Plasma and peritoneal fluid population pharmacokinetics of micafungin in post-surgical patients with severe peritonitis

Grau, Santiago; Luque, S.; Campillo, Nuria E.; Samsó, E.; Rodriguez, U Garcia‐Dubus; García-Bernedo, Carlos A; Salas, E.; Sharma, Raman; Hope, William; Roberts, Jason A.

doi:10.1093/jac/dkv173

Cited by 66 publications

(55 citation statements)

References 30 publications

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“…However, anidu- a Specimens were from patients sampled for Ͻ24 h. C max , anidulafungin peak concentration; T max , time to C max ; AUC 0 -n , area under the concentration-time curve from the start of the anidulafungin infusion to the last sampling; sampling period, time from the first to the last sampling; PR, penetration ratio, specifically, AUC 0 -n ascites fluid /AUC 0 -n plasma for ascites fluid or AUC 0 -n pleural effusion /AUC 0 -n plasma for pleural effusion. lafungin levels in thoracic empyema specimens and peritoneal concentrations of micafungin during peritonitis were ϳ1 g/ml, resembling anidulafungin levels that we have measured in uninflamed body fluids (10,11). Micafungin achieved mean concentrations of 0.7 and 1.0 g/ml in pleural effusion and in ascites fluid, respectively (12)(13)(14).…”

supporting

confidence: 62%

Anidulafungin Pharmacokinetics in Ascites Fluid and Pleural Effusion of Critically Ill Patients

Welte

Eller

Lorenz

et al. 2018

Antimicrob Agents Chemother

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Anidulafungin concentrations were quantified with high-pressure liquid chromatography (HPLC) and UV detection of the ascites fluid and pleural effusion of 10 adult critically ill patients. Samples were collected from ascites fluid and from pleural drains or during paracentesis and thoracentesis, respectively. Anidulafungin levels in ascites fluid (0.12 to 0.99 μg/ml) and in pleural effusion (0.32 to 2.02 μg/ml) were below the simultaneous levels in plasma (1.04 to 7.70 and 2.48 to 13.36 μg/ml, respectively) and below the MIC values for several pathogenic strains.

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supporting

confidence: 62%

Anidulafungin Pharmacokinetics in Ascites Fluid and Pleural Effusion of Critically Ill Patients

Welte

Eller

Lorenz

et al. 2018

Antimicrob Agents Chemother

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“…Inter-individual variability on CL was 40% CV in our cohort and therefore higher than observed in healthy volunteers [ 24 ] or ICU patients on CVVH (17–20% CV) [ 26 ] but similar to ICU patients with sepsis and mechanical ventilation (34%) [ 29 ]. Volume of distribution was higher than in healthy volunteers (13.3 L for a healthy 70-kg patient) [ 24 ] and the central V was higher than in ICU with severe peritonitis, sepsis or burn injuries [ 27 – 29 ] but very similar to ICU patients on CVVH (22.5 L for a 70-kg patient) [ 26 ]. IIV on V 1 was 73% CV in our cohort and thereby two- to ten-fold higher compared with other studies (8–38% CV) [ 24 , 26 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetic Model and Pharmacokinetic Target Attainment of Micafungin in Intensive Care Unit Patients

et al. 2017

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ObjectiveTo study the pharmacokinetics of micafungin in intensive care patients and assess pharmacokinetic (PK) target attainment for various dosing strategies.MethodsMicafungin PK data from 20 intensive care unit patients were available. A population-PK model was developed. Various dosing regimens were simulated: licensed regimens (I) 100 mg daily; (II) 100 mg daily with 200 mg from day 5; and adapted regimens 200 mg on day 1 followed by (III) 100 mg daily; (IV) 150 mg daily; and (V) 200 mg daily. Target attainment based on a clinical PK target for Candida as well as non-Candida parapsilosis infections was assessed for relevant minimum inhibitory concentrations [MICs] (Clinical and Laboratory Standards Institute). Parameter uncertainty was taken into account in simulations.ResultsA two-compartment model best fitted the data. Clearance was 1.10 (root square error 8%) L/h and V 1 and V 2 were 17.6 (root square error 14%) and 3.63 (root square error 8%) L, respectively. Median area under the concentration–time curve over 24 h (interquartile range) on day 14 for regimens I–V were 91 (67–122), 183 (135–244), 91 (67–122), 137 (101–183) and 183 (135–244) mg h/L, respectively, for a typical patient of 70 kg. For the MIC/area under the concentration–time curve >3000 target (all Candida spp.), PK target attainment was >91% on day 14 (MIC 0.016 mg/L epidemiological cut-off) for all of the dosing regimens but decreased to (I) 44%, (II) 91%, (III) 44%, (IV) 78% and (V) 91% for MIC 0.032 mg/L. For the MIC/area under the concentration–time curve >5000 target (non-C. parapsilosis spp.), PK target attainment varied between 62 and 96% on day 14 for MIC 0.016.ConclusionsThe licensed micafungin maintenance dose results in adequate exposure based on our simulations with a clinical PK target for Candida infections but only 62% of patients reach the target for non-C. parapsilosis. In the case of pathogens with an attenuated micafungin MIC, patients may benefit from dose escalation to 200 mg daily. This encourages future study.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-017-0509-5) contains supplementary material, which is available to authorized users.

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“…Information describing the PKs of antifungals in critically ill patients is limited, especially for echinocandins, which is of concern, given that it has been widely described how critical illness may significantly alter the PKs of many agents and compromise their efficacy (12,27,28). A prospective, multicenter study of the PKs of different antifungals that enrolled patients from 68 intensive care units across Europe reported a considerable interindividual variability in the PKs of caspofungin and anidulafungin, a Data are presented as the mean Ϯ SD for burn patients only, intra-abdominal infection patients only, and all patients combined and as the coefficient of variation and median for all patients.…”

Section: Discussionmentioning

confidence: 99%

Comparative Population Plasma and Tissue Pharmacokinetics of Micafungin in Critically Ill Patients with Severe Burn Injuries and Patients with Complicated Intra-Abdominal Infection

Garcı́a-de-Lorenzo

Luque

Grau

et al. 2016

Antimicrob Agents Chemother

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g Severely burned patients have altered drug pharmacokinetics (PKs), but it is unclear how different they are from those in other critically ill patient groups. The aim of the present study was to compare the population pharmacokinetics of micafungin in the plasma and burn eschar of severely burned patients with those of micafungin in the plasma and peritoneal fluid of postsurgical critically ill patients with intra-abdominal infection. Fifteen burn patients were compared with 10 patients with intra-abdominal infection; all patients were treated with 100 to 150 mg/day of micafungin. Micafungin concentrations in serial blood, peritoneal fluid, and burn tissue samples were determined and were subjected to a population pharmacokinetic analysis. The probability of target attainment was calculated using area under the concentration-time curve from 0 to 24 h/MIC cutoffs of 285 for Candida parapsilosis and 3,000 for non-parapsilosis Candida spp. by Monte Carlo simulations. Twenty-five patients (18 males; median age, 50 years; age range, 38 to 67 years; median total body surface area burned, 50%; range of total body surface area burned, 35 to 65%) were included. A three-compartment model described the data, and only the rate constant for the drug distribution from the tissue fluid to the central compartment was statistically significantly different between the burn and intra-abdominal infection patients (0.47 ؎ 0.47 versus 0.15 ؎ 0.06 h ؊1 , respectively; P < 0.05). Most patients would achieve plasma PK/pharmacodynamic (PD) targets of 90% for non-parapsilosis Candida spp. and C. parapsilosis with MICs of 0.008 and 0.064 mg/liter, respectively, for doses of 100 mg daily and 150 mg daily. The PKs of micafungin were not significantly different between burn patients and intra-abdominal infection patients. After the first dose, micafungin at 100 mg/day achieved the PK/PD targets in plasma for MIC values of <0.008 mg/liter and <0.064 mg/liter for non-parapsilosis Candida spp. and Candida parapsilosis species, respectively.

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Plasma and peritoneal fluid population pharmacokinetics of micafungin in post-surgical patients with severe peritonitis

Abstract: After the first dose, micafungin at 100 mg/day achieves pharmacokinetic/pharmacodynamic targets in plasma for Candida spp. and C. parapsilosis MICs of 0.008-0.016 and 0.125-0.25 mg/L, respectively.

Cited by 66 publications

References 30 publications

Anidulafungin Pharmacokinetics in Ascites Fluid and Pleural Effusion of Critically Ill Patients

Anidulafungin Pharmacokinetics in Ascites Fluid and Pleural Effusion of Critically Ill Patients

Population Pharmacokinetic Model and Pharmacokinetic Target Attainment of Micafungin in Intensive Care Unit Patients

Comparative Population Plasma and Tissue Pharmacokinetics of Micafungin in Critically Ill Patients with Severe Burn Injuries and Patients with Complicated Intra-Abdominal Infection

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