Understanding adefovir pharmacokinetics as a component of a transporter phenotyping cocktail.

PURPOSE: Adefovir (as dipivoxil) was selected as a probe drug in a previous transporter cocktail phenotyping study to assess renal organic anion transporter 1 (OAT1), with renal clearance (CLR) as the primary parameter describing renal elimination. An approximately 20% higher systemic exposure of adefovir was observed when combined with other cocktail components (metformin, sitagliptin, pitavastatin, and digoxin) compared to sole administration. The present evaluation applied a population pharmacokinetic (popPK) modeling approach to describe adefovir pharmacokinetics as a cocktail component in more detail. METHODS: Data from 24 healthy subjects were reanalyzed. After establishing a base model, covariate effects, including the impact of co-administered drugs, were assessed using forward inclusion then backward elimination. RESULTS: A one-compartment model with first-order absorption (including lag time) and a combination of nonlinear renal and linear nonrenal elimination best described the data. A significantly higher apparent bioavailability (73.6% vs. 59.0%) and a lower apparent absorption rate constant (2.29 h-1 vs. 5.18 h-1) were identified in the combined period compared to the sole administration period, while no difference was seen in renal elimination. The population estimate for the Michaelis-Menten constant (Km) of the nonlinear renal elimination was 170 nmol/L, exceeding the observed range of adefovir plasma maximum concentration, while the maximum rate (Vmax) of nonlinear renal elimination was 2.40 µmol/h at the median absolute estimated glomerular filtration rate of 105 mL/min. CONCLUSION: The popPK modeling approach indicated that the co-administration primarily affected the apparent absorption and/or prodrug conversion of adefovir dipivoxil, resulting in the minor drug-drug interaction observed for adefovir as a victim. However, renal elimination remained unaffected. The high Km value suggests that assessing renal OAT1 activity by CLR has no relevant misspecification error with the cocktail doses used.

A study of size-selective renal elimination using a novel human model.

The recently discovered selective glomerular hypofiltration syndromes have increased interest in the actual elimination of molecules in the human kidney. In the present study, a novel human model was introduced to directly measure the single-pass renal elimination of molecules of increasing size. Plasma concentrations of urea, creatinine, C-peptide, insulin, pro-BNP, ß2-microglobulin, cystatin C, troponin-T, orosomucoid, albumin, and IgG were analysed in arterial and renal venous blood from 45 patients undergoing Transcatheter Aortic Valve Implantation (TAVI). The renal elimination ratio (RER) was calculated as the arteriovenous concentration difference divided by the arterial concentration. Estimated glomerular filtration rate (eGFR) was calculated by the CKD-EPI equations for both creatinine and cystatin C. Creatinine (0.11 kDa) showed the highest RER (21.0 ± 6.3%). With increasing molecular size, the RER gradually decreased, where the RER of cystatin C (13 kDa) was 14.4 ± 5.3% and troponin-T (36 kDa) was 11.3 ± 4.6%. The renal elimination threshold was found between 36 and 44 kDa as the RER of orosomucoid (44 kDa) was -0.2 ± 4.7%. The RER of creatinine and cystatin C showed a significant and moderate positive linear relationship with eGFR (r = 0.48 and 0.40). In conclusion, a novel human model was employed to demonstrate a decline in renal elimination with increasing molecular size. Moreover, RERs of creatinine and cystatin C were found to correlate with eGFR, suggesting the potential of this model to study selective glomerular hypofiltration syndromes.

Estimation of piperacillin clearance with different glomerular filtration rate formulas in critically ill children.

AIMS: Glomerular filtration rate (GFR) is difficult to assess in critically ill children using gold standard method and alternatives are needed. This study aimed to determine the most accurate GFR estimation formula for assessing piperacillin clearance in critically ill children, using a published piperacillin pharmacokinetics (PK) population model. METHODS: All children hospitalized in the paediatric intensive care unit of a single institution who were receiving piperacillin were included. PK were described using the nonlinear mixed effect modelling software MONOLIX. In the initial PK model, GFR was estimated according to the Schwartz 1976 formula. We evaluated a set of 12 additional validated formulas, developed using plasma creatinine and/or cystatin C concentrations, in the building model to assess the lowest between-subject variability for piperacillin clearance. RESULTS: We included 20 children with a median (range) postnatal age of 1.9 (0.1-19) years, body weight of 12.5 (3.5-69) kg. Estimated GFR according to the Schwartz 1976 formula was 160.5 (38-315) mL min-1 1.73 m-2 . Piperacillin clearance was best predicted by the Bouvet combined formula. CONCLUSION: The combined Bouvet formula was the most accurate GFR estimation formula for assessing piperacillin clearance in critically ill children.

Does infusion time affect the retention of parenteral trace elements?

When readymade parenteral nutrition in multi-chamber bags is supplied without vitamins and minerals, these have to be added or given separately. Separate rapid infusion has logistical advantages but has been claimed to saturate tissue mechanisms, potentially increasing urine micronutrient losses. The present study compared urinary losses after fast (1 h) v. slow (10 h) trace elements infusion. The study enrolled thirty-nine consecutive patients who were starting parenteral nutrition postoperatively. One day's dose of a complete intravenous micronutrient product was infused over 1 h and over 10 h, in random order, with a washout day after each infusion day. Urinary Zn, Mn, Se, Cr, Cu and Fe losses were measured by 24-h urine collection, recorded for each infusion day and subsequent washout day. For Zn, a dose of 100 µmol was given, and total urinary loss over the next 2 d was mean 40·6 (sd 23·8) µmol after the fast (1 h) infusion v. 33·4 (sd 25·4) µmol after the slow (10 h) infusion, that is, 7 % more of the 1-d dose was lost after fast infusion (P = 0·01). For Mn, after a dose of 1000 nmol, losses were 9·8 (sd 23·9) nmol after the fast infusion v. 22·1 (sd 47·2) nmol after the slow infusion, that is, 1 % more of the 1-d dose was lost after slow infusion (P = 0·04). There were no other significant differences: after 1 µmol Se, the losses were 1·5 (sd 0·6) µmol fast v. 1·3 (sd 0·5) µmol slow; after 200 nmol Cr, 257 (sd 92) µmol fast v. 246 (sd 107) nmol slow; after 8 µmol Cu, 1·6 (sd 1·4) µmol fast v. 1·5 (sd 1·3) µmol slow; and after 20 µmol Fe, 0·6 (sd 1·1) µmol fast v. 0·8 (sd 1·6) µmol slow (P > 0·05 for all). Overall, trace element retention appears to be minimally affected by infusion time.

Pharmacokinetics of Polymyxins in Animals.

All of the small number of studies conducted during the second half of last century to investigate the pharmacokinetics of polymyxins in animals used microbiological methods to quantify the compounds in biological fluids. Those methods generally lacked the accuracy and precision required for such investigations and, in the case of studies involving administration of colistin methanesulfonate (CMS), ongoing conversion to colistin during microbiological incubation of collected samples artifactually elevated the measured concentration of colistin. The pharmacokinetic studies reviewed in this chapter involved use of more accurate, precise and specific methods for the measurement of the relevant compounds in biological matrices. The studies have been conducted in a number of pre-clinical animal species following administration via various routes (e.g. intravenous, intrapulmonary), and have provided important insights into not only the global pharmacokinetics as viewed from plasma but also the tissue distribution and handling by key organs particularly the kidneys.

R-Limonene metabolism in humans and metabolite kinetics after oral administration.

We studied the R-limonene (LMN) metabolism and elimination kinetics in a human in vivo study. Four volunteers were orally exposed to a single LMN dose of 100-130 µg kg-1 bw. In each case, one pre-exposure and subsequently all 24 h post-exposure urine samples were collected. From two subjects, blood samples were drawn up to 5 h after exposure. The parent compound was analysed in blood using headspace GC-MS. The metabolites cis- and trans-carveol (cCAR), perillyl alcohol (POH), perillic acid (PA), limonene-1,2-diol (LMN-1,2-OH), and limonene-8,9-diol (LMN-8,9-OH) were quantified in both blood and urine using GC-PCI-MS/MS. Moreover, GC-PCI-MS full-scan experiments were applied for identification of unknown metabolites in urine. In both matrices, metabolites reached maximum concentrations 1-2 h post-exposure followed by rapid elimination with half-lives of 0.7-2.5 h. In relation to the other metabolites, LMN-1,2-OH was eliminated slowest. Nonetheless, overall renal metabolite elimination was completed within the 24-h observation period. The metabolite amounts excreted via urine corresponded to 0.2 % (cCAR), 0.2 % (tCAR), <0.1 % (POH), 2.0 % (PA), 4.3 % (LMN-1,2-OH), and 32 % (LMN-8,9-OH) of the orally administered dose. GC-PCI-MS full-scan analyses revealed dihydroperillic acid (DHPA) as an additional LMN metabolite. DHPA was estimated to account for 5 % of the orally administered dose. The study revealed that human LMN metabolism proceeds fast and is characterised by oxidation mainly of the exo-cyclic double bond but also of the endo-cyclic double bond and of the methyl side chain. The study results may support the prediction of the metabolism of other terpenes or comparable chemical structures.

Human metabolism of α-pinene and metabolite kinetics after oral administration.

We studied the human in vivo metabolism and the elimination kinetics of α-pinene (αPN), a natural monoterpene which commonly occurs in the environment. Four volunteers were exposed to a single oral dose of 10 mg αPN. Each subject provided one pre-exposure and subsequently all post-exposure urine samples up to 24 h after administration. Additionally, blood samples were drawn hourly from two volunteers for 5 h. The analysis of the parent compound in blood was performed by a headspace GC-MS procedure, whereas the proposed αPN metabolites myrtenol (MYR) and cis- and trans-verbenol (cVER; tVER) were quantified in blood and urine using GC-PCI-MS/MS. Unknown metabolites were investigated using GC-PCI-MS full-scan analyses. The urinary concentration of the metabolites reached their maxima 1.6 h after exposure. Afterwards, they declined to the pre-exposure levels within the 24-h observation period with elimination half-lives of 1.5 h (MYR) and 1.6 h (cVER and tVER). The total eliminated amounts corresponded to 1.5 % (MYR), 5.6 % (cVER), and 4.1 % (tVER) of the orally applied dose. The GC-PCI-MS full-scan analyses identified three novel metabolites, of which one conforms to myrtenic acid (MYRA). A re-analysis of MYRA in urine showed maximum elimination 1.6 h after αPN ingestion, an elimination half-life of 1.4 h, and a share of the oral dose of 6.7 %. The study revealed that the human in vivo metabolism of αPN proceeds fast and elimination of metabolites takes places rapidly. The metabolism of αPN is dominated by extensive oxidation reactions at the methyl side-chains yielding in carboxylic acid structures as well as by allylic oxidation of the cyclohexenyl backbone, whereas predicted products of a double-bond oxidation were not detected.

Projecting ADME Behavior and Drug-Drug Interactions in Early Discovery and Development: Application of the Extended Clearance Classification System.

PURPOSE: To assess the utility of Extended Clearance Classification System (ECCS) in understanding absorption, distribution, metabolism, and elimination (ADME) attributes and enabling victim drug-drug interaction (DDI) predictions. METHODS: A database of 368 drugs with relevant ADME parameters, main metabolizing enzymes, uptake transporters, efflux transporters, and highest change in exposure (%AUC) in presence of inhibitors was developed using published literature. Drugs were characterized according to ECCS using ionization, molecular weight and estimated permeability. RESULTS: Analyses suggested that ECCS class 1A drugs are well absorbed and systemic clearance is determined by metabolism mediated by CYP2C, esterases, and UGTs. For class 1B drugs, oral absorption is high and the predominant clearance mechanism is hepatic uptake mediated by OATP transporters. High permeability neutral/basic drugs (class 2) showed high oral absorption, with metabolism mediated generally by CYP3A, CYP2D6 and UGTs as the predominant clearance mechanism. Class 3A/4 drugs showed moderate absorption with dominant renal clearance involving OAT/OCT2 transporters. Class 3B drugs showed low to moderate absorption with hepatic uptake (OATPs) and/or renal clearance as primary clearance mechanisms. The highest DDI risk is typically seen with class 2/1B/3B compounds manifested by inhibition of either CYP metabolism or active hepatic uptake. Class 2 showed a wider range in AUC change likely due to a variety of enzymes involved. DDI risk for class 3A/4 is small and associated with inhibition of renal transporters. CONCLUSIONS: ECCS provides a framework to project ADME profiles and further enables prediction of victim DDI liabilities in drug discovery and development.

Cystatin C as a potential biomarker for dosing of renally excreted drugs.

The objective of the present study was to review the available pharmacokinetic evidence for the utility of cystatin C (CysC) as a marker of renal function to predict the dose of renally excreted drugs.The bibliographic search used PubMed and EMBASE databases, from its inception through to January 2014, with the following keywords 'pharmacokinetics' and 'cystatin C'.Sixteen pharmacokinetic publications were identified and seven drugs primarily excreted by the kidney were studied. Among them, only one study was performed in children, the others were performed in adults and/or elderly subjects, either healthy volunteers or patients with variable clinical conditions, such as cystic fibrosis and cancer. Most of studies (n = 13/16) demonstrated that CysC was better correlated with clearance/trough concentration of evaluated drugs compared with creatinine.Our review supports that CysC is a good marker of renal function to predict dose of renally excreted drugs. Efforts should be made to evaluate the impact of CysC in special populations in order to define its clinical value in dosing optimization.

Age-related pharmacokinetic changes of acetaminophen, antipyrine, diazepam, diphenhydramine, and ofloxacin in male cynomolgus monkeys and beagle dogs.

1. The pharmacokinetics of acetaminophen (marker of gastric emptying), antipyrine (marker of hepatic metabolic activity and total body water), diazepam (lipophilic and highly distributed), diphenhydramine (hepatic blood flow-limited and alpha-1 acid glycoprotein bound) and ofloxacin (renally eliminated) were evaluated in cynomolgus monkeys (3-18 years old) and beagle dogs (2-11 years old) as models in elderly persons. 2. Gastric pH fluctuated with aging in monkeys and dogs. The concentration of alpha-1 acid glycoprotein appeared to be increased by aging. There were no age-related differences in the absorption rates of the drugs under the conditions used in the study. Total body fat increased and water decreased in monkeys, but these parameters did not change in dogs. 3. Hepatic blood flow decreased in both species, but a significant decrease of hepatic clearance was only seen in monkeys. Renal clearance decreased significantly with age in monkeys and showed a tendency to decrease in dogs. 4. Age-related alterations of physiological parameters in monkeys are in agreement with clinical observations in humans, except for the lack of a change in the plasma albumin concentration. Therefore, this study suggests that monkey might be a suitable animal model for prediction of age-related changes in pharmacokinetics in humans.

Elimination study of intact lipid nanocapsules after intravenous rat administration.

Aim: The present study investigated renal elimination after intravenous administration of four different formulations of lipid nanocapsules (LNCs) containing dyes adapted to Förster resonance energy transfer (FRET-LNCs).Materials & methods: FRET-LNCs of 85 or 50 nm with or without a pegylated surface were injected and collected in the blood or urine of rats at different time points. Quantitative analysis was performed to measure intact FRET-LNCs.Results & conclusion: No intact LNCs were found in urine (0 particles/ml) for all formulations. The 50-nm pegylated LNCs were eliminated faster from the blood, whereas 85-nm pegylated LNCS were eliminated slower than nonpegylated LNCs. Elimination of FRET-LNCs was mainly due to liver tissue interaction and not renal elimination.

This study confirmed that the elimination of FRET LNCs is likely mainly due to liver tissue interaction and not renal elimination. #nanomedicines #lipidnanocapsules #FRET #pharmacokinetic #biodistribution.

Sex-Specific Association of Ambient Temperature With Urine Biomarkers in Southwest Coastal Bangladesh.

Introduction: Men are vulnerable to ambient heat-related kidney disease burden; however, limited evidence exists on how vulnerable women are when exposed to high ambient heat. We evaluated the sex-specific association between ambient temperature and urine electrolytes, and 24-hour urine total protein, and volume. Methods: We pooled a longitudinal 5624 person-visits data of 1175 participants' concentration and 24-hour excretion of urine electrolytes and other biomarkers (24-hour urine total protein and volume) from southwest coastal Bangladesh (Khulna, Satkhira, and Mongla districts) during November 2016 to April 2017. We then spatiotemporally linked ambient temperature data from local weather stations to participants' health outcomes. For evaluating the relationships between average ambient temperature and urine electrolytes and other biomarkers, we plotted confounder-adjusted restricted cubic spline (RCS) plots using participant-level, household-level, and community-level random intercepts. We then used piece-wise linear mixed-effects models for different ambient temperature segments determined by inflection points in RCS plots and reported the maximum likelihood estimates and cluster robust standard errors. By applying interaction terms for sex and ambient temperature, we determined the overall significance using the Wald test. Bonferroni correction was used for multiple comparisons. Results: The RCS plots demonstrated nonlinear associations between ambient heat and urine biomarkers for males and females. Piecewise linear mixed-effects models suggested that sex did not modify the relationship of ambient temperature with any of the urine parameters after Bonferroni correction (P < 0.004). Conclusion: Our findings suggest that women are as susceptible to the effects of high ambient temperature exposure as men.

External Validation of the Augmented Renal Clearance Predictor in Critically Ill COVID-19 Patients.

The ARC predictor is a prediction model for augmented renal clearance (ARC) on the next intensive care unit (ICU) day that showed good performance in a general ICU setting. In this study, we performed a retrospective external validation of the ARC predictor in critically ill coronavirus disease 19 (COVID-19) patients admitted to the ICU of the University Hospitals Leuven from February 2020 to January 2021. All patient-days that had serum creatinine levels available and measured creatinine clearance on the next ICU day were enrolled. The performance of the ARC predictor was evaluated using discrimination, calibration, and decision curves. A total of 120 patients (1064 patient-days) were included, and ARC was found in 57 (47.5%) patients, corresponding to 246 (23.1%) patient-days. The ARC predictor demonstrated good discrimination and calibration (AUROC of 0.86, calibration slope of 1.18, and calibration-in-the-large of 0.14) and a wide clinical-usefulness range. At the default classification threshold of 20% in the original study, the sensitivity and specificity were 72% and 81%, respectively. The ARC predictor is able to accurately predict ARC in critically ill COVID-19 patients. These results support the potential of the ARC predictor to optimize renally cleared drug dosages in this specific ICU population. Investigation of dosing regimen improvement was not included in this study and remains a challenge for future studies.

Effect of Ursodeoxycholic Acid on the Biodistribution and Excretion of Technetium-99m Radiopharmaceuticals in Rat: A Potential Image Quality Enhancer.

PURPOSE: This study aimed to investigate the effect of ursodeoxycholic acid (UDCA) on the biodistribution and excretion of technetium-99m (Tc-99m)-labeled radiopharmaceuticals. MATERIALS AND METHODS: Tc-99m hydroxy-methylene-diphosphonate (HDP), Tc-99m pertechnetate, and Tc-99m dimercaptosuccinic acid (DMSA) were injected via the tail vein of rats. After 30 min, the control group was administered saline, and the UDCA group was given UDCA orally. Scintigraphy images were acquired after 30 min and 1, 2, 3, and 4 h. Radioactivity and rate of change were compared. Tc-99m mercaptoacetyltriglycine (MAG3) imaging was also performed. RESULTS: In image analysis of Tc-99m HDP, radioactivity of the buttock was lower in the UDCA group at 4 h. Rates of change in the buttock were significantly different at 3 h-30 min and 4 h-30 min, and buttock radioactivity in the UDCA group had decreased more. In analysis of Tc-99m pertechnetate, radioactivity of the buttock was higher in the control group. Rates of change in the thyroid gland and buttock were different at 1 h-30 min, 3 h-30 min, and 4 h-30 min, with radioactivity in the UDCA group decreasing more. In the analysis of Tc-99m DMSA, while the radioactivity of the kidneys in the control group showed little decrease at 1 h-30 min, that in the UDCA group increased. In the analysis of Tc-99m MAG3 images, radioactivity and radioactivity/total body radioactivity (TBA) values for the kidneys were higher in the UDCA group at 2 min. At 5 and 10 min, radioactivity/TBA values for soft tissue in the UDCA group were lower than those in the control group. CONCLUSION: This study demonstrated that administration of UDCA increases renal excretion and soft tissue clearance of radiopharmaceuticals. This investigation could contribute to the broadening of applications of UDCA.

In Vitro and In Vivo Inhibition of MATE1 by Tyrosine Kinase Inhibitors.

The membrane transport of many cationic prescription drugs depends on facilitated transport by organic cation transporters of which several members, including OCT2 (SLC22A2), are sensitive to inhibition by select tyrosine kinase inhibitors (TKIs). We hypothesized that TKIs may differentially interact with the renal transporter MATE1 (SLC47A1) and influence the elimination and toxicity of the MATE1 substrate oxaliplatin. Interactions with FDA-approved TKIs were evaluated in transfected HEK293 cells, and in vivo pharmacokinetic studies were performed in wild-type, MATE1-deficient, and OCT2/MATE1-deficient mice. Of 57 TKIs evaluated, 37 potently inhibited MATE1 function by >80% through a non-competitive, reversible, substrate-independent mechanism. The urinary excretion of oxaliplatin was reduced by about 2-fold in mice with a deficiency of MATE1 or both OCT2 and MATE1 (p < 0.05), without impacting markers of acute renal injury. In addition, genetic or pharmacological inhibition of MATE1 did not significantly alter plasma levels of oxaliplatin, suggesting that MATE1 inhibitors are unlikely to influence the safety or drug-drug interaction liability of oxaliplatin-based chemotherapy.

Development of a Virtual Chinese Pediatric Population Physiological Model Targeting Specific Metabolism and Kidney Elimination Pathways.

Background: Physiologically based pharmacokinetic (PBPK) modeling and simulating may be a powerful tool in predicting drug behaviors in specific populations. It is a mathematical model that relates the pharmacokinetic (PK) profile of a compound with human anatomical characteristics, physiological characteristics, and biochemical parameters. Predictions using PBPK models offer a promising way to guide drug development and can be used to optimize clinical dosing regimens. However, PK data of new drugs in the pediatric population are too limited to guide clinical therapy, which may lead to frequent adverse events or insufficient efficacy for pediatric patients, particularly in neonates and infants. Objective: The objective of this study was to establish a virtual Chinese pediatric population based on the physiological parameters of Chinese children that could be utilized in PBPK models. Methods: A Chinese pediatric PBPK model was developed in Simcyp Simulator by collecting published Chinese pediatric physiological and anthropometric data to use as system parameters. This pediatric population model was then evaluated in the Chinese pediatric population by predicting the pharmacokinetic characteristics of four probe drugs: theophylline (major CYP1A2 substrate), fentanyl (major CYP3A4 substrate), vancomycin, and ceftazidime (renal-eliminated). Results: The predicted maximum concentration (Cmax), area under the curve of concentration-time (AUC), and clearance (CL) for theophylline (CYP1A2 metabolism pathway) and fentanyl (CYP3A4 metabolism pathway) were within two folds of the observed data. For drugs mainly eliminated by renal clearance (vancomycin and ceftazidime) in the Chinese pediatric population, the ratio of prediction to observation for major PK parameters was within a 2-fold error range. Conclusion: The model is a supplement to the previous Chinese population PBPK model. We anticipate the model to be a better representative of the pediatric Chinese population for drugs PK, offering greater clinical precision for medication given to the pediatric population, ultimately advancing clinical development of pediatric drugs. We can refine this model further by collecting more physiological parameters of Chinese children.

Pharmacokinetic and pharmacodynamic considerations in antimicrobial therapy for sepsis.

Introduction: Antimicrobial dose optimization for the treatment of sepsis remains challenging because of dynamic pharmacokinetic alterations and physiological/pathological responses of the host. Subtherapeutic plasma levels of antimicrobials are commonly observed in patients with sepsis, which potentially leads to both treatment failure and emergence of antimicrobial resistance. The knowledge of antimicrobial pharmacokinetics and pharmacodynamics is helpful in order to tailor antimicrobial dosing strategies.Areas covered: This narrative review summarizes pharmacokinetic alterations of antimicrobial agents and provides useful information on antimicrobial dose optimization. Literature was searched using PubMed database, focusing on pharmacokinetics and pharmacodynamics of antibacterial and antifungal agents in sepsis.Expert opinion: In patients with sepsis, increased volume of distribution and variable changes in renal clearance are the two major factors for antimicrobial pharmacokinetic alterations. Traditional 'one-dose-fits-all' dosing strategy is not suitable for patients with sepsis and hence individualized antimicrobial dosing adjustment is preferable. In general, the initial dose of hydrophilic antimicrobials such as ß-lactams, aminoglycosides, and vancomycin should be given at a high dose regardless of renal function. Improved methods of drug administration (e.g. extended/continuous infusion of ß-lactams) help to increase the chance of pharmacodynamic target attainment. The use of therapeutic drug monitoring should be considered where available.

Updates in Diagnosis and Management of Preeclampsia in Women with CKD.

It is estimated that women with CKD are ten times more likely to develop preeclampsia than women without CKD, with preeclampsia affecting up to 40% of pregnancies in women with CKD. However, the shared phenotype of hypertension, proteinuria, and impaired excretory kidney function complicates the diagnosis of superimposed preeclampsia in women with CKD who have hypertension and/or proteinuria that predates pregnancy. This article outlines the diagnoses of preeclampsia and superimposed preeclampsia. It discusses the pathogenesis of preeclampsia, including abnormal placentation and angiogenic dysfunction. The clinical use of angiogenic markers as diagnostic adjuncts for women with suspected preeclampsia is described, and the limited data on the use of these markers in women with CKD are presented. The role of kidney biopsy in pregnancy is examined. The management of preeclampsia is outlined, including important advances and controversies in aspirin prophylaxis, BP treatment targets, and the timing of delivery.

Evaluation of renal function equations to predict amikacin clearance.

Objective: To evaluate the predictive performance of eight renal function equations to describe amikacin elimination in a large standard population with a wide range of age. Methods: Retrospective study of adult hospitalized patients treated with amikacin and monitored in the clinical pharmacokinetics laboratory of a pharmacy service. Renal function was calculated as Cockcroft-Gault with total, adjusted and ideal body weight, MDRD-4, CKD-EPI, rLM, BIS1, and FAS. One compartment model with first-order elimination, including interindividual variability on clearance and volume of distribution and combined residual error model was selected as a base structural model. A pharmaco-statistical analysis was performed following a non-linear mixed effects modeling approach (NONMEM 7.3 software). Results: 198 patients (61 years [18-93]) and 566 measured amikacin plasma concentrations were included. All the estimated glomerular filtration rate and creatinine clearance equations evaluated described properly the data. The linear relationship between clearance and glomerular filtration rate based on rLM showed a statistically significant improvement in the fit of the data. rLM must be evaluated carefully in renal failure for amikacin dose adjustment. Conclusions: Revised Lund-Malmö (rLM) and CKD-EPI showed the superior predictive performance of amikacin drug elimination comparing to all the alternative metrics evaluated.

Comparison of Renal Function Estimation Formulae for Dosing Direct Oral Anticoagulants in Patients with Atrial Fibrillation.

The Cockcroft-Gault (CG) formula is recommended to guide clinicians in the choice of the appropriate dosage for direct oral anticoagulants (DOACs). However, the performance of the CG formula varies depending on the patient's age, weight, and degree of renal function. We aimed to compare the validity of the CG formula with that of Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) formulae for dosing DOACs. A total of 6268 consecutive patients on anticoagulants for atrial fibrillation (AF) were retrospectively investigated. Among underweight and elderly patients, the CG formula underestimated renal function compared with the non-CG formulae. However, the concordant rate of drug indications between the CG and the non-CG formulae was approximately 94%. On-label uses under the three formulae were associated with a lower risk of major bleeding (but not thromboembolism) compared to warfarin. Although we found differences in estimating renal function and the proportions of drug indications between the CG and non-CG formulae, the risks of thromboembolism and major bleeding were similar to those with warfarin regardless of which formula was used.