Importance Of Therapeutic Drug Monitoring Research Articles

P-1250. Pharmacokinetic Evaluation of Colistin Methanesulfonate in Critically Ill Patients: Implications for Clinical Management

Abstract Background The study aims to assess the pharmacokinetics of colistin methanesulfonate (CMS) and colistin, and its impact on clinical outcomes, particularly clinical cure (CC), and the development of acute kidney injury (AKI) in critically ill patients with normal baseline renal function. Methods This prospective observational study focuses on adult critically ill patients with MDR/XDR infections treated with intravenous CMS. Patients receive a loading dose (LD) of 9 MU followed by a maintenance dose (MD) of 3 MU every 8 hours. Pharmacokinetic (PK) sampling occurs pre- and post-LD, and during MD. Colistin plasma levels are quantified using liquid chromatography–mass spectrometry (LC–MS). Clinical outcomes, including clinical cure, impact on renal failure and mortality, are assessed. Results A total of 144 serum samples were analyzed from the 12 patients, with 60% having pneumonia. Predominant pathogens were Klebsiella pneumoniae (7) and Acinetobacter spp. (5). The mean estimated creatinine clearance (CrCl) was 120 ± 22 mL/minute (range: 75.4–215.2). All patients received combination therapy, with 80% receiving meropenem and 40% receiving tigecycline. The clinical cure rate was 50% (6/12), with a mortality rate of 25% (3/12). The mean LD colistin Cmax was 3.1 ± 1.2 mg/L (range: 1.6–5.5) and 2.4 ± 1.3 mg/L (range: 1.4–5.8) among the CC and CF groups, respectively (P = 0.14). MD colistin Css avg was 2.3 ± 1.4 mg/L and 1.8 ± 1.2 mg/L in CC and CF groups, respectively. The mean AUC0–24/MIC ratio of MD colistin was 94.3 ± 68.2 and 78.1 ± 53.6 for CC and CF groups, respectively (P = 0.28). In pneumonia, AUC0–24/MIC for Acinetobacter spp. was higher in the CC (72.1 ± 11.3) than in the CF group (41.5 ± 15.8) (P = 0.06). Renal injury was observed in 40% (5/12) of patients at the end of therapy, with acute kidney injury (AKI) being the most common complication. Additionally, a subset of patients (n = 3) demonstrated evidence of chronic kidney disease (CKD) progression, highlighting the nephrotoxic potential of colistin therapy. Conclusion The findings underscore the importance of therapeutic drug monitoring in optimizing colistin therapy and the necessity for vigilant monitoring of renal function to mitigate the risk of AKI and CKD progression. Disclosures All Authors: No reported disclosures

Simultaneous determination of three β-Lactam/β-lactamase inhibitor combinations in critically ill patients by UPLC-MS/MS.

Simultaneous determination of three β-Lactam/β-lactamase inhibitor combinations in critically ill patients by UPLC-MS/MS.

Effect of hypoalbuminemia on drug pharmacokinetics.

Hypoalbuminemia, defined as serum albumin levels below 35g/L, is common in patients with conditions such as nephrotic syndrome, cirrhosis, or sepsis. This review examines the impact of hypoalbuminemia on the pharmacokinetics of selected drugs-such as antibiotics, immunosuppressants, antifungals, or anticonvulsants-emphasizing its role in drug efficacy and safety. Albumin is the main drug transporter and key binding protein, which influences the free drug concentration and drug activity. The review includes all studies available in the scientific literature found in the PubMed, Scopus, and Cochrane databases. The paper emphasizes the importance of therapeutic drug monitoring (TDM) in patients with hypoalbuminemia to avoid subtherapeutic or toxic drug levels. Many drugs need for dose adjustments to achieve therapeutic levels, especially in critically ill patients. The results of studies emphasize the need for individualized dosing regimens based on TDM to optimize drug therapy in patients with hypoalbuminemia. Our review is the first article to summarize the influence of hypoalbuminemia on the pharmacokinetic parameters of drugs and may be a useful tool for clinicians in their daily work.

Determination of Antiepileptics in Biological Samples-A Review.

Epilepsy remains a disease that affects many people around the world. With the development of new drugs to treat this condition, the importance of therapeutic drug monitoring continues to rise and remains a challenge for the medical community. This review article explores recent advances in the detection of antiepileptic drugs across various sample types commonly used for drug monitoring, with a focus on their applications and impact. Some of these new methods have proven to be simpler, greener, and faster, making them easier to apply in the context of therapeutic drug monitoring. Additionally, besides the classic use of blood and its derivatives, there has been significant research into the application of alternative matrices due to their ease of sample collection and capacity to reflect drug behavior in blood. These advances have contributed to increasing the efficacy of therapeutic drug monitoring while enhancing its accessibility to the population.

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

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

Relevance of plasma lenvatinib concentrations and endogenous urinary cytochrome P450 3A activity biomarkers in clinical practice.

Lenvatinib (LEN), a multitarget tyrosine kinase inhibitor used in various cancer treatments, is mainly metabolized by cytochrome P450 3A (CYP3A) enzymes. The importance of therapeutic drug monitoring (TDM) in patients administered LEN has been proposed. Although some biomarkers of endogenous CYP3A activity have been reported, their utility in dosage adjustments has not been well evaluated. This study investigated the correlation between plasma LEN concentrations and endogenous urinary CYP3A biomarkers in clinical practice. Concentrations of plasma LEN (N = 225) and CYP3A biomarkers (cortisol, 6β-hydroxycortisol, deoxycholic acid, and 1β-hydroxydeoxycholic acid) in urine (N = 214) from 20 patients (hepatocellular carcinoma, N = 6; thyroid cancer, N = 3; endometrial cancer, N = 8; and renal cell carcinoma, N = 3) collected for consultation for up to 1 year were evaluated using liquid chromatography-tandem mass spectrometry. Moreover, plasma trough LEN concentrations were predicted using a three-compartment model with linear elimination for outpatients administered LEN before sample collection. Moderate correlations were observed between the quantified actual concentrations and the predicted trough concentrations of LEN, whereas there was no correlation with endogenous urinary CYP3A biomarkers. The utility of endogenous urinary CYP3A biomarkers could not be determined. However, TDM for outpatients administered orally available medicines may be predicted using a nonlinear mixed effect model (NONMEM). This study investigated the utility of endogenous urinary CYP3A biomarkers for personalized medicine and NONMEM for predicting plasma trough drug concentrations. These findings will provide important information for further clinical investigation and detailed TDM.

Improved high-performance liquid chromatography tandem mass spectrometry method for quantification of infliximab in pediatric plasma and its application in therapeutic drug monitoring.

The application of infliximab (IFX) to immune-mediated disease is limited by the significant individual variability and associated clinical nonresponse, emphasizing the importance of therapeutic drug monitoring (TDM). Because of the cross-reactivity, limited linear range, and high costs, the clinical application of the previous reported methods was limited. Here, an improved high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method was developed to address the issues. This study developed an improved bioanalytical HPLC-MS/MS method coupling nanosurface and molecular-orientation limited proteolysis technology. The commercially available compound P14R was selected as the internal standard. This method was developed with fewer volume of reagents and was thoroughly validated. The validated method was applied to TDM in pediatric inflammatory bowel disease (IBD). Chromatography was performed using a Shim-pack GISS-HP C18 metal-free column (3 μm, 2.1 × 100 mm) with a gradient elution of 0.1% formic acid in water and acetonitrile at 0.4 mL/min. Detection and quantitation were performed using electrospray ionization (ESI) and multiple reaction monitoring in the positive ion mode. The method was validated to demonstrate its selectivity, linearity, accuracy, precision, recovery, matrix effect, and stability. The method exhibited a linear dynamic range of 0.3-100 μg/mL, with intra- and inter-day precision and relative errors below 15%. The recovery and matrix effect were measured as 87.28%-89.72% and 41.98%-67.17%, respectively, which were effectively compensated by the internal standard. A total of 32 samples collected from 24 pediatric patients with IBD were analyzed using the validated method, and only 46.9% achieved the reported targeted trough level. This study developed an improved HPLC-MS/MS method for the quantitative determination of IFX concentration in human plasma. The accurate, reliable, and cost-effective method was validated and utilized in the analysis of clinical samples. The results confirmed the importance of TDM on IFX and the clinical application prospects of the improved method.

In Vivo Evaluation of the Pharmacokinetic Interaction between Levothyroxine and Amiodarone in Rat Plasma: Evaluation of Importance of Therapeutic Drug Monitoring during Co-Therapy.

Amiodarone-induced thyrotoxicosis (AIT) is a common condition in patients who are receiving amiodarone for cardiac arrhythmia. This risk is elevated in iodine-deficient regions. Levothyroxine is the standard treatment for patients with hypothyroidism. This investigation is concerned with the evaluation of the possible pharmacokinetic interaction between amiodarone and levothyroxine upon co-therapy in rats and to investigate the cause of thyrotoxicosis. A selective, sensitive and precise RP-HPLC method was developed for the simultaneous determination of levothyroxine and amiodarone in rat plasma. A stationary phase of C18 Xterra RP column and a mobile phase consisting of acetonitrile: acidified water with 0.1% trifluoracetic acid (pH = 4.8) with gradient elution were used. The experiment was conducted at ambient temperature with flow rate of 1.5mL/min for the chromatographic separation and quantitation of the investigated drugs. Protein precipitation with methanol was applied for the analysis of the two drugs in rat plasma. The method was linear over concentration range of 5-200μg/mL for both levothyroxine and amiodarone. The European Medicines Agency guideline was applied for the validation of the developed bioanalytical method. The method was successfully applied to in vivo pharmacokinetic study in which levothyroxine and amiodarone were quantified in plasma of rats after receiving an oral dose of levothyroxine and amiodarone. After the calculation of the pharmacokinetic parameters, a statistical analysis was performed to elucidate the existence of significant difference between test and control groups in rats. The combination of levothyroxine and amiodarone significantly decreased levothyroxine bioavailability in rats, making the therapeutic drug monitoring mandatory in patients receiving levothyroxine and amiodarone. In addition, the increased clearance of levothyroxine upon the co-administration with amiodarone may explain the reported hypothyroidism.

Simultaneous determination of eight antiepileptic drugs and two metabolites in human plasma by liquid chromatography/tandem mass spectrometry

AbstractEpilepsy is one of the most prevalent neurological conditions and antiepileptic drugs are the mainstay of epilepsy treatment. High variation in pharmacokinetic profiles of several antiepileptic drugs highlights the importance of therapeutic drug monitoring to estimate pharmacokinetic properties and consequently individualize drug posology. In this work, a simple, rapid and robust liquid chromatography-tandem mass spectrometry method was developed for simultaneous quantification of carbamazepine and its metabolite carbamazepine-10,11-epoxide, gabapentin, levetiracetam, lamotrigine, oxcarbazepine and its metabolite mono-hydroxy-derivative metabolite, phenytoin, topiramate, and valproic acid in human plasma for therapeutic drug monitoring. d6-Levetiracetam, d4-gabapentin and d6-valproic acid were used as internal standards. After addition of internal standards along with two-step protein precipitation and dilution sample preparation, plasma samples were analyzed on a C18 column using a gradient elution in 5 min without interference. The calibration curves were linear over a 100-fold concentration range, with determination coefficients (r2) greater than 0.99 for all analytes. The limit of quantification was 0.5 μg mL−1 (0.1 μg mL−1 for oxcarbazepine, 2 μg mL−1 for levetiracetam, and 10 μg mL−1 for valproic acid) with precision and accuracy ranging from 3% to 9% and from 94% to 112%, respectively. Intra- and inter-day precision and accuracy values were within 15% at low, medium and high quality control levels. No significant matrix effect was observed in the normal, hemolyzed, lipemic, and hyperbilirubin blood samples. This method was successfully used in the identification and quantitation of antiepileptic drugs in patients undergoing mono- or polytherapy for epilepsy.

Factors associated with subtherapeutic levels of oral posaconazole tablet: a detailed analysis from a tertiary care center in India

ObjectivesPosaconazole is a broad-spectrum triazole antifungal, with activity against various clinically important fungi. The delayed release (DR) tablet of posaconazole has been shown to have a superior pharmacokinetic profile in comparison with the oral suspension. MethodsWe retrospectively analyzed the factors associated with posaconazole levels <1.25 μg/ml in 164 patients receiving the DR tablet for therapeutic purposes. ResultsOf the 164 patients, 53 (32.3%) showed subtherapeutic trough levels of posaconazole. The use of proton pump inhibitors (95% CI 1.41-3.91; P-value = 0.028) and the presence of diarrhea (95% CI 1.95-6.93; P-value = 0.001) were significantly associated with subtherapeutic levels. A total of 13 of the 21 patients receiving posaconazole tablets through a nasogastric tube had therapeutic levels. ConclusionThis is the largest study from India that analyzed factors associated with subtherapeutic levels of the DR tablet of posaconazole. These findings reinforce the importance of therapeutic drug monitoring. Unlike in previous studies, obesity and hypoalbuminemia were not found to be significant factors in our settings. The use of proton pump inhibitors and diarrhea remained significant factors, as found in previous studies. Administering the DR tablet of posaconazole through a nasogastric tube may be a viable option.

Pharmacokinetic interaction between raltegravir and rifampicin in an infant with HIV exposed to active TB: a case report

We report a case of an infant with HIV receiving raltegravir granules for oral suspension and rifampicin-based TB prophylaxis. Raltegravir trough levels remained subtherapeutic and viral load increased during concurrent rifampicin therapy despite using double-dosed raltegravir. Even after rifampicin therapy, a higher dose was needed. This highlights the importance of therapeutic drug monitoring and dose adjustments of raltegravir in infants with rifampicin as comedication.

Factors influencing the vancomycin trough level in patients admitted at King Fahad Specialist Hospital, Qassim, KSA.

Although vancomycin is an effective antibiotic against methicillin-resistant Staphylococcus aureus, its usage is often associated with nephrotoxicity which necessitates optimization of the vancomycin dose to be both precise and appropriate. To achieve this, the importance of therapeutic drug monitoring arises, and serum trough vancomycin concentrations are the most accurate and practical method for monitoring vancomycin effectiveness and even risk of nephrotoxicity. This study evaluated the influences on the trough levels of vancomycin given to admitted patients at King Fahad Specialist Hospital (KFSH). This cross-sectional hospital-based study has been conducted at KFSH among 197 patients, of which 53.3% were male and 46.7% were female. They received intravenous vancomycin at intermittent dose of 30 mg/kg/day with no clinical or laboratory renal impairment. The serum was drawn trough concentrations within 15 to 45 minutes before the fourth vancomycin dose. One-way ANOVA test showed a significantly higher trough level of vancomycin among females, patients older than 50 years, and CCU and CSICU admitted patients (p-value < 0.05). Spearman correlation test also showed significant correlation with the serum vancomycin trough levels, site of infection (Rho=0.406, p=0.009), age (Rho=0.341, p=0.044) and patients' admission (Rho=0.321, p=0.041). Even at body adjusted dosing, vancomycin serum trough levels varied among patients with significant variations of age, gender, site of infection and type of admission, especially CCU and CSICU, which raises the concept of dose individualization, age and gender considerations especially among critically ill patients.

Nano-sized magnetic core-shell and bulk molecularly imprinted polymers for selective extraction of amiodarone from human plasma

Nano-sized magnetic core-shell and bulk molecularly imprinted polymers for selective extraction of amiodarone from human plasma

PBPK Modeling and Simulation and Therapeutic Drug Monitoring: Possible Ways for Antibiotic Dose Adjustment

Pharmacokinetics (PK) is a branch of pharmacology present and of vital importance for the research and development (R&amp;D) of new drugs, post-market monitoring, and continued optimizations in clinical contexts. Ultimately, pharmacokinetics can contribute to improving patients’ clinical outcomes, helping enhance the efficacy of treatments, and reducing possible adverse side effects while also contributing to precision medicine. This article discusses the methods used to predict and study human pharmacokinetics and their evolution to the current physiologically based pharmacokinetic (PBPK) modeling and simulation methods. The importance of therapeutic drug monitoring (TDM) and PBPK as valuable tools for Model-Informed Precision Dosing (MIPD) are highlighted, with particular emphasis on antibiotic therapy since dosage adjustment of antibiotics can be vital to ensure successful clinical outcomes and to prevent the spread of resistant bacterial strains.

Clinical awareness of therapeutic drug monitoring among medical students—A descriptive cross-sectional study

“A doctor without effective clinical skills is a dodo knowledge.” Today’s budding medical student is tomorrow’s prolific doctor and the pillar of the health care system. The objective was to determine the level of medical students’ knowledge on therapeutic drug monitoring (TDM) and create awareness. This study was an institutional-based, descriptive cross-sectional study among the medical students and interns using self-designed, experts validated TDM questionnaire. The questionnaire was divided into Section A—Importance of TDM, Section B—Questions on the core concept, and Section C—On analysis, interpretation, measuring, monitoring, and limitations of TDM. We scored the outcomes for the framed positive and negative questions. On analyzing the grading of scores of students and interns, 11.3% (44/390) scored excellently, 59.5% (232/390) showed a good response, and 29.2% (114/390) reciprocated with a poor grade. We performed an analysis of responses of all three categories related to “most impactful and significant clinical concepts of TDM” requiring in-depth knowledge. The knowledge in medical students, including interns' stands average. The only way to improve this knowledge deficit by conducting well-designed training programs, implementing the concept of TDM so the students are made aware at the undergraduate level and become productive clinically.

Utility, promise, and limitations of liquid chromatography‐mass spectrometry‐based therapeutic drug monitoring in precision medicine By Vanessa P. Gaspar, Sahar Ibrahim, René P. Zahedi and Christoph H. Borchers

Drug pharmacodynamics is monitored by directly measuring physiological indices of therapeutic response. For many drugs, however, methods for the direct measurement of a drug’s effect are either not available or not sufficiently sensitive. In these cases, the percentage of a drug, or its active moiety that actually reaches the systemic circulation and becomes available to its target, known as the drug bioavailability, has become the most accepted indicator of efficacy. This explains the importance of therapeutic drug monitoring (TDM), which is the analysis, assessment, and evaluation of the circulating concentrations of drugs in serum, plasma, or whole blood in order to ensure that the patient's drug concentrations are within the established therapeutic range for the respective indication. In this month’s special feature, Christoph Borchers and co-workers review the advances, challenges, and limitations of the existing repertoire of TDM methods, and discuss future opportunities for TDM-based precision medicine. Dr. Borchers is Professor of Oncology in Faculty of Medicine at McGill University (Montreal Canada). His research involves the improvement, development, and application of proteomics and metabolomics technologies, especially quantitative techniques for clinical diagnostics.

Relapse risk following truncation of pegylated asparaginase in childhood acute lymphoblastic leukemia

Relapse risk following truncation of pegylated asparaginase in childhood acute lymphoblastic leukemia

A combined assay for quantifying remdesivir and its metabolite, along with dexamethasone, in serum.

BackgroundAs global confirmed cases and deaths from coronavirus disease 2019 (COVID-19) surpass 100 and 2.2 million, respectively, quantifying the effects of the widespread treatment of remdesivir (GS-5734, Veklury) and the steroid dexamethasone is becoming increasingly important. Limited pharmacokinetic studies indicate that remdesivir concentrations in serum decrease quickly after dosing, so its primary serum metabolite GS-441524 may have more analytical utility.ObjectivesWe developed and validated a method to quantify remdesivir, its metabolite GS-441524 and dexamethasone in human serum.MethodsWe used LC-MS/MS and applied the method to 23 serum samples from seven patients with severe COVID-19.ResultsThe method has limits of detection of 0.0375 ng/mL for remdesivir, 0.375 ng/mL for GS-441524 and 3.75 ng/mL for dexamethasone. We found low intra-patient variability, but significant inter-patient variability, in remdesivir, GS-441524 and dexamethasone levels.ConclusionsThe significant inter-patient variability highlights the importance of therapeutic drug monitoring of COVID-19 patients and possible dose adjustment to achieve efficacy.

HPLC method for the determination of antiepileptic drugs in human saliva and its application in therapeutic drug monitoring

HPLC method for the determination of antiepileptic drugs in human saliva and its application in therapeutic drug monitoring

New Analytical Method for Simultaneous Analysis of Losartan and E-3174 by HPLC in Human Plasma: Application in Pharmaceutical Science

Background: Losartan, one of the most frequently used drugs in Heart Failure (HF) treatment, could be modified for its bioavailability (BA) by generic formulations and other factors. Hence, the importance of therapeutic drug monitoring. Objective: Development and validation of a simplified analytical method using HPLC for simultaneous quantification of losartan and E-3174 in human plasma samples. The method was tested for determining the pharmacokinetics parameters of HF patients. Methods: Analytical conditions were optimized using a C18 column (4.6 X 50 mm, 3 μm. Thermo Scientific) at 25ºC. Conditions of mobile phase: a phosphate buffer (0.01M), adjusted to pH 2.5 with phosphoric acid (1M) and Acetonitrile (60:40 v/v). The flow rate was maintained at 1.2 mL/min, on a running time of 5 min and a sample injection volume of 50 μL. Absorbance for measurement of losartan and E-3174 was 200 nm. Pharmacokinetics profiles were determined with Phoenix Win- Nonlin 8.1 software in a non-compartmental model. Results: Analytical method developed and validated in this work is precise and accurate for simultaneous determination of losartan and E-3174 in human plasma samples in a range of 0.02 -10 μg/mL. In HF subjects, lower Tmax and higher Cmax for losartan and E-3174 patent than generic formulation were observed, which can be translated into less biological effect and more time to present it by the generic drug. Conclusion: The pharmacokinetic profile is dependent on the type of formulation studied (generic/ patent) hence the importance of conducting evaluations in our patients to ensure that the expected therapeutic effect is achieved with treatment administered.