Drug Dosing In Patients Research Articles

Evaluation of Drug Accuracy and Cardiac Drug Dose Accuracy in Heart Failure Patients Hospitalized in Samarinda Medika Citra Hospital

Background: Heart failure is a condition where the heart is unable to pump blood to the tissues to meet the body's metabolic needs. Heart failure has a variety of therapies and drug options available, so careful consideration is needed in selecting drugs for heart failure patients. Evaluation is carried out to identify problems with the accuracy of drug use and dosage accuracy. The many types of drugs available present its their problems in the use of drugs, especially in the selection and use of drugs that are effective, correct, and safe. Inappropriate and rational use of drugs can increase morbidity and mortality. Objectives: To determine the accuracy of drugs and heart drug dosages in patients with heart failure at the inpatient installation of Samarinda Medika Citra Hospital. Material and Methods: This research is a descriptive observational study with retrospective data collection in 2022. The sample consisted of all adult heart failure inpatients who met the inclusion criteria of 60 patients. Results: The results of the study showed that out of 60 patients, the accuracy of therapy included 93% of the correct drug and 88% of the correct dose. The heart failure drugs used were furosemide (39%), spironolactone (19%), digoxin (18%), candesartan (15%), captopril (4%), bisoprolol (3%), and lisinopril (2%). Conclusions: From the research results, it was found that 93% of the drug accuracy and 88% of the drug dose accuracy in heart failure patients.

Fatalities associated with failure to adjust drug dose in patients with renal insufficiency: A retrospective study at the Institute of Forensic Medicine in Munich (2019-2023)

Comorbidities in the elderly not only make them more susceptible to kidney disease, but also increase the risk of drug interactions due to polypharmacy. Such patients require regular kidney function tests when treated with renally excreted drugs. We conducted a retrospective study of post-mortem cases over a five- year period. Of 3040 toxicologically investigated cases, 3.8% had a history of renal failure. Thirteen deaths were directly attributable to inadequate drug dosing, 46% of which were related to lactic acidosis due to metformin accumulation. Appropriate dose adjustment could prevent fatal drug toxicity in patients with renal insufficiency.

Circadian time-dependent effects of experimental colitis on theophylline disposition and toxicity.

Drug disposition undergoes significant alteration in patients with inflammatory bowel disease (IBD), yet circadian time-dependency of these changes remains largely unexplored. In this study, we aimed to determine the temporal effects of experimental colitis on drug disposition and toxicity. RNA-sequencing was used to screen genes relevant to colitis induced by dextran sodium sulfate in mice. Liver microsomes and pharmacokinetic analysis were used to analyze the activity of key enzymes. Dual luciferase assays and chromatin immunoprecipitation (ChIP) were employed to elucidate regulatory mechanisms. RNA sequencing analysis revealed that colitis markedly influenced expression of cytochrome P450 (CYP) enzymes. Specifically, a substantial down-regulation of CYP1A2 and CYP2E1 was observed in livers of mice with colitis at Zeitgeber Time 8 (ZT8), with no significant changes detected at ZT20. At ZT8, the altered expression corresponded to diminished metabolism and enhanced incidence of hepato-cardiac toxicity of theophylline, a substrate specifically metabolized by these enzymes. A combination of assays, integrating liver-specific Bmal1 knockout and targeted activation of BMAL1 showed that dysregulation in CYP1A2 and CYP2E1 during colitis was attributable to perturbed BMAL1 functionality. Luciferase reporter and ChIP assays collectively substantiated the role of BMAL1 in regulating Cyp1a2 and Cyp2e1 transcription through its binding affinity to E-box-like sites. Our findings establish a strong link between colitis and chronopharmacology, shedding light on how IBD affects drug disposition and toxicity over time. This research provides a theoretical foundation for optimizing drug dosage in patients with IBD.

Nephrological management and drug dosing in patients with rheumatic diseases and renal insufficiency—Part 2

Nephrological management and drug dosing in patients with rheumatic diseases and renal insufficiency—Part 2

Nephrological management and drug dosing in patients with rheumatic diseases and renal insufficiency—Part 1

Nephrological management and drug dosing in patients with rheumatic diseases and renal insufficiency—Part 1

Recommended Methods of Drug Dosing Adjustment for Patients With Renal Impairment.

Since 2020, there have been changes in Food and Drug Administration guidance and in recommendations by national organizations with a focus on kidney diseases pertaining to the choice of equations used to estimate creatinine clearance and glomerular filtration rate in patients with renal impairment. This includes a recommendation by the National Kidney Foundation to avoid the use of the Cockcroft-Gault equation for drug dosing in patients with renal impairment. This commentary provides an overview of recent recommendations concerning kidney function assessment that have important implications for drug dosing in patients with renal impairment and provides suggestions for implementing these recommendations.

US FDA Postmarketing Requirements and Commitments: A Systematic Assessment of Clinical Pharmacology Studies and Their Impact on US FDA Prescribing Information.

Many of the conditions for the safe and effective use of new molecular entities (NMEs) are understood at the time of initial drug approval. However, some remaining knowledge gaps can be addressed after drug approval through postmarketing requirements (PMRs) or commitments (PMCs) established by the US Food and Drug Administration (FDA). Our objective was to conduct an assessment of clinical pharmacology-related PMRs and PMCs established at the time of approval and evaluate the impact of fulfilled PMRs and PMCs on prescription information (PI). This analysis included clinical pharmacology-related PMRs and PMCs established for NMEs approved between 2009 and 2020. Of the 1171 PMRs and PMCs, over one-third were clinical pharmacology-related. Of these, 46% were to evaluate drug interactions, 16% were to evaluate drug dosing in patients with hepatic impairment, and 10% were related to dose. The majority (57%) of PMRs and PMCs were fulfilled at the time of analysis, with a median time to fulfillment of approximately 2.3years. The majority (94%) of the fulfilled PMRs and PMCs, either with or without a PI revision, resulted in new or modified instructions for use or supported existing instructions for use. This is the first time that clinical pharmacology-related PMRs and PMCs have been catalogued and analyzed to understand their impact on PI. An understanding of the knowledge gaps that exist at the time of drug approval could inform the most effective and efficient methods for evidence generation prior to and after new drug approval.

Interpretation of Estimated Glomerular Filtration Rate

Glomerular filtration rate (GFR) plays an important role in the clinical evaluation of renal function, classification, prognosis prediction, and drug dosing in patients with acute or chronic kidney disease . Estimated GFR (eGFR) is calculated based on endogenous filtration markers, such as creatinine and cystatin C. These are useful markers, but it is necessary to understand the clinical settings in which eGFR, calculated using creatinine or cystatin C, may be less accurate. Several equations, including the Cockcroft and Gault, modification of diet in renal disease, and chronic kidney disease-epidemiology collaboration (CKD-EPI) equations, are used to calculate eGFR. The latter is most common because it has high accuracy and can predict prognosis. Recently, a new race-omitting CKD-EPI equation has been developed but further studies are required to determine whether it can be applied in clinical practice and research. Furthermore, careful use of eGFR is needed in acute kidney injury, kidney transplantation, and dialysis patients. Drug dosing must be guided by accurate GFR assessment. In addition to medical care, GFR assessment is also important for public health and research. Therefore, further studies are needed to reevaluate and develop the equations for accurate eGFR calculations.

Specifičnost antibiotske terapije kod pacijenata sa hroničnom insuficijencijom bubrega

Chronic kidney diseases cause disruption of kidney function, but also of other organs which affects both the pharmacodynamics and the pharmacokinetics of many drugs. Prescribing drugs to patients with chronic kidney disease requires knowledge of changes in absorption, distribution, metabolism and excretion of drugs and their metabolites. Avoiding nephrotoxic drugs is the most important principle that we must follow in patients with chronic kidney disease. If administration of nephrotoxic drugs is necessary, regular control of glomerular filtration rate, serum electrolyte concentration, and serum drug concentration is required if possible. The dosing of drugs in patients with chronic renal insufficiency is very delicate, both when determining the initial dose and during the maintenance dose, so it is necessary to adjust the doses for each patient individually, depending on the degree of kidney damage. For most drugs, there are recommendations from the Agency for Drugs and Medical Devices of the Republic of Serbia on how to correct the dose of the drug in chronic kidney failure. If such a recommendation does not exist, general rules are used: the maintenance dose can be adapted to kidney function by reducing the dose, extending the intervals in which the unchanged dose of the drug is administered, or a combination of these two methods. In patients with chronic kidney damage, the infection accelerates the progression towards the terminal stage, when it is necessary to apply one of the methods to replace kidney function. The infection should be treated with appropriate doses of antibiotics and/or antifungals and for a sufficient period of time. Likewise, in dialysis patients, there are various causes of infections that must also be adequately treated in order not to compromise the dialysis method or endanger the patient's life. There are recommendations for the use of antibiotics and antimycotics in these cases, which should be applied and adjusted to the individual patient. In intensive care units, in hemodynamically unstable patients with sepsis and acute chronic kidney failure, instead of intermittent hemodialysis, the following methods can be used: prolonged intermittent hemodialysis (PID) and continuous procedures - continuous venovenous hemodialysis (CVVHD), continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodiafiltration (CVVHDF). The dosage of antibiotics in these patients is specific and adjusted to the individual patient and his kidney function. Peritoneal dialysis patients in the terminal phase of chronic kidney failure are at risk of developing peritonitis. The guides describe which antibiotics are used to start the treatment of peritonitis and how the antibiotics are then adjusted, according to the causative agent, after the dialysate culture is obtained. Treatment of peritonitis is mainly by intraperitoneal administration of antibiotics, but it is also possible with oral or parenteral antibiotics, i.e. their combination. The guidelines describe the initial and maintenance doses of antibiotics and antifungals. If treatment is not started on time, the dialysis method may be compromised and the patient may die. If fungi are isolated by culture, the treatment of the patient with peritoneal dialysis is stopped and the dialysis catheter is removed, and the treatment is continued with the administration of antibiotics intravenously.

Development and Evaluation of a Physiologically Based Pharmacokinetic Model of Labetalol in Healthy and Diseased Populations.

Labetalol is a drug that exhibits both alpha and beta-adrenergic receptor-blocking properties. The American Heart Association/American Stroke Association (AHA/ASA) has recommended labetalol as an initial treatment option for the management of severe hypertension. The physiologically based pharmacokinetic (PBPK) model is an in silico approach to determining the pharmacokinetics (PK) of a drug by incorporating blood flow and tissue composition of the organs. This study was conducted to evaluate the primary reasons for the difference in PK after intravenous (IV) and oral administration in healthy and diseased (renal and hepatic) populations. A comprehensive literature search was done using two databases, PubMed and Google Scholar. Various PK parameters were screened for the development of the PBPK model utilizing a population-based PK-Sim simulator. Simulations were performed after creating building blocks firstly in healthy individuals and then in diseased patients after IV and oral administration. The disposition of labetalol after IV and oral administration occurring in patients with the hepatic and renal disease was predicted. The model was evaluated by calculating the Robs/pred ratio and average fold error (AFE), which was in the two-fold error range. Moreover, Box-whisker plots were made to compare the overall concentration of the drug in the body at various stages of disease severity. The presented model provides useful quantitative estimates of drug dosing in patients fighting against severe chronic diseases.

New anticancer drug adjustment guidelines for kidney disease attempt to filter out mess

New anticancer drug adjustment guidelines for kidney disease attempt to filter out mess

Estimation of glomerular filtration rate for drug dosing in patients with very high or low body mass index.

An accurate estimated glomerular filtration rate (eGFR) is essential in drug dosing. This study demonstrates the limitations of indexed (ml/min/1.73 m2) and de‐indexed (ml/min) eGFR based drug dosing in patients with obesity or underweight. This systematic study aimed to determine the most appropriate approach to estimate the GFR for standardized eGFR based drug dosing in these patients. (Raw) data of 12 studies were selected to investigate the accuracy and bias of both the indexed and de‐indexed estimations of the Modification of Diet in Renal Disease (MDRD) study equation and the Chronic Kidney Disease Epidemiology Collaboration equation (CKD‐EPI), and of the Cockcroft–Gault (CG) in patients with obesity or underweight. Accuracy was calculated as the proportion of eGFR values within 30% of the measured GFR (P30) using an inert tracer (e.g., iohexol, inulin, 51Cr‐EDTA, or iothalamate clearance). An accuracy of at least 80% was considered acceptable. GFR values estimated with the CG, MDRD, and CKD‐EPI differ significantly within a patient with obesity or underweight regardless of whether it is indexed or de‐indexed. All studies, with two exceptions, show that all three equations are inaccurate for patients with underweight or class II obesity (P30: 55%–94%). De‐indexing eGFR improves not or modestly the accuracy, and mostly remains below the 80% (P30: 62%–100%). CG was highly inaccurate in obese and underweight patients (P30: 7%–82%). Although these results show that CG is obsolete, the accuracy of MDRD and CKD‐EPI is low in patients with obesity or underweight and de‐indexing is not the solution. Better education and more accurate methods for appropriate drug dosing (e.g., measured GFR with inert tracer, therapeutic drug monitoring, or 24‐h creatinine clearance) are recommended.

Telavancin pharmacokinetics in patients with chronic kidney disease receiving haemodialysis.

Telavancin is a lipoglycopeptide antibiotic with limited pharmacokinetic data to guide drug dosing in patients receiving haemodialysis. This study characterized telavancin pharmacokinetics in patients receiving haemodialysis. This was a Phase IV, prospective, open-label, single-centre, crossover pharmacokinetic study (ClinicalTrials.gov: NCT02392208). Eight subjects with end-stage kidney disease requiring maintenance haemodialysis (mean ± SD: 47 ± 20 years, 69.5 ± 17.1 kg) received 5 mg/kg telavancin IV 3 h before starting a 3.5 hour haemodialysis treatment with a high-permeability haemodialyser (haemodialysis period). After a 14 day washout period, a second 5 mg/kg dose was administered post-haemodialysis (control period). Telavancin plasma concentrations were measured over a 2 day period after each dose and non-compartmental pharmacokinetic analyses were performed. The geometric mean (GM) of telavancin overall clearance was 11.2 mL/h/kg (intrinsic clearance and dialytic clearance) in the haemodialysis period and 5.9 mL/h/kg (off-haemodialysis clearance) in the control period [GM ratio (GMR) = 1.89; 90% CI: 1.70-2.10; P < 0.01]. The GM t½ was 13.1 h when haemodialysis occurred 3 h post-dosing in the haemodialysis period but extended to 20.9 h with post-haemodialysis dosing in the control period (GMR = 0.63; 90% CI: 0.54-0.73; P < 0.01). The GM of telavancin plasma concentrations removed by haemodialysis was 27.7%. The GMR of peak plasma concentration and volume of distribution of the haemodialysis period and the control period were 0.88 (90% CI: 0.79-0.98; P = 0.08) and 1.17 (90% CI: 1.05-1.30; P = 0.048), respectively. Haemodialysis with high-permeability haemodialysers removes telavancin considerably (∼⅓ of body load). Telavancin 5 mg/kg every 48 h post-haemodialysis dosing is recommended, but dose adjustments may be warranted if haemodialysis starts within 3 h of telavancin administration.

Antimicrobial Dosing in Specific Populations and Novel Clinical Methodologies: Kidney Function.

Kidney function is a common parameter used to define antimicrobial drug dosage and frequency of administration. Several methods exist to measure kidney function but for pragmatic reasons rely on estimated kidney function equations based on the endogenous biomarker serum creatinine and common clinical variables. Current regulatory guidance on the design of studies in patients with abnormal kidney function in the United States also recommend consideration of estimated kidney function for this reason. Over the past few decades, alternate endogenous biomarkers, administration of exogenous biomarkers for noninvasive measurement, use of probe substrates to characterize individual kidney drug clearance pathways, modifications to conventional equations to account for time-varying clearance, and improved clinical trial modeling and simulation to factor in these uncertainties have occurred. Furthermore, major changes to kidney replacement therapy delivery in the outpatient, inpatient, and at-home setting are occurring. Antimicrobial drug dose adjustment in this diverse population is complex and in a state of flux due to technical innovations. Over-reliance on kidney function estimates to guide drug dosing in patients with infectious diseases can bias underdosing especially among the acutely ill. A holistic approach to drug dose adjustment in patients with abnormal kidney function is necessary to optimize clinical outcomes.

The Glomerular Filtration Rate Estimators in the Pharmacokinetic Modelling in Acute Kidney Injury: An Observational Study.

The glomerular filtration rate (GFR), according to which the drug dose for patients with chronic kidney disease (CKD) is adjusted, is computed with estimators (eGFR) that are developed specifically for CKD. These particular types of estimators are also used in population pharmacokinetic (pop PK) modelling in drug development. Similar approaches without scientific validation have been proposed for patients with acute kidney injury (AKI), yet it is uncertain which specific eGFR should be used for drug dosing or in pop PK models in patients with AKI. In our study, we included 34 patients with AKI and vancomycin (VCM) treatment, and we built both individual PK and pop PK (non-linear mixed-effects, one-compartment) models to see which eGFR estimator is the best covariate. In these models different eGFRs (Cockcroft-Gault, MDRD, CKD-EPI 2009, Jelliffe and Jelliffe, Chen et al., and Yashiro et al. 2013) were used. We included six additional patients to validate the final pop PK model. All eGFRs underrate the true renal clearance in the AKI, so we created pop PK models for VCM dosing in AKI with all eGFRs, to discover that the most accurate model was the one with the Cockcroft-Gault estimator. Since the eGFRs underestimate the true renal clearance in AKI, they are inaccurate for clinical drug dosing decisions, with the exception of the Cockcroft-Gault one, which is appropriate for the pop PK models intended for drug development purposes in AKI.

Comparison of Equations To Estimate Glomerular Filtration Rate and Their Impact on Frequency of Cisplatin-associated Acute Kidney Injury.

Accurate estimation of kidney function is essential for patient selection and drug dosing in patients with cancer. eGFR equations are necessary for decision making and monitoring. Our aim was to identify which of these equations-estimated creatinine clearance (eCrCl) by Cockcroft-Gault (CG), eGFR by Modification of Diet in Renal Disease (eGFRMDRD), CKD Epidemiology Collaboration (eGFRCKD-EPI) or the recently proposed Janowitz-Williams equation (eGFRJ-W)-would be most suitable for GFR estimation among patients with cancer receiving cisplatin. We assembled a cohort of 5274 patients with cancer treated with cisplatin-based chemotherapy at two large cancer centers. We ascertained the frequency of cisplatin-associated AKI (C-AKI) defined as a ≥0.3 mg/dl rise in serum creatinine over baseline. We compared baseline eGFR and eCrCl using Bland-Altman (B-A) plots, coefficients of variation (CV), and concordance correlation coefficients. We calculated the positive predictive value (PPV), negative predictive value (PPV), accuracy, and area under the curve (AUC). Patients were predominantly middle aged (median 58 years, IQR 49-66 years), overweight (median BMI 26.2, IQR 23.1-29.8 kg/m2), and White (88%), with a median baseline creatinine of 0.8 mg/dl and median cisplatin dose of 99 mg. C-AKI developed in 12% of the cohort. eGFRCKD-EPI had the highest PPV and AUC. eGFRCKD-EPI and eGFRMDRD, along with their BSA-modified counterparts, had the closest agreement with the lowest CV (7.2, 95% CI, 7.0 to 7.3) and the highest concordance. C-AKI was lowest when using eGFRCKD-EPI to define eGFR ≥60 ml/min per 1.73 m2. On the basis of its superior diagnostic performance, eGFRCKD-EPI should be used to estimate GFR in patients being considered for cisplatin-based chemotherapy.

ONE FOR THE MONEY, TWO FOR THE ECMO: A SUCCESSFUL PHARMACOTHERAPEUTIC STRATEGY FOR VANCOMYCIN-RESISTANT ENTEROCOCCUS FAECIUM AND CANDIDA GLABRATA FUNGEMIA IN VENO-VENOUS EXTRACORPOREAL MEMBRANE OXYGENATION AND CONTINUOUS RENAL REPLACEMENT

SESSION TITLE: Fellows Critical Care Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) are modalities with a relative paucity in understanding of the disposition of antimicrobials, and even less for when used simultaneously. Preliminary investigations have demonstrated that ECMO leads to pharmacokinetic changes, which include alterations in volume of distribution, drug clearance, and sequestration by the circuit.1 CASE PRESENTATION: Our patient was a 66-year-old-male with a history of alcohol use disorder, transferred to our hospital for acute respiratory distress syndrome due to influenza A pneumonia with superimposed bacterial pneumonia, cannulated for venous-venous ECMO. Encephalopathy, atrial fibrillation, pulmonary embolisms, distributive shock, and anuric acute kidney injury requiring CRRT complicated his course. Following a prolonged course, blood cultures were obtained and Candida glabrata and vancomycin resistant Enterococcus faecium (VRE) were isolated. We initiated high dose micafungin 150 mg IV q 24 h, high dose, high frequency daptomycin 10 mg/kg IV q 24 h. An echocardiogram, Ophthalmology consult, and repeat blood cultures were also requested to document clearance of fungemia and bacteremia. A trans-esophageal echocardiogram was performed, without evidence of masses or vegetations. Fundal exam did not show any signs of fungal endophthalmitis. Repeat cultures were without growth, all existing IV lines were exchanged except for ECMO cannulas. His leukocytosis began to downtrend, and he became afebrile after start of antimicrobial therapy. Given that his most likely source of infection was line associated, a two-week antimicrobial course for uncomplicated fungemia and bacteremia was recommended. DISCUSSION: We hope to add to the limited data on daptomycin and micafungin dosing strategies for patients on ECMO and CRRT. A thorough understanding of the altered pharmacokinetics is essential to apply in these complex patients. Daptomycin has a low volume of distribution, and it is highly protein bound, making it less likely to be affected by ECMO. It is known that for patients on CRRT, daptomycin dosing q 24 h up to 12 mg/kg provides comparable drug exposure to patients with a CrCl = 30 mL/min,2 therefore, a dose of 10 mg/kg q 24 h was deemed appropriate to treat our patient. Creatinine kinase was monitored weekly without any changes from baseline. Micafungin is highly protein bound, minimally renally cleared and does not require CRRT dose adjustment. CONCLUSIONS: Prior studies in ECMO patients have shown decreased plasma concentrations due to drug degradation and increased clearance,3 which warrant a dose increase. As such, micafungin 150 mg q 24 h was used in our patient. This report highlights the need for more research on optimal dosing strategies of antimicrobials in this patient population. Reference #1: Cheng V, Abdul-Aziz MH, Roberts JA, Shekar K. Optimising drug dosing in patients receiving extracorporeal membrane oxygenation. J Thorac Dis. 2018;10(Suppl 5):S629-S641. Reference #2: Xu X, Khadzhynov D, Peters H, et al. Population pharmacokinetics of daptomycin in adult patients undergoing continuous renal replacement therapy. Br J Clin Pharmacol. 2017;83(3):498-509. Reference #3: Watt KM, Cohen-Wolkowiez M, Williams DC, et al. Antifungal extraction by the extracorporeal membrane oxygenation circuit. J Extra Corpor Technol. 2017;49(3):150-159. DISCLOSURES: No relevant relationships by M. Gabriela Cabanilla, source=Web Response No relevant relationships by Nicholas Villalobos, source=Web Response

Using a pharmacogenetic clinical decision support system to improve psychopharmacotherapy dosing in patients with affective disorders.

Although pharmacogenetic tests provide the information on a genotype and the predicted phenotype, these tests do not themselves provide the interpretation of data for a physician. Currently, there are approximately two dozen pharmacogenomic clinical decision support systems (CDSSs) used in psychiatry. Implementation of the CDSSs forming the recommendations on drug and dose selection according to the results of pharmacogenetic testing is an urgent task. Fulfillment of this task will allow increasing the efficacy of therapy and decreasing the risk of undesirable side effects. The study included 118 male patients (48 in the main group and 70 in the control group) with affective disorders and comorbid alcohol use disorder. To evaluate the efficacy and safety of therapy, several international psychometric scales and rating scales to measure side effects were used. Genotyping was performed using the real-time polymerase chain reaction with allele-specific hybridization. Pharmacogenetic testing results were interpreted using free software PGX2 (LLE Medicine, Russian Federation, Biomedical Cluster of Skolkovo, Moscow Innovative Cluster; www.pgx2.com). The statistically significant differences across the scores on psychometric scales were revealed. For instance, the total score on the Hamilton Rating Scale for Depression by day 9 was 9.0 [8.0; 10.0] for the main group and 11.0 [10.0; 12.0] (p<0.001) for the control group and by day 16 it was 4.0 [2.0; 6.0] for the main group and 14.0 [13.0; 14.0] (p<0.001) for the control group. The UKU Side-Effect Rating Scale (UKU) also revealed a statistically significant difference. The total score on the UKU scale by day 9 was 4.0 [4.0; 5.0] for the main group and 5.0 [5.0; 6.0] (p<0.001) for the control group and by day 16 this difference grew significantly: 3.0 [0.0; 4.2] for the main group and 9.0 [7.0; 11.0] (p<0.001) for the control group. Pharmacogenetic-guided personalization of the drug dose in patients with affective disorders and comorbid alcohol use disorder can reduce the risk of undesirable side effects and pharmacoresistance. It allows recommending the use of pharmacogenetic CDSSs for optimizing drug dosage.

Management of major bleeding in patients treated with direct oral anticoagulants: from experience to standardized protocols

Evaluation of clinical-laboratory-therapeutic management and related clinical outcomes (thrombotic-hemorrhagic complications) of patients undergoing treatment with direct oral anticoagulants (DOACs) during major bleeding. This is a two-year observational retrospective study. 27 cases of major bleeding in patients undergoing a therapy with DOACs presented to the Emergency Department of Arcispedale Santa Maria Nuova (Reggio Emilia Hospital). 16 cases (59%) underwent reversal of anticoagulation treatment: 19% using specific reversal therapy (idarucizumab) and 81% using non-specific agents [4-factor prothrombin complex concentrate (4F-PCC)]. Routine laboratory data were available for all the cases, but only for some patients it was possible to obtain the plasma dosage of the oral anticoagulant. Laboratory data confirm rapid correction of activated partial thromboplastin time within one hour from the reversal of anticoagulation with idarucizumab. The absence of correlation between standard blood tests and plasma drug dosage in patients treated with factor Xa Inhibitors was confirmed too. The management of major bleeding during treatment with DOACs using reversal therapy (idarucizumab) and non-specific reversal agent (4F-PCC) showed minimal thrombotic (0.3%) and hemorrhagic (0.3%) complications at 90 days; no events occurred after 6 months.

Using Kinetic eGFR for Drug Dosing in AKI: Concordance between Kinetic eGFR, Cockroft-Gault Estimated Creatinine Clearance, and MDRD eGFR for Drug Dosing Categories in a Pilot Study Cohort

Introduction: Drug dosing in patients with acute kidney injury (AKI) is based on the Cockroft-Gault (CG) equation-derived estimated Creatinine clearance (CGeCrCl) for historical reasons due to the lack of a validated method for estimating glomerular filtration rate (GFR) when Cr is rapidly changing. The kinetic equation (kinetic estimated GFR [KeGFR]) estimates GFR for the nonsteady-state Cr level. It is being validated in patient cohorts and could potentially be used for drug dosing when the Cr level is in the nonsteady state. Objective: The aim of the study was to measure the concordance and the degree of agreement between KeGFR-, CGeCrCl, and MDRD eGFR-based drug dosing categories in patients with nonsteady Cr levels. Methods: In the pilot study published previously, 80 adult patients with a significant change in Cr level after admission to the acute medical ward were classified as per the Acute Kidney Injury Network (AKIN) criteria and compared to a KeGFR-based criterion. The CG equation and the MDRD equation were applied retrospectively to the same dataset, and the concordance of the eGFR categories between the 3 methods was studied. The 3 eGFR categories (<30, 30–49, and >50 mL/min) were chosen to reflect the frequently used drug dosing categories in patients with renal impairment. Results: The concordance between CGeCRCL and KeGFR for drug dosing categories was only 62%, with 27 (90%) of the 30 discordant subjects falling into a higher eGFR category when KeGFR was used. The agreement between KeGFR and CGeCrCl was also unsatisfactory. There was better concordance (75%), but the agreement was also not satisfactory between MDRD eGFR and KeGFR for the drug dosing categories. Conclusions: In AKI, compared to CGeCrCL, using KeGFR may affect drug dosing significantly by changing the eGFR category. Further studies of KeGFR for drug dosing will need therapeutic drug monitoring and pharmacokinetic studies for validation.