Dose Adjustment In Patients Research Articles

P508 Dose adjustment in patients with moderate to severe ulcerative colitis: results from year 3 of the UNIFI maintenance study long-term extension

Abstract Background The UNIFI randomized-withdrawal maintenance study and long-term extension (LTE) evaluated the safety and efficacy of subcutaneous (SC) ustekinumab (UST) in patients with moderately to severely active ulcerative colitis (UC) who had responded to intravenous (IV) UST during induction. We evaluated the efficacy of UST dose adjustment through Week (Wk) 152 of the long-term extension (LTE). Methods 523 intravenous UST induction responders were randomized to SC maintenance therapy (SC placebo [PBO], n=175; UST 90mg every 12 weeks [q12w], n=172; or UST 90mg q8w, n=176). 284 UST patients who completed wk44 entered the LTE. PBO patients were discontinued after wk44 unblinding. Based on the investigator’s clinical judgement of their UC disease activity, patients in the LTE were eligible to receive dose adjustment starting at Wk 56: PBO to q8w, q12w to q8w, and q8w to q8w (sham adjustment). Patients in PBO or q8w groups were only eligible for dose adjustment or sham dose adjustment before unblinding. Patients were assessed for symptomatic remission, partial Mayo scores, and inflammatory markers ≥16 wks after dose adjustment. Results Overall, 60 patients (42.6%) in the q12w group and 40 patients (28.0%) in the q8w group underwent dose adjustment (or sham dose adjustment) prior to Wk 156 of the LTE; 51 and 39 patients in each group, respectively, had dose adjustment at Wk 136 or before, providing≥16 wks of data after dose adjustment (Table). At the first visit ≥16 weeks after dose adjustment, 70.6% of patients who adjusted from q12w to q8w and 61.5% who sham dose adjusted from q8w to q8w were in symptomatic remission. At the time of dose adjustment, 27/51 patients (52.9%) in the q12w group and 25/39 patients (64.1%) in the q8w group were in symptomatic remission. Of those who were in symptomatic remission at the time of dose adjustment, the majority (81.5% and 68.0%, respectively) were maintained in symptomatic remission at the first visit ≥16 wks after dose adjustment. Of those who were not in symptomatic remission at the time of dose adjustment, 58.3% and 50.0%, respectively, were in symptomatic remission at the first visit ≥16 wks after dose adjustment. Mean partial Mayo scores and CRP levels decreased after dose adjustment (Table). Conclusion Patients may benefit from UST dose adjustment to q8w.

Osteoporosis treatment with risedronate: a population pharmacokinetic model for the description of its absorption and low plasma levels.

Risedronate exhibits very low plasma levels and high residence time in the body. The aim of this study is to describe and explain the risedronate transit through the body. The impact of volunteers' characteristics on the kinetics of risedronate is also investigated. Simulations are used to compare the risedronate plasma levels after different dosage schemes and assess the need for dose adjustment in patients with impaired kidney functionality. Plasma concentration-time data were obtained from a four-period, two sequence, single-dose, crossover bioequivalence study. The effects of several covariates (e.g., weight, albumin, creatinine, alkaline phosphatase, and calcium) on model parameters were tested. Non-linear mixed-effect modeling was applied and a variety of models were evaluated placing emphasis on absorption and disposition properties. The modeling and simulation work was implemented in MonolixTM 2020R1. Following oral administration, the kinetics of risedronate was best described by a two-compartment model with lag time, first-order absorption, and elimination. The extent of peripheral distribution (i.e., bones) was found to be remarkably high. No volunteer characteristics were identified to affect significantly the disposition of risedronate. Using simulations, risedronate plasma profiles were obtained for different doses and frequencies of administration. The absorption and disposition kinetics of risedronate were successfully characterized. Simulations revealed the high discrepancy in the concentration levels observed after different dosage regimens, implying the safety profile of risedronate. In virtual patients with renal impairment, the blood levels of risedronate are increased, but not in an extent requiring dose adaptation.

Pharmacogenetics and adhd treatment outcomes in the danish population-based IPSYCH sample

IntroductionPharmacogenetics (PGx) studies genetic variance and related differences in drug outcomes. The aim of PGx testing is to increase therapy efficacy and safety, by applying e.g. dose adjustments in patients with a specific geno- or phenotype. PGx guidelines for psychotropic drugs are available (PGx drugs), including atomoxetine used in the treatment of attention deficit hyperactivity disorder (ADHD). In Denmark, broad implementation of PGx is currently still low, possibly due to the lack of population-based studies investigating the real-world impact of PGx variability.ObjectivesThe aim of this study is to investigate the association of PGx variability (patients’ genotype/phenotype) in users of atomoxetine and different treatment outcomes in a large population-based sample of individuals with ADHD.MethodsThis study will use data of the large Danish population-based iPSYCH case-cohort study sample including information on genetic variants, prescription drug use and outcome data, e.g. psychiatric and somatic hospitalizations and death. The study population comprises all individuals diagnosed with ADHD born 1981-2005 with at least one prescription for atomoxetine between 1995 and 2016. All individuals will be categorized according to their CYP2D6 phenotypes. We will perform Cox regression analysis to estimate the hazard ratios comparing the rates of the different outcomes in people with different phenotypes adjusted for a number of confounding factors.ResultsWe have identified approximately 20,000 individuals with ADHD, of whom an estimated 10-20% have filled at least one prescription of atomoxetine.ConclusionsWe expect results in the beginning of 2021.DisclosureWe thank the iPSYCH consortium, in specific the iPSYCH PI’s (Merete Nordentoft, Anders Børglum, Preben B. Mortensen, Ole Mors, Thomas Werge and David M. Hougaard). The iPSYCH project is funded by the Lundbeck Foundation Denmark and the universities and un

Dosing of Direct Oral Anticoagulants in Patients with Moderate Chronic Kidney Disease in US Clinical Practice: Results from the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF II).

Direct oral anticoagulants (DOACs) have partial renal clearance and generally require dosage adjustments based on renal function. While current US and European guidance recommends dose adjustments in patients with moderate chronic kidney disease (CKD), it is unclear how often this is done appropriately in routine clinical practice. We examined rates of appropriate and inappropriate dosing in patients with atrial fibrillation (AF) and moderate CKD, as determined by creatinine clearance (CrCl) of 30-50 mL/min calculated with the Cockcroft-Gault formula. Descriptive statistics were used to describe the rate of appropriate and inappropriate dosing as well as event rates. Among 1134 patients (8.5% of the overall ORBIT-AF II registry) with AF and CrCl 30-50 mL/min, the median age was 82 (25th, 75th percentile: 78, 86), 38% were male, and the median CHA2DS2VASC score was 4 (25th, 75th percentile: 4, 5). At baseline, more than one-third (34%) of patients with moderate CKD were inappropriately dosed with DOACs. When evaluating the specific prescribed doses in those with moderate CKD, 15% (N = 170/1134) were underdosed, 66% (743/1134) were appropriately dosed, and 20% (N = 221/1134) were overdosed. There were no significant differences in comorbid medical conditions between patients with moderate CKD who were appropriately and inappropriately dosed with a DOAC. In routine clinical practice, prescribing of DOACs in patients with AF with moderate CKD is often inconsistent with drug labeling, with up to one-third of patients being inappropriately dosed.

Capmatinib (Tabrecta™)

Capmatinib (Tabrecta™)

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.

Drug Utilization Evaluation Study and Dose Adjustment in Patients with Kidney Disease in Tertiary Care Hospital

INTRODUCTION: Kidney disease is becoming a worldwide public health problem with an increase in incidence and prevalence, poor outcomes and high cost. Rational prescription is necessary in kidney disease patients. These patients are at higher risk of developing drug related problems since they need complex therapeutic regimens that include comorbid conditions like diabetes mellitus, hypertension, coronary artery disease and infection that require frequent monitoring and dosage adjustment. Inappropriate use of medications can increase adverse drug effects, which can be reflected by excessive length of hospital stays, excessive health care utilization and cost. OBJECTIVES: The objective of the study was to assess, evaluate and analyze the prescribing pattern of drugs in kidney disease and their dose adjustments in medicine and emergency department of tertiary care teaching hospital. METHODOLOGY: The study was conducted for a period of 6 months. Ethical clearance was obtained from Institutional Ethical Committee of S C S College of Pharmacy, Harapanahalli. Collected data was analyzed to identify the current prescribing trend and dosage regimen in the management of renal failure patients and to know whether the prescribing rationality was obtained in Medicine and Emergency unit in hospital by using KDIGO guidelines. RESULTS: A total of 140 patients were enrolled in the study according to the inclusion criteria in which 104 were males and 36 were females. 134 CKD cases and 6 AKI cases were found. In the study, 105 (75%) patients were hypertensive, 62 (44.28%) patients were anemic, 54 (38.57%) patients were diabetic and dyslipidemia was associated with 21 (15%) patients. 87 patients were on hemodialysis. On the basis of ATC classification of drugs, cardiovascular system (35.7%) class of drugs was the commonly prescribed followed by drugs for alimentary tract and metabolism (25.97%), anti-infective (10.11%) and blood and blood forming agents (7.97%). Out of 1028 studied drugs, only 105 (10.21%) required dose adjustment where 76 (72.38%) were adjusted and 29 (27.61%) were not adjusted. CONCLUSION: This study illustrates the need for proper dose adjustment and drug utilization pattern in patients with renal failure. Appropriate dosing of antibiotics as well as other drugs, including narrow therapeutic drugs play a vital role in preventing dose related adverse reactions and toxicities. This study will provide an outline for management strategies and will influence the decision making process in clinical practice.

Dose adjustment of antidiabetic medications in chronic kidney disease.

ABSTRACTPurpose:The purpose of this study is to identify whether Internal Medicine house-staff (IMHS) have awareness and knowledge about the correct dosage of antidiabetic medications for patients with chronic kidney disease (CKD), as dosing errors result in adverse patient outcomes for those with diabetes mellitus (DM) and CKD.Methods:There were 353 IMHS surveyed to evaluate incorrect level of awareness of medication dose adjustment in patients with CKD (ILA) and incorrect level of knowledge of glomerular filtration rate level for medication adjustment (ILK-GFR) for Glipizide, Pioglitazone, and Sitagliptin.Results:Lack of awareness and knowledge was high, with the highest for Pioglitazone at 72.8%. For ILA, the percentages were: Pioglitazone: 72.8%, Glipizide: 43.9%, and Sitagliptin: 42.8%. For ILK-GFR, the percentages were: Pioglitazone: 72.8%, Glipizide: 68.3%, and Sitagliptin: 65.4%.Conclusions:IMHS have poor awareness and knowledge for antidiabetic medication dose adjustment in patients with DM and CKD. Both Electronic Medical Rerecord best practice advisory and physician–pharmacist collaborative drug therapy management can enhance safe drug prescribing in patients with CKD. In addition, IMHS’s practice for antidiabetic medication dose adjustment was better with Nephrology exposure. A formal didactic educational training during medical school and residency for antidiabetic medication dose adjustment in patients with DM and CKD is highly encouraged to prevent medication dosing errors and to more effectively and safely allow IMHS to manage complex treatment regimens.

Antiseizure Medication use in Gastric Bypass Patients and Other Post-Surgical Malabsorptive States.

Healthcare professionals are encountering an increasing number of patients who have undergone bariatric surgeries. Antiseizure medications (ASM) have a narrow therapeutic window, and patients with malabsorptive states receiving ASM present a complex situation as the pharmacokinetics of these drugs have only been studied in patients with a normal functioning gastrointestinal tract. Patients with malabsorptive states may have altered pharmacokinetics, and there is limited literature to guide drug selection and dosage adjustment in patients with malabsorptive states. This review highlights pharmacokinetic parameters of common ASM, and considerations when managing patients on them. The effect of pH, lipophilicity, absorption, and metabolism should be taken into account when selecting and managing ASMs in this patient population. Based on these parameters, levetiracetam, and topiramate have fewer issues referable to absorption related to bariatric surgery while oral formulations of phenytoin, carbamazepine, oxcarbamazepine and valproic acid have reduced absorption due to effects of bariatric surgery based on the pharmacokinetic properties of these medications. Extended formulations should be avoided and ASM serum concentrations should be checked before and after surgery. The care of patients with epilepsy who are scheduled to undergo bariatric surgery should be guided by a multidisciplinary team including a pharmacist and a neurologist who should be involved in the adjustment of the ASMs throughout the pre-surgical and post-surgical periods.

Tinzaparin Safety in Patients With Cancer and Renal Impairment: A Systematic Review.

Low-molecular-weight heparins are approved for primary and secondary venous thromboembolism prevention. Tinzaparin is the low-molecular-weight heparin with the highest average molecular weight. The purpose of this systematic review is to provide an update regarding the safety profile of tinzaparin, prescribed either as a prophylactic or as a therapeutic regimen for venous thromboembolism in special populations, including cancer patients and patients with renal impairment. We identified prospective studies up to August 2020 reporting safety outcomes for cancer patients and patients with renal impairment on tinzaparin regimens. In patients with cancer major bleeding rates fluctuated between 0.8% and 7%. Patients on tinzaparin exhibited significantly lower rates of clinically relevant nonmajor bleeding events in comparison with those on vitamin K antagonists. Bioaccumulation of tinzaparin was not correlated with age, body weight or creatinine clearance. Periodic administration of either prophylactic or therapeutic doses of tinzaparin did not result in bioaccumulation, even in patients with severe renal impairment and creatinine clearance < 20 ml/min. Major bleeding rates for non-cancer patients with renal impairment on prophylactic tinzaparin regimens were 0%. Non-cancer patients with renal impairment on therapeutic tinzaparin regimens exhibited major bleeding in 0 to 3.4% of cases; major bleeding rates were higher for cancer patients with renal impairment on therapeutic tinzaparin regimens (4.3 to 10%). Tinzaparin can be used without dose adjustment in patients with severe renal impairment and creatinine clearance > 20 ml/min. Tinzaparin represents a safe choice for special populations at increased risk for thrombosis and bleeding.

1318. Pharmacokinetics and Safety of Cefepime-Taniborbactam (formerly Cefepime/VNRX-5133) in Subjects with Renal Impairment

BackgroundTaniborbactam is a novel, non-ß-lactam, ß-lactamase inhibitor with activity against serine (Class A, C, D) and metallo (Class B) ß-lactamases including epidemiologically important carbapenemases. Both cefepime and taniborbactam are predominantly renally excreted and are likely to require dose adjustment in patients with renal impairment and end-stage renal disease (ESRD). The current study was designed to evaluate the pharmacokinetics and safety in patients with renal impairment and ESRD.MethodsThis was a Phase 1, open-label study in subjects with normal renal function (eCLCR ≥ 90 mL/min) matched to subjects with mild, moderate, and severe renal impairment (eGFR 60-89, 30-59, and < 30 mL/min/1.73m2, respectively), and patients with ESRD on hemodialysis. Subjects received a single dose of cefepime 2 g and taniborbactam 500 mg; subjects with ESRD received a single dose before HD and after a 9 day washout period, following HD. PK parameters including AUC0-inf and total body clearance (CL) were evaluated. Safety assessments included adverse events (AEs), vital signs, clinical laboratory evaluations, electrocardiograms, and physical examinations.ResultsThirty-three subjects were enrolled; 67% male, 58% white and 39% black/African Americans. Median age and BMI were 55.0 years and 29.5 kg/m2, respectively. For both cefepime and taniborbactam, exposures increased, and CL decreased with increasing renal impairment (see Table). The hemodialysis extraction ratio was 49.7% and 47.4% for taniborbactam and cefepime respectively. No safety signals were observed and there were no serious adverse events.Table ConclusionCefepime and taniborbactam CL is similarly reduced with varying degrees of renal impairment. Dialysis removes a high fraction of both drugs. Dose adjustments recommended for cefepime are appropriate for taniborbactam.DisclosuresBrooke Geibel, BS, Venatorx Pharmaceuticals (Employee, Shareholder) James A. Dowell, PhD, Venatorx Pharmaceuticals (Independent Contractor) Thomas C. Marbury, MD, Venatorx Pharmaceuticals (Independent Contractor) William Smith, MD, Venatorx Pharmaceuticals (Independent Contractor) Paul C. McGovern, MD, Venatorx Pharmaceuticals (Employee) Cynthia Richards, MD, Venatorx Pharmaceuticals (Independent Contractor) Tim Henkel, MD, PhD, Venatorx Pharmaceuticals (Employee, Shareholder)

Drug use evaluation of cefepime at Khartoum North Teaching Hospital in Sudan.

Cefepime is essentially used for life-threatening infections. Although overutilisation of antibiotics is strongly discouraged around the world, they are still overused in developing countries including Sudan. This study aims to evaluate the rational use of cefepime at Khartoum North Teaching Hospital-Sudan. A retrospective cross-sectional, hospital-based study was conducted in the internal medicine ward at Khartoum North Teaching Hospital from August/2018 to April/2019. The study covered medical records of adult patients receiving cefepime during the study period. Patient's data were analysed using simple descriptive statistics (frequency and percentage) and inferential statistics (logistic regression) to describe the relationship between dependent and independent variables. P≤.05 was considered statistically significant. Out of 90 patients, only 16.7% of patients were tested for antibiotic sensitivity. Cefepime was prescribed to 50% and 23.3% of patients for the treatment of UTIs/post-dialysis and sepsis, respectively. Although the majority of patients (72.2%) received cefepime with appropriate indication, only 21.1% and 15.6% received the drug with appropriate dose and duration, respectively. Cefepime had been prescribed appropriately in a correct dose, duration, and indications for only 7.8% of patients. The vast majority of patients tested for kidney functions had elevated creatinine levels (96.1%); however, cefepime dose had been adjusted for only 4.1% of them. This study highlighted the irrational use of cefepime regarding inappropriate dose, duration, and inadequate antibiotic sensitivity tests. A lack of attention to dosage adjustment in patients with renal impairment had been observed. Positive clinical outcome was significantly associated with antibiotic sensitivity test.

Safety and efficacy of omadacycline for treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections in patients with mild-to-moderate renal impairment

Many antibiotics require dosage adjustments in patients with renal impairment. In Phase III studies, omadacycline was non-inferior to moxifloxacin and linezolid in adults with community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI), respectively. This analysis evaluated efficacy and safety measures from three omadacycline studies by patient renal function. Patients were stratified as having normal renal function (creatinine clearance >89 mL/min), mild renal impairment (creatinine clearance 60-89 mL/min) or moderate renal impairment (creatinine clearance <60 mL/min); creatine clearance ≤30 mL/min (severe renal impairment) was an exclusion criterion. Efficacy endpoints were clinical success at the early clinical response (ECR) and post-treatment evaluation (PTE) time-points. Safety was evaluated as treatment-emergent adverse events (TEAEs) and laboratory measures. This subgroup analysis included 773 patients with CABP and 1339 patients with ABSSSI in intent-to-treat (ITT) and modified ITT populations, respectively. Clinical success rates were high at ECR and PTE across the studies (CABP 75-90%; ABSSSI 74-95%), and broadly similar between treatments, irrespective of renal function. Rates of TEAEs in patients with ABSSSI ranged from 33% to 52%, and were similar across renal function groups. In patients with CABP, higher rates were observed in patients with moderate renal impairment (56-61%) compared with patients with normal renal function or mild renal impairment (35-49%). The most common TEAEs were nausea and vomiting. Clinical success was similar across renal function groups, indicating no notable difference in the efficacy of omadacycline in patients with mild or moderate renal impairment. Omadacycline and comparators displayed similar safety profiles. CLINICALTRIALS. OPTIC (NCT02531438); OASIS-1 (NCT02378480); OASIS-2 (NCT02877927).

1259: Early vs. Late ß-Lactam Antibiotic Dose Adjustment in Patients With Sepsis and Acute Kidney Injury

Aldardeer, Namareq1; Alghalbi, Maram2; Alharbi, Emad3; Alajmi, Ghada4; Aljabri, Ahmad3; Aljawadi, Mohammad5; Almangour, Thamer5; Alhammad, Abdullah5 Author Information

Дозирование низкомолекулярных гепаринов и анти-фактор Xa активность у пациентов с новой коронавирусной инфекцией COVID-19.

Дозирование низкомолекулярных гепаринов и анти-фактор Xa активность у пациентов с новой коронавирусной инфекцией COVID-19.

Evaluation of Voriconazole CYP2C19 Phenotype-Guided Dose Adjustments by Physiologically Based Pharmacokinetic Modeling.

Controversy exists regarding dose adjustment in patients treated with voriconazole due to the severity of the infections for which it is prescribed. The Dutch Pharmacogenetics Working Group (DPWG) recommends a 50% dose increase or decrease for cytochrome P450 (CYP)2C19 ultrarapid (UM) or poor (PM) metabolizers, respectively. In contrast, for the previous phenotypes, the Clinical Pharmacogenetics Implementation Consortium (CPIC) voriconazole guideline only recommends a change of treatment. Based on observed data from single-dose bioequivalence studies and steady-state observed concentrations, we aimed to investigate voriconazole dose adjustments by means of physiologically based pharmacokinetic (PBPK) modeling. PBPK modeling was used to optimize voriconazole single-dose models for each CYP2C19 phenotype, which were extrapolated to steady state and evaluated for concordance with the therapeutic range of voriconazole. Based on optimized models, dose adjustments were evaluated for better adjustment to the therapeutic range. Our models suggest that the standard dose may only be appropriate for normal metabolizers (NM), although they would benefit from a 50-100% loading dose increase. Intermediate metabolizers (IMs) and PMs required a daily dose reduction of 50 and 75%, respectively. Rapid metabolizers (RMs) and UMs required a daily dose increase of 100% and 300%, respectively. The prescription of voriconazole in clinical practice should be personalized according to the CYP2C19 phenotype, followed by therapeutic drug monitoring of plasma concentrations to guide dose adjustment.

IN-VITRO EVALUATION OF DIFFERENT AVAILABLE BRANDS OF DEXLANSOPRAZOLE MR CAPSULES

Dexlansoprazole delayed release is a newly developed class of Proton Pump Inhibitor (PPI). The drug is effective in the treatment of erosive esophagitis, maintenance of eosinophilic esophagitis and relief of heartburn. Additionally, it is also beneficial in the treatment of heartburn with symptomatic gastroesophageal reflux disease. The drug offers the advantage of no dosage adjustment in patients with hepatic impairment. Dexlansoprazole inhibits the stomach acid secrection by specific inhibition of the hydrogen-potassium–ATPase in parietal cells of stomach.

Prediction of Serum-Free and Cerebrospinal Fluid Valproic Acid Levels in Patients With Hypoalbuminemia After Craniotomy.

In patients with hypoalbuminemia after craniotomy, total serum concentrations of valproic acid (VPA) may provide poor clinical insights, owing to saturated protein binding and increased unbound fractions. However, very few clinical laboratories routinely analyze free concentrations of the drug. The aim of this study was to develop a model to predict serum-free and cerebrospinal fluid (CSF) levels of VPA based on its total concentration and to investigate the model's applicability. Total serum and CSF concentrations of VPA in 79 patients were measured using a validated immunoassay between January 2015 and December 2015. The demographic, clinical, and laboratory information of patients were retrieved from medical records. A multiple linear regression analysis was adopted to determine the potential variations and establish the functional relationship between CSF concentration and significant clinical factors. Based on the stepwise multiple linear regression analysis performed using the natural logarithm of the concentration of VPA in the CSF as the dependent variable, serum concentrations of VPA (X1, β' = 0.844), serum albumin concentration (X2, β' = -0.393), and CSF protein concentration (X3, β' = 0.098) were identified as the 3 variables that significantly predicted the dependent variable: (Equation is included in full-text article.), with a coefficient of determination (R) of 0.874. As the CSF protein level is often unavailable, the model was redefined to include 2 variables-serum concentrations of VPA (X1, β' = 0.840) and serum albumin concentration (X2, β' = -0.359): (Equation is included in full-text article.), with R = 0.813. Based on total VPA and serum albumin concentrations, we developed a model to predict serum-free and CSF levels of VPA. This model is useful for correcting dose adjustment in patients with hypoalbuminemia after craniotomy.

Cefiderocol, a New Siderophore Cephalosporin for the Treatment of Complicated Urinary Tract Infections Caused by Multidrug-Resistant Pathogens: Preclinical and Clinical Pharmacokinetics, Pharmacodynamics, Efficacy and Safety.

Cefiderocol (Fetroja®) is a siderophore cephalosporin and has demonstrated potent activity against extended-spectrum beta-lactamases producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and nonfermenting Gram-negative bacilli, including Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Acinetobacter baumannii, Burkholderia cepacia, and Klebsiella pneumoniae. However, cefiderocol has limited activity against Gram-positive bacteria and anaerobes like Bacterodies fragilis. In the APEKS-cUTI study, 183 (73%) of 252 patients in the cefiderocol group versus 65 (55%) of 119 patients in the imipenem-cilastatin group achieved the composite outcome of clinical and microbiological eradication of Gram-negative bacteria (treatment difference of 18.58%; 95% CI 8.23–28.92, p = 0.0004) in complicated urinary tract infections (cUTIs). Cefiderocol was non-inferior to imipenem-cilastatin in cUTIs caused by Gram-negative bacteria such as E. coli, K. pneumoniae, P. aeruginosa, Proteus mirabilis, Enterobacter cloacae, Morganella morganii, and Citrobacter freundii. Cefiderocol required dose adjustment in patients with renal impairment and percentage of time that free drug concentrations above the minimum inhibitory concentration (%fT > MIC) best correlated with clinical outcomes. The most common adverse events with cefiderocol were gastrointestinal symptoms such as diarrhea, constipation, nausea, vomiting, or upper abdominal pain. Two phase III clinical trials, the CREDIBLE-CR study and the APEKS-NP study, investigated the efficacy and safety of cefiderocol for the treatment of pneumonia or cUTI, and both studies showed higher all-cause mortality associated with cefiderocol. Therefore, the use of cefiderocol should be limited only to the treatment of cUTIs from Gram-negative bacteria, especially in patients who have limited or no alternative treatment options.

Using PBPK Modeling to Predict Drug Exposure and Support Dosage Adjustments in Patients With Renal Impairment: An Example with Lamivudine

Lamivudine is a nucleoside reverse transcriptase inhibitor used to treat HIV and hepatitis B. It is primarily cleared by the kidney with renal secretion mediated by OCT2 and MATE. To use PBPK modeling to assess the impact of renal impairment on lamivudine pharmacokinetics using the Simcyp® Simulator. The model incorporated the Simcyp® Mechanistic Kidney Model option to predict renal disposition. The model was initially verified using the Simcyp® Healthy Volunteer population. Two discrete patient populations were then created for moderate (GFR 10-40 mL/min) and severe (GFR < 10 mL/min) renal failure (RF), and model simulations were compared to published data. The developed model was then utilized in a clinical study evaluating the clinical experience and plasma exposure of lamivudine when administered at higher than recommended doses to HIV-infected patients with varying degrees of renal impairment. Predicted systemic exposure metrics (Cmax, AUC) compared favorably to published clinical data for each population, with the following fold errors (FE, ratio of predicted and observed data) for Cmax/AUC: Healthy Volunteers 1.04/1.04, Moderate RF 1.03/0.78, Severe RF 0.89/0.79. The model captured lamivudine plasma concentrations measured pre- and post-dose (0.5-1.5hr) in study participants (n = 34). Model simulations demonstrated comparable systemic profiles across patient cohorts, supporting the proposed dosage adjustment scheme. This study illustrates how PBPK modeling can help verify dosing guidelines for patients with varying levels of renal impairment. This approach may also be useful for predicting potential changes in exposure during renal insufficiency for compounds undergoing clinical development.