AUC goals.

VANCOmycin dose adjustments comparing trough levels to the ratio of the area under de curve to the minimum inhibitory concentration method using a BAYESian approach: A feasibility study.

WHAT IS KNOWN AND OBJECTIVE?: The latest published guidelines advocate for the area under the concentration-time curve to minimal inhibitory concentration (AUC0-24h /MIC) estimated with bayesian calculations. This recommended pharmacokinetic monitoring transition is not based on randomized controlled prospective data. METHODS: In this open-label feasibility RCT, patients were assigned to have their vancomycin dosing adjusted based on bayesian-guided AUC0-24h /MIC or trough levels. Primary outcomes were consent rate, number of patients recruited per month, compliance with blood sampling schedule and compliance with bayesian software recommendations. Secondary outcomes focused on target attainment, safety and operational impacts. RESULTS AND DISCUSSION: Forty-five patients underwent randomization (23 bayesian, 22 trough). Consent rate was 37,5% for an average of 9.8 patients recruited per month meeting pre-specified objectives of 30% (p= 0.073) and 10 (p= 0.74) respectively. A 74.8% compliance with blood sampling schedule was below the pre-specified objective of 80% (p= 0.038). There was no statistically significant difference between the 83.7% compliance with bayesian software recommendations and the pre-specified objective of 90% (p= 0.21). Although exploratory, key clinical results were significant increases in the bayesian group for proportion of levels at target (RR 1.32; 95% CI 1.01-1.72; P=0.038), number of blood samplings for patients (p= 0.036) and pharmacists' time spent on monitoring (p< 0.0001). A tendency towards a reduced incidence of nephrotoxicity in the Bayesian group was observed (RR 0.57; 95% CI 0.16-2.12; p= 0.46). WHAT IS NEW AND CONCLUSIONS?: This trial demonstrates that it would be feasible to conduct a properly sized RCT comparing vancomycin Bayesian-guided AUC0-24h /MIC to trough level monitoring. Although exploratory, this trial also showed a tendency towards reduced incidence of nephrotoxicity and an increased proportion of dosages at therapeutic targets with Bayesian monitoring.

Monitoring of blood immunosuppressant concentrations and lymphocyte activation for predicting viral infections following kidney transplantation: A pilot study.

The current standard pharmacokinetic monitoring of immunosuppressive therapy does not consider inter- and intra-individual differences in the biological response to multidrug immunosuppressive therapy. The authors evaluated the blood levels of the immunosuppressive drugs IL-2 and IFN-γ in circulating lymphocytes as surrogate indicators of the development of viral infections after living kidney transplantation. This single-center prospective study included 20 kidney transplant recipients who underwent living-donor transplantation at the Mie University Hospital. All the study participants received tacrolimus, mycophenolic acid, methylprednisolone, and basiliximab. The area under the concentration curves (AUCs) of blood tacrolimus and serum mycophenolic acid were measured 1 day prior to transplantation and on post-transplantation days (PTD) for up to 5 months. IL-2 and IFN-γ levels in circulating lymphocytes were measured simultaneously. One recipient experienced an acute graft rejection. Although the AUC of tacrolimus at PTD 7 was significantly higher in the virus-infected group than that in the non-infected group, the AUC of mycophenolic acid did not differ significantly between the 2 groups. The expression levels of IFN-γ+ NK, IFN-γ+ CD4+ T, and CD8+ T cells in the infected group also tended to be higher than those in the noninfected group. During the study period, there was a clear difference in the expression of IFN-γ+ CD8+ T cells, which increased significantly during or after infection. Circulating IFN-γ+ CD8+ T cell counts may serve as promising biomarkers for predicting opportunistic viral infections early after kidney transplantation.

Robotic APTamer-Enabled Electrochemical Reader (RAPTER) System for Automated Aptamer-Mediated Electrochemical Analysis.

Electrochemical aptamer-based (E-AB) sensors using conformational change-induced electron transfer kinetics are sensitive, reagent-less, and cost-effective tools for molecular sensing. Current advances in this technology can allow continuous drug pharmacokinetic monitoring in living animals (Dauphin-Ducharme et al., ACS Sens 4(10):2832-2837, 2019; Idili et al., Chem Sci 10(35):8164-8170, 2019), as well as automated analysis of hormone pulsatility (Liang et al., Nat Commun 10(1):852, 2019). In this chapter, we provide the methodology for an automated E-AB conformational change-based robotic sensing platform. By using an open-source programmable robotic system, this method can be adapted to a wide range of experimental scenarios.

Microfluidic chip interfacing microdialysis and mass spectrometry for in vivo monitoring of nanomedicine pharmacokinetics in real time

Although liposomes have demonstrated significant clinical success as drug delivery vehicles, pharmacokinetic (PK) profiling of liposomal nanomedicines remains difficult due to technical challenges accurately measuring low concentrations of free drug in complex biological matrices. Microdialysis (MD) is well established as a powerful in vivo sampling tool for PK studies, but non-volatile salts present in the microdialysate are incompatible with mass spectrometry (MS) analysis without tedious sample pre-treatment. To address this issue, a µSPE-based microfluidic chip was fabricated to interface MD with MS. By incorporating PEG 20,000 as an effective anti-foulant, the µSPE-based microfluidic chip demonstrated excellent efficiencies in drug extraction and de-salting of the microdialysate, providing a promising approach to real-time monitoring of nanomedicine PK profiles.

Impact of Patient-Specific Aminoglycoside Monitoring for Treatment of Pediatric Cystic Fibrosis Pulmonary Exacerbations.

Aminoglycosides are frequently used for empiric and definitive treatment of cystic fibrosis (CF) pulmonary exacerbations. Various methods have been described for aminoglycoside therapeutic drug monitoring. The objective of this study is to evaluate the effect of patient-specific pharmacokinetic calculations for aminoglycosides used to treat CF pulmonary exacerbations. Ambidirectional cohort study of patients admitted to a children's hospital from June 1, 2018, through February 28, 2019, and June 1, 2019, through February 8, 2021. The primary outcome was the occurrence of dosing changes after analysis of initial serum concentrations in either group. Secondary outcomes included occurrence of nephrotoxicity, duration of antibiotics, and length of stay. Twenty-four patients (75%) in the intervention group versus zero in the control group required dosing adjustments after initial analysis of serum concentrations were completed (p < 0.001). There was not a statistically significant between-group difference for duration of antibiotics in days (median, 14 vs 13.5; Z, 1.07; p = 0.29) or length of stay (median, 11 vs 11; Z, -0.31; p = 0.76). There was also not a statistically significant between-group difference in forced expiratory volume in one second (FEV1) change from admission to discharge (11.4% vs 13.9%; t, 0.61; Degrees of Freedom, 39; p = 0.55). Two patients (6.25%) in the intervention group experienced nephrotoxicity compared with zero patients in the control group (risk difference, 6.25%; 95% CI, -2.14 to 14.64; number needed to harm, 16). Patient-specific pharmacokinetic monitoring led to significantly more dosing changes and was associated with similar patient outcomes as trough-only monitoring. Further studies are needed to identify methods to optimize aminoglycoside dosing and monitoring for these patients with the goal of reducing toxicities while maximizing efficacy.

Clinical Application of Pharmacokinetics to Appraise Adherence to Levetiracetam in Portuguese Epileptic Patients.

Adherence to antiseizure drug treatment determines its effectiveness and safety, and consequently affects patients’ quality of life. Herein, we assessed adherence to levetiracetam in Portuguese patients with refractory epilepsy (n = 115), with resort to a pharmacokinetic drug monitoring approach. The pharmacokinetic parameters of levetiracetam in each patient were determined in steady-state while admitted to the hospital. Then, adherence was assessed by comparing the plasma concentration of the drug observed on the first day of hospitalization with the predicted plasma concentration, considering previously determined pharmacokinetic parameters. The rate of adherence was assessed according to gender, age, diagnosis, and antiseizure drug regimen. Among 115 enrolled patients, 49 (42.6%) were identified as non-adherent, 30 (26.1%) classified as under-consumers, and 19 (16.5%) as over-consumers. A relationship between adherence, daily dose and plasma concentrations was herein reported for the first time. Adherent patients received higher daily doses of levetiracetam [2500 (2000–3000) mg] than non-adherent over-consumers [1500 (1000–2000) mg] and non-adherent under-consumers [2000 (1500–3000) mg]. Higher average steady-state plasma concentrations of levetiracetam were found in non-adherent under-consumers [27.28 (15.33–36.36) mg/L], followed by adherent patients [22.05 (16.62–29.81) mg/L] and non-adherent over-consumers [17.50 (10.69–24.37) mg/L]. This study demonstrates that adherence (or lack thereof) influences the plasma concentrations of levetiracetam in steady-state and its pharmacological effects. Moreover, it emphasizes the importance of educating patients to encourage adherence to therapy. Otherwise, the risk of developing toxic and subtherapeutic concentrations is undeniable, compromising the therapeutic effect and safety of treatment.

Toxicity analysis of busulfan pharmacokinetic therapeutic dose monitoring.

Busulfan-based conditioning regimens are associated with serious toxicities and literature reports increased risk of toxicities when daily area under the curve concentrations exceed 6000 µM-minute. We implemented real time pharmacokinetic-guided therapeutic drug monitoring of busulfan for myeloablative conditioning regimens. The objective was to compare toxicity of intravenous busulfan before and after therapeutic drug monitoring implementation. The primary endpoint was incidence of hepatotoxicity. Medical records were retrospectively reviewed with weight-based dose Busulfan/Cyclophosphamide (BuCy) conditioning from August 2017 through March 2018 (N = 14) and therapeutic drug monitoring from April 2018 through December 2018 (N = 22). Recipients of busulfan therapeutic drug monitoring were younger than those receiving weight-based dose (median: 45 vs. 58 years, p = 0.008). No other baseline differences were observed. There was no difference in hepatotoxicity between therapeutic drug monitoring and weight-based dose (median 1 vs. 0 days, p = 0.40). In the therapeutic drug monitoring group, 45% of patients had increases and 41% had decreases in busulfan dose after Bu1. Repeat pharmacokinetic after Bu2 were required in 32% of patients. A pharmacokinetic dose monitoring program for myeloablative conditioning intravenous busulfan regimens may be considered a safe practice in stem cell transplant recipients. The majority of patients receiving pharmacokinetic-guided therapeutic drug monitoring required dose changes and therapeutic drug monitoring patients had no significant difference in toxicity compared to those receiving weight-based dose.

Method Development and Validation for the Determination of Linezolid Drug in Human Plasma by Reversed-Phase High-Performance Liquid Chromatography

Objective: Linezolid is a significant antibiotic used against severe infections initiated by multi-resistant bacterial pathogens. Method: The aim of this study is to develop and validate a simple, selective and accurate highperformance liquid chromatographic HPLC method for the analysis of linezolid LZD. Method: Linezolid extraction from plasma is obtained using methanol. Chromatographic separation is achieved isocratically on a C18 column [Zorbax C18, 5 μm particle size, 150 mm˟ 4.6 mm] making use of a mobile phase of acetonitrile / 0.05 M phosphate buffer, pH = 4.5 (30: 70 v/v) at a flow rate of 1.2 mL/min with photodiode array detector DAD, at a wavelength of 256 nm. Results : The retention time of linezolid was 2.5 min. The analytical method was linear (r2 &gt; 0.998) over the calibration range of 0.30 to 50.0 μg/mL. The extraction recoveries of linezolid range from 71.03 to 91.93 %. The limit of quantification and the limit of detection were 0.112 μg and 0.037 μg, respectively. The RSDs for intraday and interday assays were &lt; 7.77 and 4.32 %, respectively. The intraday and interday accuracies were in the range 80.6-112 % and 77.44- 104.85 %, respectively. Conclusion: The applied method is precise, accurate and appropriate for pharmacokinetic studies and therapeutic drug monitoring of linezolid in routine clinical practice.

Allogeneic hematopoietic stem cell transplantation for inherited metabolic disorders.

Allogeneic hematopoietic stem cell transplantation (HSCT) has been used to treat patients with inherited metabolic disorders (IMDs) for more than 40years. In the first two decades, various IMDs were treated by HSCT with a wide variety of donor sources and conditioning regimens selected at the institutional level. However, HSCT was not always successful due to post-transplant complications such as graft failure. In the third decade, myeloablative conditioning with targeted busulfan-based pharmacokinetic monitoring was established as an optimal conditioning regimen, and unrelated cord blood was recognized as an excellent donor source. During the fourth decade, further improvements were made to transplant procedures, including modification of the conditioning regimen, and the survival rate after HSCT markedly improved. Simultaneously, several long-term observational studies for patients after HSCT clarified its therapeutic effects on growth and development of cognitive function, fine motor skills, and activities of daily living when compared with enzyme replacement therapy. Although immune-mediated cytopenia was newly highlighted as a problematic morbidity after HSCT for IMDs, especially in younger patients who received unrelated cord blood, a recent study with rituximab added to the conditioning raised expectations that this issue can be overcome.

Drug-Induced QTc Prolongation: What We Know and Where We Are Going.

Drug-induced QTc prolongation is a concerning electrocardiogram (ECG) abnormality. This cardiac disturbance carries a 10% risk of sudden cardiac death due to the malignant arrhythmia, Torsades de Pointes. The Arizona Center for Education and Research on Therapeutics (AzCERT) has classified QTc prolonging therapeutic classes, such as antiarrhythmics, antipsychotics, anti-infectives, and others. AzCERT criteria categorize medications into three risk categories: "known," "possible," and "conditional risk" of QTc prolongation and Torsades de Pointes. The list of QTc prolonging medications continues to expand as new drug classes are approved and studied. Risk factors for QTc prolongation can be delineated into modifiable or non-modifiable. A validated risk scoring tool may be utilized to predict the likelihood of prolongation in patients receiving AzCERT classified medication. The resultant risk score may be applied to a clinical decision support system, which offers mitigation strategies. Mitigation strategies including discontinuation of possible offending agents with a selection of an alternative agent, assessment of potential drug interactions or dose adjustments through pharmacokinetic and pharmacodynamic monitoring, and initiation of both ECG and electrolyte monitoring are essential to prevent a drug-induced arrhythmia. The challenges presented by the COVID-19 pandemic have led to the development of innovative continuous monitoring technology, increasing protection for both patients and healthcare workers. Early intervention strategies may reduce adverse events and improve clinical outcomes in patients identified to be at risk of QTc prolongation.