Drug absorption, distribution, metabolism and excretion considerations in critically ill adults

Roberts, Derek J.; Hall, Richard

doi:10.1517/17425255.2013.799137

Cited by 79 publications

(81 citation statements)

References 141 publications

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“…As regards the pharmacokinetic parameters, the maximum elimination rate ( V max ) of voriconazole obtained in our patients, despite having a wide variability, was lower than reported in other groups of non‐critically ill patients . The different levels of liver involvement in the seriously ill patient and the subsequent reduction in the metabolic activity of different cytochromes could partly explain this phenomenon, as well as an elevated risk of overdosing that these patients have. In fact, the volume of distribution in the peripheral compartment ( V p ) value obtained was also higher than the value observed in previous studies, which suggest an important drug accumulation in these patients.…”

Section: Discussioncontrasting

confidence: 61%

Impact of voriconazole plasma concentrations on treatment response in critically ill patients

et al. 2019

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Summary What is known and objective Several authors have demonstrated the relationship between voriconazole concentrations and the risk of therapeutic failure and adverse events However, the information about voriconazole concentrations in the critically ill patient is scarce. The aim of this study was to analyse the plasma concentrations and pharmacokinetic behaviour of voriconazole in critically ill patients and their association with the treatment response and development of toxicity. Methods A prospective, observational study was conducted. Patients admitted to an intensive care unit and on treatment with intravenous voriconazole were included. Plasma concentrations were measured between days 4 and 7 from the start of the treatment. The pharmacokinetic analysis was performed using the NONMEM® software. A regression model was used to evaluate the variables associated with the values outside the therapeutic range, as well as the relationship between the plasma concentrations and the treatment response and the development of hepatotoxicity. Results and discussion A total of 33 patients were included. Plasma concentrations outside the therapeutic range (1‐5.5 mg/L) were observed in 15 patients, being above the established range in 9 (27.3%) cases, and below it in 6 (18.2%) cases. The presence of a bilirubin value of >1.5 mg/dL and a C‐reactive protein >100 mg/dL was associated with supra‐therapeutic concentrations. Voriconazole concentrations greater than 5.5 mg/dL were associated with the development of hepatotoxicity. What is new and conclusions There is a wide variation in voriconazole concentrations in critically ill patients, being associated with a high frequency of adverse events. Close monitoring of these values is required in order to decrease the risk of therapeutic failure and toxicity.

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Section: Discussioncontrasting

confidence: 61%

Impact of voriconazole plasma concentrations on treatment response in critically ill patients

et al. 2019

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“…With a protein binding of 54%, a mean decline of about 20% in albumin levels between Day-0 and Day-4 observed in this study is unlikely to have a major effect on favipiravir distribution or elimination. Lastly, liver failure could impact favipiravir concentrations [16,17] but this should rather favour drug accumulation than accelerate elimination. Of note, no significant correlation was found between biochemical and haematological parameters and drugs concentrations but the number of observations available was limited ( S2 Fig ).…”

Section: Discussionmentioning

confidence: 99%

Favipiravir pharmacokinetics in Ebola-Infected patients of the JIKI trial reveals concentrations lower than targeted

Nguyen¹,

Guedj²,

Anglaret³

et al. 2017

PLoS Negl Trop Dis

167

146

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BackgroundIn 2014–2015, we assessed favipiravir tolerance and efficacy in patients with Ebola virus (EBOV) disease (EVD) in Guinea (JIKI trial). Because the drug had never been used before for this indication and that high concentrations of the drugs were needed to achieve antiviral efficacy against EBOV, a pharmacokinetic model had been used to propose relevant dosing regimen. Here we report the favipiravir plasma concentrations that were achieved in participants in the JIKI trial and put them in perspective with the model-based targeted concentrations.Methods and findingsPre-dose drug concentrations were collected at Day-2 and Day-4 of treatment in 66 patients of the JIKI trial and compared to those predicted by the model taking into account patient’s individual characteristics. At Day-2, the observed concentrations were slightly lower than the model predictions adjusted for patient’s characteristics (median value of 46.1 versus 54.3 μg/mL for observed and predicted concentrations, respectively, p = 0.012). However, the concentrations dropped at Day-4, which was not anticipated by the model (median values of 25.9 and 64.4 μg/mL for observed and predicted concentrations, respectively, p<10−6). There was no significant relationship between favipiravir concentrations and EBOV viral kinetics or mortality.ConclusionsFavipiravir plasma concentrations in the JIKI trial failed to achieve the target exposure defined before the trial. Furthermore, the drug concentration experienced an unanticipated drop between Day-2 and Day-4. The origin of this drop could be due to severe sepsis conditions and/or to intrinsic properties of favipiravir metabolism. Dose-ranging studies should be performed in healthy volunteers to assess the concentrations and the tolerance that could be achieved with high doses.Trial registrationClinicalTrials.gov NCT02329054

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“…In addition, the gastrointestinal resorption is severely impaired in critically ill patients, 28 which might have resulted in an erratic absorption of the drug. There might also be poor absorption after dissolution in water due to the poor solubility of PER, which best dissolves in mild acidotic fluids.…”

Section: Discussionmentioning

confidence: 99%

Perampanel in patients with refractory and super‐refractory status epilepticus in a neurological intensive care unit: A single‐center audit of 30 patients

et al. 2018

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In refractory status epilepticus (SE), γ-aminobutyric acidergic drugs become less effective and glutamate plays a major role in seizure perpetuation. Data on the efficacy of perampanel (PER) in treatment of refractory SE in humans are limited. Here, we present a single-center case series of patients with refractory SE who received PER orally in an intensive care unit. We retrospectively analyzed treatment response, outcome, and adverse effects of all patients with refractory SE in our Neurological Intensive Care Unit who received add-on PER between September 2012 and February 2018. Thirty patients with refractory SE (median = 72 years, range = 18-91, 77% women) were included. In 14 patients (47%), a high-dose approach was used, with a median initial dose of 24 mg (range = 16-32). In five patients (17%), SE could be terminated after PER administration (median dose = 6 mg, range = 6-20 mg, 2/5 patients in high-dose group). Clinical response was observed after a median of 24 hours (range = 8-48 hours), whereas electroencephalogram resolved after a median of 60 hours (range = 12-72 hours). Time to treatment response tended to be shorter in patients receiving high-dose PER (median clinical response = 16 hours vs 18 hours; electroencephalographic response = 24 hours vs 72 hours), but groups were too small for statistical analysis. Continuous cardiorespiratory monitoring showed no changes in cardiorespiratory function after "standard" and "high-dose" treatment. Elevated liver enzymes without clinical symptoms were observed after a median of 6 days in seven of 30 patients (23%; 57% high dose vs 43% standard dose), of whom six also received treatment with phenytoin (PHT). Outcome was unfavorable (death, persistent vegetative state) in 13 patients (43%; 39% high dose vs 61% standard dose), and good recovery (no significant disability, moderate disability) was achieved in nine patients (56% high dose vs 44% standard dose). Oral PER in loading doses up to 32 mg were well tolerated but could terminate SE only in a few patients (5/30; 17%). Long duration of SE, route of administration, and severe underlying brain dysfunction might be responsible for the modest result. An intravenous formulation is highly desired to explore the full clinical utility in the treatment of refractory SE.

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Drug absorption, distribution, metabolism and excretion considerations in critically ill adults

Cited by 79 publications

References 141 publications

Impact of voriconazole plasma concentrations on treatment response in critically ill patients

Impact of voriconazole plasma concentrations on treatment response in critically ill patients

Favipiravir pharmacokinetics in Ebola-Infected patients of the JIKI trial reveals concentrations lower than targeted

Perampanel in patients with refractory and super‐refractory status epilepticus in a neurological intensive care unit: A single‐center audit of 30 patients

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