Dosing In Renal Impairment Research Articles

A Comprehensive Physiologically Based Pharmacokinetic Model for Predicting Vildagliptin Pharmacokinetics: Insights into Dosing in Renal Impairment.

Physiologically based pharmacokinetic (PBPK) modeling is of great importance in the field of medicine. This study aims to construct a PBPK model, which can provide reliable drug pharmacokinetic (PK) predictions in both healthy and chronic kidney disease (CKD) subjects. To do so, firstly a review of the literature was thoroughly conducted and the PK information of vildagliptin was collected. PBPK modeling software, PK-Sim®, was then used to build and assess the IV, oral, and drug-specific models. Next, the average fold error, visual predictive checks, and predicted/observed ratios were used for the assessment of the robustness of the model for all the essential PK parameters. This evaluation demonstrated that all PK parameters were within an acceptable limit of error, i.e., 2 fold. Also to display the influence of CKD on the total and unbound AUC (the area under the plasma concentration-time curve) and to make modifications in dose, the analysis results of the model on this aspect were further examined. This PBPK model has successfully depicted the variations of PK of vildagliptin in healthy subjects and patients with CKD, which can be useful for medical practitioners in dosage optimization in renal disease patients.

Removing race and body surface area indexation for estimated kidney function based drug dosing: Aminoglycosides as justification of these principles.

The use of race in medicine can contribute to health inequity. Updated equations for estimated glomerular filtration rate (eGFR) without race have been published. Likewise, de-indexation of eGFR to body surface area (BSA) has been recommended by regulatory guidance for drug dosing in renal impairment. Clinical data justifying these recommendations for drug dosing are sparse. We examined the gain or loss of precision in drug dosing with estimated creatinine clearance (eCLcr) and eGFR using serum creatinine (eGFRcr) with and without race and BSA indexation by evaluating the population pharmacokinetics of the aminoglycosides as a classic drug class to probe kidney function. Medical records from adult patients treated with gentamicin or tobramycin over a 13-year period were queried. Population pharmacokinetic analyses were performed using a 1-compartment base structural model. Models compared body size descriptors as covariates of the volume of distribution (V). Estimated creatinine clearance and eGFRcr using multiple contemporary equations with and without BSA indexation were tested as covariates of clearance (CL). The final data set included 2968 patients treated with either gentamicin (20.2%) or tobramycin (79.8%). Patients self-identified as Caucasian (82%), African-American (10%), or other. The median [5th, 95th percentile] weight and BSA were 80.5 [49.4, 136]kg and 1.94 [1.48, 2.56]m2 , respectively. Models of eCLcr and eGFRcr without indexation to BSA had a better model fit than eGFRcr indexed to BSA for aminoglycoside CL. The 2021 Chronic Kidney Disease Epidemiology collaboration (CKD-EPI) eGFRcr equation (no race, no BSA indexation) provided a comparable model fit to the 2009 CKD-EPI eGFRcr equation (with race, no BSA indexation) for aminoglycoside CL. Race is not a relevant covariate of aminoglycoside CL. The 2021 CKD-EPI eGFR equation without race and BSA indexation is a better method for gentamicin and tobramycin CL estimation. Confirmation of these results for other drugs can support the harmonization of dosing by kidney function.

Fibrates in Chronic Kidney Disease Patients: A Controversial Issue

Background: Fenofibrates were not previously known to affect renal function tests until some reports indicated that these drugs may lead to a decrease in renal function. Likewise, the nephrotoxic effect of fibrates remains to be vague and unclear. Guidelines regarding fenofibrate dosing in renal impairment vary internationally. Patients and methods: A prospective cohort study over 6 months with a total of 80 patients on fibrates divided into 2 groups, 40 of which received statins, and the other 40 continued on fibrates. All patients were subjected to full history, clinical examination, and complete baseline labs. The KFTs including serum creatinine and eGFR were measured at 0, 1, 2, and 6-months intervals and lipid profile at 0,3,6 months serially in both groups. Results: Out of the baseline values of KFTs, the statin group showed a significant decrease in all kidney function values including mean serum creatinine by (0.9mg/dL, P=0.001) and an increase in eGFR (8.9 mL/min/1.73 m2, P<0.001). Whilst in patients who continued to receive fibrates the KFTs continued to rise as serum creatinine showed a significant increase in their mean serum Cr levels (by 0.9 mg/dL or 20%, P=0.001), and a significant decrease in their mean eGFR values (by 8.2 mL/min/1.73 m2 or 20.55%, P<0.001). On the other hand, total and LDL Cholesterol were significantly lower in the statin group at all follow-up intervals. Also, triglycerides were significantly higher in the Statin group at the end of month-6 from baseline. Conclusion: In our study fibrates administration showed a short-term state of renal insufficiency. The long-term effects of fibrates versus variable renal derangement are yet to be identified.

Fibrates in Chronic Kidney Disease Patients: A Controversial Issue

Fenofibrates were not previously known to affect renal function tests until some reports indicated that these drugs may lead to a decrease in renal function. Likewise, the nephrotoxic effect of fibrates remains to be vague and unclear. Guidelines regarding fenofibrate dosing in renal impairment vary internationally.

Reappraisal of Linezolid Dosing in Renal Impairment To Improve Safety.

Linezolid is administered as a fixed dose to all patients despite evidence of increased exposure and myelosuppression in renal impairment. The objectives of these studies were to assess the risk of thrombocytopenia with standard-dose linezolid in renal impairment and to identify an alternate dosing strategy. In study 1, data from adult patients receiving linezolid for ≥10 days were retrospectively reviewed to determine the frequency of thrombocytopenia in patients with and without renal impairment. Time-to-event analyses were performed using Cox proportional-hazards models. In study 2, population pharmacokinetic modeling was employed to build covariate-structured models using an independent data set of linezolid concentrations obtained during routine therapeutic drug monitoring (TDM). Monte Carlo simulations were performed to identify linezolid dosing regimens that maximized attainment of therapeutic trough concentrations (2 to 8 mg/liter) across various renal-function groups. Toxicity analysis (study 1) included 341 patients, 133 (39.0%) with renal impairment. Thrombocytopenia occurred more frequently among patients with renal impairment (42.9% versus 16.8%; P < 0.001), and renal impairment was independently associated with this toxicity in multivariable analysis (adjusted hazard ratio [aHR], 2.37; 95% confidence interval [CI], 1.52 to 3.68). Pharmacokinetic analyses (study 2) included 1,309 linezolid concentrations from 603 adult patients. Age, body surface area, and estimated glomerular filtration rate (eGFR) were identified as covariates of linezolid clearance. Linezolid dose reductions improved the probability of achieving optimal exposures in simulated patients with eGFR values of <60 ml/min. Thrombocytopenia occurs more frequently in patients with renal impairment receiving standard linezolid doses. Linezolid dose reduction and trough-based TDM are predicted to mitigate this treatment-limiting toxicity.

Patterns of diuretic use in the intensive care unit.

PurposeTo inform future outcomes research on diuretics, we sought to describe modern patterns of diuretic use in the intensive care unit (ICU), including diuretic type, combination, and dosing. We also investigated two possible quality improvement targets: furosemide dosing in renal impairment and inclusion of an initial bolus with continuous furosemide infusions.Materials and methodsIn this descriptive study, we retrospectively studied 46,037 adult ICU admissions from a publicly available database of patients in an urban, academic medical center.ResultsDiuretics were employed in nearly half (49%, 22,569/46,037) of ICU admissions. Mechanical ventilation, a history of heart failure, and admission to the post-cardiac surgery unit were associated with a higher frequency of diuretic use. Combination use of different diuretic classes was uncommon. Patients with severely impaired kidney function were less likely to receive diuretics. Furosemide was by far the most common diuretic given and the initial intravenous dose was only 20 mg in more than half of ICU admissions. Among patients treated with a continuous infusion, 30% did not receive a bolus on the day of infusion initiation.ConclusionsPatterns of diuretic use varied by patient-specific factors and by ICU type. Diuretic dosing strategies may be suboptimal.

Prescribing of diabetes medications to people with type 2 diabetes and chronic kidney disease: a national cross-sectional study

BackgroundPrevious studies in general practice and hospital settings have identified that prescribing of non-insulin diabetes medications may be sub-optimal in people with type 2 diabetes (T2D) and renal impairment. Since these publications, a number of new medications have become available for the management of T2D. Study aims were to, in a cohort of Australians with T2D and renal impairment attending general practice, (1) investigate whether the prescribing of non-insulin diabetes medications is consistent with dosing adjustments recommended within current Australian Diabetes Society (ADS) guidelines; and (2) identify patient socio-demographic and clinical factors associated with at least one prescription of a non-insulin diabetes medication inconsistent with current ADS guidelines for medication doses.MethodsCross-sectional study using data from the MedicineInsight general practice database managed by NPS MedicineWise. Patients with T2D who were aged 18 years and over, with an average eGFR< 60 ml/min/1.73m2 and at least one prescription of a non-insulin diabetes medication between 1st January 2015 and 30th June 2017 were included. Descriptive statistics were used to summarise patient characteristics and medication use. Marginal logistic regression models were used to estimate associations between sociodemographic and clinical factors and prescribing of ≥1non-insulin diabetes medicine not consistent with ADS guidelines.ResultsThe majority of the 3505 patients included (90.4%) had an average eGFR of 30-59 ml/min/1.73m2. In terms of absolute numbers, metformin was the medication most frequently prescribed at a dose not consistent with current ADS guidelines for dosing in renal impairment (n = 1601 patients), followed by DPP4 inhibitors (n = 611) and sulphonylureas (n = 278). The drug classes with the highest proportion of prescriptions with dosage not consistent with ADS guidelines were SGLT2 inhibitors (83%), followed by biguanides (58%) and DPP4 inhibitors (46%). Higher HbA1c, longer known diabetes duration and diagnosis of retinopathy were associated with receiving ≥1prescription with a dosage not consistent with guidelines.ConclusionsPrescribing of non-insulin diabetes medications at doses inconsistent with current ADS guideline recommendations for dosing adjustments for people with renal impairment was common. Further research is needed to understand how general practitioners access, interpret and apply the ADS guidelines and the impact this may have on patient outcomes.

DEVELOPMENT OF RENAL DOSING GUIDELINES FOR NONSTEROIDAL ANTI-INFLAMMATORY DRUGS AND ANTIBIOTICS - A PROSPECTIVE STUDY

Objectives: The objectives of this study were to determine the impact of renal dosing guidelines on prescribing pattern for nonsteroidal anti-inflammatory drugs and antibiotic in patients with chronic kidney disease (CKD).Methods: This was a prospective interventional study. The study was divided into two phases, pre-intervention and post-intervention phases. Data regarding the kidney function and the pattern of drug dosing will record in the pre-intervention phase. Pocket guides were prepared for the drug dosing in renal impairment and were distributed to clinicians and the pharmacist as a part of intervention. In the post-intervention phase, the dosing pattern of renal eliminated drugs was observed for any improvement. The patterns of dosing of renal eliminated drugs were compared in both the phases.Results: In pre-interventional phase, a total of 43 cases were reviewed, 20 of them were non-hemodialysis (non-HD) (9 female and 11 male) cases with a mean±standard deviation (SD) age of 56.05+8.22 (56) and 23 were undergoing HD (11 female and 12 male) cases with a mean±SD age of 56.72+6.85 (56). In the post-intervention phase, a total of 41 cases were reviewed, 22 of them were non-HD (12 female and 10 male) cases with a mean±SD age of 55.85+6.87 (57) and 19 were undergoing HD (10 female and 9 male) cases with a mean±SD age of 55.77+8.39 (56.6).Conclusion: Health-care professionals have an important responsibility in monitoring the dose for renal impairment patients. Development of renal dosing guidelines for patients hospitalized with CKD can improve the pattern of prescribing in renal failure population.

Retrospective chart evaluation of hypercalcemia management in oncology patients at the University of Chicago Medical Center.

Introduction Due to the lack of formal guideline recommendations, available primary literature was used to develop a proposed protocol for management of hypercalcemia of malignancy at the University of Chicago Medical Center. Methods A retrospective, single center, observational study was performed including adult patients hospitalized with a diagnosis of hypercalcemia and active malignancy. Patients were retrospectively identified as treated in a manner aligned with the proposed protocol ("per protocol") or not treated according to the proposed protocol ("off protocol"), and the outcomes were compared. The primary outcome for efficacy was normalization of corrected calcium within four and seven days of treatment. Results Normalization of corrected calcium was observed in 66% of patients managed per protocol compared to 65% of patients managed off protocol ( p = 1.00) at day four, and in 73% of per protocol patients compared to 65% of off protocol patients ( p = 0.44) at day seven. Areas identified where prospective implementation of the proposed protocol can improve management include: decreasing utilization of bisphosphonates in mild hypercalcemia, optimizing bisphosphonate dosing in renal impairment, decreasing intravenous phosphate repletion, and ensuring proper fluid management and calcitonin dosing. Conclusion Although a statistical difference was not detected in terms of normalization of corrected calcium levels, areas for optimization in management were identified. Therefore, implementation of the proposed protocol is expected to promote evidence-based management of hypercalcemia of malignancy management at University of Chicago Medical Center.

COLISTIN: adult and paediatric guideline for South Africa, 2016

This document was created to serve as a guideline for colistin prescribing in South Africa. Antimicrobial resistance is threatening the effective prevention and treatment of a wide variety of infections, especially those that are caused by multi-drug-resistant (MDR) gram-negative bacteria. Colistin is typically used as salvage therapy, or last-line treatment, for MDR gram-negative infections. The dosing regimen should be optimised to be therapeutic and halt the emergence of resistance, whilst minimizing toxicity. This document provides evidence-based recommendations for adult and paediatric dosing, dosing in renal impairment, and the use of combination therapy to increase synergistic effects, as well as guidelines on the reconstitution and administration of colistin. This guideline is specifically aimed at healthcare workers who routinely treat patients with MDR gram-negative infections, especially in the intensive care setting.

COLISTIN: adult and paediatric guideline for South Africa, 2016

This document was created to serve as a guideline for colistin prescribing in South Africa. Antimicrobial resistance is threatening the effective prevention and treatment of a wide variety of infections, especially those that are caused by multi-drug-resistant (MDR) gram-negative bacteria. Colistin is typically used as salvage therapy, or last-line treatment, for MDR gram-negative infections. The dosing regimen should be optimised to be therapeutic and halt the emergence of resistance, whilst minimizing toxicity. This document provides evidence-based recommendations for adult and paediatric dosing, dosing in renal impairment, and the use of combination therapy to increase synergistic effects, as well as guidelines on the reconstitution and administration of colistin. This guideline is specifically aimed at healthcare workers who routinely treat patients with MDR gram-negative infections, especially in the intensive care setting.

Renal drug dosing recommendations: evaluation of product information for brands of the same drug

To review the product information (PI) for various brands of the same generic drugs and investigate the extent to which information is currently available on dosing in renal impairment and the concordance between the dosing recommendations for the same generic drug. The Monthly Index of Medical Specialities (MIMS) was examined for 28 generic drugs recommended to be used with caution in renal impairment. For each generic drug all available brands listed as having solid oral dosage form were recorded. For each identified brand, the current PI was consulted and data referring to renal impairment was collated. The dissimilarity between these PI regarding the renal dosage recommendation was determined. There was generally a lack of detailed information in the PI on the use of drugs in patients with renal impairment. The majority of PI documents (88 of 155 PI; 57%) provided quantitative dosage recommendations, but this was often not detailed enough to help users to make an informed decision. For 37 PI documents (24%), an altered dosage regimen was proposed without a quantifiable measure of renal function reported in the dose recommendation. The renal function severity category terms used and the associated quantitative values were also not consistent. It was observed that the recommendations varied among different brands of hydromorphone, morphine, oxycodone, tramadol, metformin and topiramate. The reporting of renal function quantification methods, and associated dosage recommendations, in PI requires standardisation to ensure optimal drug dosing. Regularly updating of PI is also necessary.

INT-006 Pharmacist-physician collaboration to ensure the safe dosing in renal impairment among patients admitted to an emergency ward in Finland

BackgroundRenal impairment (RI) increases the risk of adverse drug events especially in elderly patients, since kidney function declines with age. Many risks can be avoided by appropriate dosing adjustment in...

Benefits and Safety of Long-Term Fenofibrate Therapy in People With Type 2 Diabetes and Renal Impairment

OBJECTIVEDiabetic patients with moderate renal impairment (estimated glomerular filtration rate [eGFR] 30–59 mL/min/1.73 m2) are at particular cardiovascular risk. Fenofibrate’s safety in these patients is an issue because it may elevate plasma creatinine. Furthermore, guidelines regarding fenofibrate dosing in renal impairment vary internationally. We investigated fenofibrate’s effects on cardiovascular and end-stage renal disease (ESRD) events, according to eGFR, in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study.RESEARCH DESIGN AND METHODSType 2 diabetic patients (aged 50–75 years) with eGFR ≥30 mL/min/1.73 m2 were randomly allocated to a fixed dose of fenofibrate (200 mg daily) (n = 4,895) or placebo (n = 4,900) for 5 years. Baseline renal function (Modification of Diet in Renal Disease equation) was grouped by eGFR (30–59, 60–89, and ≥90 mL/min/1.73 m2). The prespecified outcome was total cardiovascular events (composite of cardiovascular death, myocardial infarction, stroke, and coronary/carotid revascularization). Serious adverse events and instances of ESRD (plasma creatinine >400 μmol/L, dialysis, renal transplant, or renal death) were recorded. Analysis was by intention to treat.RESULTSOverall, fenofibrate reduced total cardiovascular events, compared with placebo (hazard ratio 0.89 [95% CI 0.80–0.99]; P = 0.035). This benefit was not statistically different across eGFR groupings (P = 0.2 for interaction) (eGFR 30–59 mL/min/1.73 m2: 0.68 [0.47–0.97], P = 0.035; eGFR ≥90 mL/min/1.73 m2: 0.85 [0.70–1.02], P = 0.08). ESRD rates were similar between treatment arms, without adverse safety signals of fenofibrate use in renal impairment.CONCLUSIONSPatients with type 2 diabetes and moderate renal impairment benefit from long-term fenofibrate, without excess drug-related safety concerns compared with those with no or mild renal impairment. Fenofibrate treatment should not be contraindicated in moderate renal impairment, suggesting that current guidelines may be too restrictive.

The Challenges of Gout Management in the Elderly

Gout is common in the elderly and its management is frequently complicated by the presence of co-morbid conditions and medications prescribed for other conditions. The management of gout is 2-fold: (i) treatment of the acute attack to rapidly resolve the pain and inflammation; and (ii) long-term urate-lowering therapy (ULT) to prevent further gouty episodes. NSAIDs, colchicine, corticosteroids and more recently interleukin (IL)-1 inhibitors are effective treatments for acute gout. The choice of agent is determined by the patient's age, co-morbidities and concomitant medications. Renal impairment is of particular concern in the elderly and may preclude the use of NSAIDs and colchicine. The IL-1 inhibitors are rapidly effective but data in the elderly are limited. ULT aiming for a serum urate <0.36 mmol/L, or lower in severe tophaceous gout, is critical for the long-term management of gout. Urate lowering can be achieved by inhibiting the production of uric acid through xanthine oxidase inhibition (allopurinol, febuxostat), increasing uric acid excretion via the kidneys (uricosuric agents: probenecid, benzbromarone) or dissolving uric acid to the more water soluble allantoin (recombinant uricases: pegloticase, rasburicase). Allopurinol is the most commonly used ULT, but there is no consensus on dosing in renal impairment. Febuxostat is effective at lowering serum urate, but there are limited data in the elderly and patients with renal impairment. Furthermore, there are concerns about cardiovascular safety. Probenecid is ineffective in patients with renal impairment (creatinine clearance <60 mL/min) and the availability of benzbromarone is limited because of concerns about its hepatotoxicity. The recombinant uricases provide an exciting new therapeutic option, but there are limited data for their use in the elderly. These agents may be particularly useful in patients with a high urate burden (e.g. those with tophi); however, they may precipitate a severe flare of gout and this will require treatment in its own right. Careful consideration of the patient's concomitant medications is required as many drugs increase serum urate. Successful urate lowering will ultimately reduce gout flares and thereby improve patient quality of life.

Medication review of community-dwelling seniors using intensified home-care service

Investigations on medication burden, falling, and inappropriate dosing in renal impairment have been obtained in patients living in nursing homes. Data from home-dwelling patients in intensified ambulatory care, especially from Germany are scant. We evaluated patients daily visited by an ambulatory care service (Cohort 1, n = 102, median age 80 y) or had care given by relatives only (cohort 2, n = 101, median age 76 y) at baseline (V1), 6 (V2) and 12 months (V3). At V1 patients in Cohort 1 had 5 (median, range 3 - 15) and at V3 6 (3 - 17) medications. No differences could be observed between cohorts regarding number and pattern of medications. At V1, 30/102 patients of Cohort 1 had creatinine measured within the last 6 months, 13/30 patients had an eGFR < 50 ml/min. 6/34 medications which need dose-adjustment were unadjusted. Low surveillance of renal function and unadjusted dosing were also observed at other visits and also in Cohort 2. Within 1 year, 29/75 mobile patients in cohort 1 had a fall, 18/29 patients had a benzodiazepine prescribed regularly, whereas a benzodiazepine was prescribed in 6/46 patients which did not fall (chi2 p = 0.004). In Cohort 2, the number of falling patients was lower (19/84 mobile patients, p = 0.028). 11/19 patients had a benzodiazepine prescribed, in contrast to 5/65 patients which did not fall (chi2 p = 0.001). It needs to be elucidated whether a care service can contribute to medication safety in patients e.g. by reviewing medication charts and organizing for controls of ancillary laboratory values.

Drugs and the kidney: more than a question of dose

Drugs and the kidney: more than a question of dose

Allopurinol Dosing in Renal Impairment: Walking the Tightrope Between Adequate Urate Lowering and Adverse Events

Allopurinol is the mainstay of urate-lowering therapy for patients with gout and impaired renal function. Although rare, a life-threatening hypersensitivity syndrome may occur with this drug. The risk of this allopurinol hypersensitivity syndrome (AHS) is increased in renal impairment. The recognition that AHS may be because of delayed-type hypersensitivity to oxypurinol, the main metabolite of allopurinol, and that oxypurinol concentrations are frequently elevated in patients with renal impairment prescribed standard doses of allopurinol has led to the widespread adoption of allopurinol-dosing guidelines. These guidelines advocate allopurinol dose reduction according to creatinine clearance in patients with renal impairment. However, recent studies have challenged the role of these guidelines, suggesting that AHS may occur even at low doses of allopurinol, and that these guidelines lead to under-treatment of hyperuricemia, a key therapeutic target in gout. Based on current data, we advocate gradual introduction of allopurinol according to current treatment guidelines, with close monitoring of serum uric acid concentrations. In patients with severe disease and persistent hyperuricemia, allopurinol dose escalation above those recommended by the guidelines should be considered, with careful evaluation of the benefits and risks of therapy. Further work is needed to clarify the safety and efficacy of allopurinol dose escalation, particularly in patients with renal impairment.

Suboptimal physician adherence to quality indicators for the management of gout and asymptomatic hyperuricaemia: results from the UK General Practice Research Database (GPRD)

: To examine adherence to validated quality indicators assessing the quality of allopurinol use in the treatment of gout and asymptomatic hyperuricaemia. We determined physician adherence in the UK General Practice Research Database (GPRD) to three validated quality indicators developed to assess the quality of allopurinol prescribing practices. These indicators were developed to assess: (i) dosing in renal impairment; (ii) concomitant use with azathioprine or 6-mercaptopurine; and (iii) use in the treatment of asymptomatic hyperuricaemia. We also examined the association of patient-level factors (sociodemographics, comorbidity, follow-up duration and concomitant medicine use) with the treatment of asymptomatic hyperuricaemia using multivariable logistic regression. Of the 63 105 gout patients, 185 (0.3%) were eligible for Quality Indicator 1 and 52 (0.1%) were eligible for Quality Indicator 2. There were an additional 471 patients with asymptomatic hyperuricaemia eligible for Quality Indicator 3. Rates of practice deviation for the three individual quality indicators ranged from 25 to 57%. Male sex, older age, a history of chronic renal failure, and a greater number of concomitant medications were significantly associated with increased odds of inappropriate treatment for asymptomatic hyperuricaemia. Hypertension and diuretic use were associated with lower odds of this practice. One-quarter to one-half of all patients eligible for at least one of the validated quality of care indicators were subject to possible allopurinol prescribing error, suggesting that inappropriate prescribing practices are widespread with this agent. Future interventions aimed at reducing inappropriate allopurinol use are needed and should be targeted towards high-risk groups, including older men and those receiving multiple concomitant medications.