Search

Background: Fexofenadine is a recommended in vivo probe drug for phenotyping P-glycoprotein (P-gp) and organic anion transporting polypeptide (OATP) 1B1/3 transporter activities. This study evaluated a limited sampling strategy using a population pharmacokinetic approach to estimate plasma fexofenadine exposure as an index of P-gp and OATP activities., Methods: In a previous study, a single oral dose of fexofenadine (120 mg) was administered alone or in combination with grapefruit juice, Panax ginseng , or Echinacea purpurea to healthy adult participants. Serial plasma samples were collected up to 72 hours after administration and fexofenadine concentrations were measured. A population pharmacokinetic model was developed using nonlinear mixed-effects modeling. Limited sampling models (LSMs) using single and 2-timepoint fexofenadine concentrations were compared with full profiles from intense sampling using empirical Bayesian post hoc estimations of systemic exposure derived from the population pharmacokinetic model. Predefined criteria for LSM selection and validation included a coefficient of determination (R 2 ) ≥ 0.90, relative percent mean prediction error ≥ -5 to ≤5%, relative percent mean absolute error ≤ 10%, and relative percent root mean square error ≤ 15%., Results: Fexofenadine concentrations (n = 1520) were well described using a 2-compartment model. Grapefruit juice decreased the relative oral bioavailability of fexofenadine by 25%, whereas P. ginseng and E. purpurea had no effect. All the evaluated single timepoint fexofenadine LSMs showed unacceptable percent mean prediction error, percent mean absolute error, and/or percent root mean square error. Although adding a second time point improved precision, the predefined criteria were not met., Conclusions: Identifying novel fexofenadine LSMs to estimate P-gp and OATP1B1/3 activities in healthy adults for future transporter-mediated drug-drug interaction studies remains elusive., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Critically ill patients undergoing continuous renal replacement therapy (CRRT) have medical conditions requiring extensive pharmacotherapy. Continuous renal replacement therapy impacts drug disposition. Few data exist regarding drug dosing requirements with contemporary CRRT modalities and effluent rates. The practical limitations of pharmacokinetic studies requiring numerous plasma and effluent samples, and lack of generalizability of observations from specific CRRT prescriptions, highlight gaps in bedside assessment of CRRT drug elimination and individualized dosing needs. We employed a porcine model using transdermal fluorescence detection of the glomerular filtration rate fluorescent tracer agent MB-102, with the aim to assess the relationship between systemic exposure of MB-102 and meropenem during CRRT. Animals underwent bilateral nephrectomies and received intravenous bolus doses of MB-102 and meropenem. Once MB-102 equilibrated in the animal, CRRT was initiated. Continuous renal replacement therapy prescriptions comprised four combinations of blood pump (low versus high) and effluent (low versus high) flow rates. Changes in transdermal detected MB-102 clearance occurred immediately with a change in CRRT rates. Blood side meropenem clearance mirrored transdermal MB-102 clearance ( r2 : 0.95-0.97, p value all <0.001). We suggest transdermal MB-102 clearance provides real-time personalized assessment of drug elimination and could optimize prescription of drugs for critically ill patients requiring CRRT., Competing Interests: Disclosure: R.B.D., J.R.J., J.-J.S., I.R.R., and T.E.R. are employees of MediBeacon Inc. The other authors have no conflicts of interest to report., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASAIO.)

Background: Metformin toxicity, a challenging clinical entity, is associated with a mortality of 30%. The role of extracorporeal treatments such as hemodialysis is poorly defined at present. Here, the Extracorporeal Treatments In Poisoning workgroup, comprising international experts representing diverse professions, presents its systematic review and clinical recommendations for extracorporeal treatment in metformin poisoning., Methods: A systematic literature search was performed, data extracted, findings summarized, and structured voting statements developed. A two-round modified Delphi method was used to achieve consensus on voting statements and RAND/UCLA Appropriateness Method to quantify disagreement. Anonymized votes and opinions were compiled and discussed. A second vote determined the final recommendations., Results: One hundred seventy-five articles were identified, including 63 deaths: one observational study, 160 case reports or series, 11 studies of descriptive cohorts, and three pharmacokinetic studies in end-stage renal disease, yielding a very low quality of evidence for all recommendations. The workgroup concluded that metformin is moderately dialyzable (level of evidence C) and made the following recommendations: extracorporeal treatment is recommended in severe metformin poisoning (1D). Indications for extracorporeal treatment include lactate concentration greater than 20 mmol/L (1D), pH less than or equal to 7.0 (1D), shock (1D), failure of standard supportive measures (1D), and decreased level of consciousness (2D). Extracorporeal treatment should be continued until the lactate concentration is less than 3 mmol/L (1D) and pH greater than 7.35 (1D), at which time close monitoring is warranted to determine the need for additional courses of extracorporeal treatment. Intermittent hemodialysis is preferred initially (1D), but continuous renal replacement therapies may be considered if hemodialysis is unavailable (2D). Repeat extracorporeal treatment sessions may use hemodialysis (1D) or continuous renal replacement therapy (1D)., Conclusion: Metformin poisoning with lactic acidosis appears to be amenable to extracorporeal treatments. Despite clinical evidence comprised mostly of case reports and suboptimal toxicokinetic data, the workgroup recommended extracorporeal removal in the case of severe metformin poisoning.

Objective: Methanol poisoning can induce death and disability. Treatment includes the administration of antidotes (ethanol or fomepizole and folic/folinic acid) and consideration of extracorporeal treatment for correction of acidemia and/or enhanced elimination. The Extracorporeal Treatments in Poisoning workgroup aimed to develop evidence-based consensus recommendations for extracorporeal treatment in methanol poisoning., Design and Methods: Utilizing predetermined methods, we conducted a systematic review of the literature. Two hundred seventy-two relevant publications were identified but publication and selection biases were noted. Data on clinical outcomes and dialyzability were collated and a two-round modified Delphi process was used to reach a consensus., Results: Recommended indications for extracorporeal treatment: Severe methanol poisoning including any of the following being attributed to methanol: coma, seizures, new vision deficits, metabolic acidosis with blood pH ≤ 7.15, persistent metabolic acidosis despite adequate supportive measures and antidotes, serum anion gap higher than 24 mmol/L; or, serum methanol concentration 1) greater than 700 mg/L (21.8 mmol/L) in the context of fomepizole therapy, 2) greater than 600 mg/L or 18.7 mmol/L in the context of ethanol treatment, 3) greater than 500 mg/L or 15.6 mmol/L in the absence of an alcohol dehydrogenase blocker; in the absence of a methanol concentration, the osmolal/osmolar gap may be informative; or, in the context of impaired kidney function. Intermittent hemodialysis is the modality of choice and continuous modalities are acceptable alternatives. Extracorporeal treatment can be terminated when the methanol concentration is <200 mg/L or 6.2 mmol/L and a clinical improvement is observed. Extracorporeal Treatments in Poisoning inhibitors and folic/folinic acid should be continued during extracorporeal treatment. General considerations: Antidotes and extracorporeal treatment should be initiated urgently in the context of severe poisoning. The duration of extracorporeal treatment extracorporeal treatment depends on the type of extracorporeal treatment used and the methanol exposure. Indications for extracorporeal treatment are based on risk factors for poor outcomes. The relative importance of individual indications for the triaging of patients for extracorporeal treatment, in the context of an epidemic when need exceeds resources, is unknown. In the absence of severe poisoning but if the methanol concentration is elevated and there is adequate alcohol dehydrogenase blockade, extracorporeal treatment is not immediately required. Systemic anticoagulation should be avoided during extracorporeal treatment because it may increase the development or severity of intracerebral hemorrhage., Conclusion: Extracorporeal treatment has a valuable role in the treatment of patients with methanol poisoning. A range of clinical indications for extracorporeal treatment is provided and duration of therapy can be guided through the careful monitoring of biomarkers of exposure and toxicity. In the absence of severe poisoning, the decision to use extracorporeal treatment is determined by balancing the cost and complications of extracorporeal treatment to that of fomepizole or ethanol. Given regional differences in cost and availability of fomepizole and extracorporeal treatment, these decisions must be made at a local level.

Purpose of Review: Chronic kidney disease is now recognized as an independent risk factor for cardiovascular events, and cardiovascular disease is the major cause of mortality in patients with the disease. Recent studies have attempted to evaluate the utility of biomarkers for assessing cardiovascular risk in patients with chronic kidney disease. This review will summarize these studies and critically assess the utility of cardiovascular risk biomarkers for clinical practice., Recent Findings: Traditional cardiovascular risk factors including dyslipidemia, hypertension, smoking and diabetes mellitus are highly prevalent in patients with chronic kidney disease. Although prediction models using traditional risk factors underestimate cardiovascular disease risk in these patients, nontraditional biomarkers (i.e. markers of inflammation, endothelial dysfunction, myocardial necrosis, and left ventricular remodeling) have been associated with increased cardiovascular event rates and mortality risk in populations with and without chronic kidney disease. Moreover, a high prevalence of biomarkers that are directly attributable to loss of kidney function is observed in patients with the disease., Summary: Recent studies suggest only limited utility of either single or multiple biomarkers of cardiovascular risk as prognostic tools in patients with and without chronic kidney disease. Novel approaches for biomarker development capturing augmented information through a systems biology approach are urgently needed to improve the usefulness of cardiovascular risk biomarkers.